2022/04/06 更新

写真a

コウ ホウ
黄 鵬
HUANG PENG
所属
中性子医療研究センター 助教
職名
助教

学位

  • 医学博士 ( 2009年3月   岡山大学 )

  • 医学博士 ( 2009年3月   岡山大学 )

研究キーワード

  • 遺伝子治療 免疫治療 腫瘍 再生医療 横紋筋肉腫 エクソソーム 免疫逃避 分子イメージング

研究分野

  • ライフサイエンス / 腫瘍診断、治療学

  • ライフサイエンス / 腫瘍生物学

  • ライフサイエンス / 泌尿器科学

  • ライフサイエンス / 免疫学

  • ライフサイエンス / 放射線科学

学歴

  • 岡山大学   Graduate School of Medicine , Dentistry and Pharmaceutical Sciences  

    2005年4月 - 2009年3月

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    国名: 日本国

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論文

  • Dkk3/REIC Deficiency Impairs Spermiation, Sperm Fibrous Sheath Integrity and the Sperm Motility of Mice 査読

    Ruizhi Xue, Wenfeng Lin, Hirofumi Fujita, Jingkai Sun, Rie Kinoshita, Kazuhiko Ochiai, Junichiro Futami, Masami Watanabe, Hideyo Ohuchi, Masakiyo Sakaguchi, Zhengyan Tang, Peng HUANG, Yasutomo Nasu, Hiromi Kumon

    Genes   2022年1月

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    担当区分:責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3390/genes13020285

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  • p Identification of MICALL2 as a Novel Prognostic Biomarker Correlating with Inflammation and T Cell Exhaustion of Kidney Renal Clear Cell Carcinoma 査読

    Wenfeng Lin, Wenwei Chen, Jisheng Zhong, Hideo Ueki, Abai Xu, Masami Watanabe, Motoo Araki, Chunxiao Liu, Yasutomo Nasu, Peng Huang

    JOURNAL OF CANCER   13 ( 3 )   1214 - 1228   2022年

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    担当区分:最終著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:IVYSPRING INT PUBL  

    Purpose: The interplay of inflammation and immunity affects all stages from tumorigenesis to progression, and even tumor response to therapy. A growing interest has been attracted from the biological function of MICALL2 to its effects on tumor progression. This study was designed to verify whether MICALL2 could be a prognostic biomarker to predict kidney renal clear cell carcinoma (KIRC) progression, inflammation, and immune infiltration within tumor microenvironment (TME). Methods: We firstly analyzed MICALL2 expressions across 33 cancer types from the UCSC Xena database and verified its expression in KIRC through GEPIA platform and GEO datasets. The clinicopathological characteristics were further analyzed based on the median expression. Kaplan-Meier method, univariate and multivariate analyses were applied to compare survival outcomes. ESTIMATE and CIBERSORT algorithms were performed to assess immune infiltration, and a co-expression analysis was conducted to evaluate the correlation between MICALL2 and immunoregulatory genes. Enrichment analysis was finally performed to explore the biological significance of MICALL2. Results: MICALL2 was highly expressed in 16 types of cancers compared with normal tissues. MICALL2 expression increased with advanced clinicopathological parameters and was an independent predictor for poor prognosis in KIRC. Moreover, MICALL2 closely correlated with inflammation-promoting signatures and immune infiltration including T cell exhaustion markers. Consistently, MICALL2 involved in the regulation of signaling pathways associated with tumor immunity, tumor progression, and impaired metabolic activities. Conclusion: MICALL2 can function as a prognostic biomarker mediating inflammation, immune infiltration, and T cell exhaustion within the microenvironment of KIRC.

    DOI: 10.7150/jca.66922

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  • A Novel Prognostic Predictor of Immune Microenvironment and Therapeutic Response in Kidney Renal Clear Cell Carcinoma based on Necroptosis-related Gene Signature. 査読 国際誌

    Wenwei Chen, Wenfeng Lin, Liang Wu, Abai Xu, Chunxiao Liu, Peng Huang

    International journal of medical sciences   19 ( 2 )   377 - 392   2022年

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    担当区分:最終著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Necroptosis, a cell death of caspase-independence, plays a pivotal role in cancer biological regulation. Although necroptosis is closely associated with oncogenesis, cancer metastasis, and immunity, there remains a lack of studies determining the role of necroptosis-related genes (NRGs) in the highly immunogenic cancer type, kidney renal clear cell carcinoma (KIRC). Methods: The information of clinicopathology and transcriptome was extracted from TCGA database. Following the division into the train and test cohorts, a three-NRGs (TLR3, FASLG, ZBP1) risk model was identified in train cohort by LASSO regression. The overall survival (OS) comparison was conducted between different risk groups through Kaplan-Meier analysis, which was further validated in test cohort. The Cox proportional hazards regression model was introduced to assess its impact of clinicopathological factors and risk score on survival. ESTIMATE and CIBERSORT algorithms were introduced to evaluate immune microenvironment, while enrichment analysis was conducted to explore the biological significance. Correlation analysis was applied for the correlation assessment between checkpoint gene expression and risk score, between gene expression and therapeutic response. Gene expressions from TCGA were verified by GEO datasets and immunohistochemistry (IHC) analysis. Results: This NRGs-related signature predicted poorer OS in high-risk group, which was also verified in test cohort. Risk score could also independently predict survival outcome of KIRC. Significant changes were also found in immune microenvironment and checkpoint gene expressions between different risk groups, with immune functional enrichment in high-risk group. Interestingly, therapeutic response was correlated with the expressions of NRGs. The expressions of NRGs from TCGA were consistent with those from GEO datasets and IHC analysis. Conclusion: The NRGs-related signature functions as a novel prognostic predictor of immune microenvironment and therapeutic response in KIRC.

    DOI: 10.7150/ijms.69060

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  • EGFR and ERK activation resists flavonoid quercetin-induced anticancer activities in human cervical cancer cells in vitro. 査読 国際誌

    Xin Chen, Pengli Xu, Huijun Zhang, Xiaosan Su, Lihua Guo, Xuhong Zhou, Junliang Wang, Peng Huang, Qingzhi Zhang, Ruifen Sun

    Oncology letters   22 ( 5 )   754 - 754   2021年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    In the present study, due to the complex and numerous targets of Sarcandrae Herb (also known as Zhong Jie Feng), network pharmacology was performed to analyze its therapeutic effect on 2 cervical cancer cell lines, which could assist with the development of novel therapies. The results suggested that the natural flavonoid quercetin (Que), the effective antitumor ingredient in SH, which is widely present in a variety of plants, may depend on the target, EGFR. Previous studies have shown that EGFR serves a crucial role in the occurrence and development of cervical cancer, but its downstream molecules and regulatory mechanisms remain unknown. The anti-cervical cancer cell properties of Que, which are present in ubiquitous plants, were examined in vitro to identify the association between Que and its underlying pathway using MTT assays, flow cytometry, western blot analysis and Transwell assays. It was found that Que reduced cervical cancer cell viability, promoted G2/M phase cell cycle arrest and cell apoptosis, as well as inhibited cell migration and invasion. The Tyr1068 phosphorylation site of EGFR and the corresponding ERK target were also examined and the 2 kinases were markedly activated by Que. Furthermore, the EGFR inhibitor, afatinib and the ERK inhibitor, U0126 blocked the increase of EGFR and ERK phosphorylation, and resulted in a notable enhancement of apoptosis and cell cycle arrest. Therefore, to the best of our knowledge, the current results provided the first evidence that EGFR and ERK activation induced by Que could resist Que-induced anticancer activities. On this basis, the present study determined the role of EGFR and the underlying signaling pathways involved in the anti-cervical cancer malignant behavior induced by Que and identified the negative regulatory association.

    DOI: 10.3892/ol.2021.13015

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  • The Cell Cycle Checkpoint Gene, RAD17 rs1045051, Is Associated with Prostate Cancer Risk. 査読

    Jingkai Sun, Wenfeng Lin, Qixu Wang, Akiko Sakai, Ruizhi Xue, Masami Watanabe, Chunxiao Liu, Takuya Sadahira, Yasutomo Nasu, Abai Xu, Peng Huang

    Acta medica Okayama   75 ( 4 )   415 - 421   2021年8月

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    担当区分:最終著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Human RAD17, as an agonist of checkpoint signaling, plays an essential role in mediating DNA damage. This hospital-based case-control study aimed to explore the association between RAD17 rs1045051, a missense sin-gle nucleotide polymorphism (SNP), and prostate cancer risk. Subjects were 358 prostate cancer patients and 314 cancer-free urology patients undergoing treatment at the Zhujiang Hospital of Southern Medical University in China. RAD17 gene polymorphism rs1045051 was evaluated by the SNaPshot method. Compared with the RAD17 gene polymorphism rs1045051 AA genotype, there was a higher risk of prostate cancer for the CC gen-otype (adjusted odds ratio [AOR] = 1.731, 95% confidence interval [95%CI] = 1.031-2.908, p = 0.038). Compared with the A allele, the C allele was significantly associated with the disease status (AOR = 1.302, 95%CI = 1.037-1.634, p = 0.023). All these findings indicate that in the SNP rs1045051, both the CC genotype and C allele may have a substantial influence on the prostate cancer risk.

    DOI: 10.18926/AMO/62379

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  • The role of Wnt signaling in male reproductive physiology and pathology 査読 国際誌

    Ruizhi Xue, Wenfeng Lin, Jingkai Sun, Masami Watanabe, Abai Xu, Motoo Araki, Yasutomo Nasu, Zhengyan Tang, Peng Huang

    Molecular Human Reproduction   2021年1月

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    担当区分:最終著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Oxford University Press ({OUP})  

    Accumulating evidence has shown that Wnt signaling is deeply involved in male reproductive physiology, and malfunction of the signal path can cause pathological changes in genital organs and sperm cells. These abnormalities are diverse in manifestation and have been constantly found in the knockout models of Wnt studies. Nevertheless, most of the research solely focused on a certain factor in the Wnt pathway, and there are few reports on the overall relation between Wnt signals and male reproductive physiology. In our review, Wnt findings relating to the reproductive system were sought and summarized in terms of Wnt ligands, Wnt receptors, Wnt intracellular signals and Wnt regulators. By sorting out and integrating relevant functions, as well as underlining the controversies among different reports, our review aims to offer an overview of Wnt signaling in male reproductive physiology and pathology for further mechanistic studies.

    DOI: 10.1093/molehr/gaaa085

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  • The role of Wnt signaling in male reproductive physiology and pathology. 査読 国際誌

    Ruizhi Xue, Wenfeng Lin, Jingkai Sun, Masami Watanabe, Abai Xu, Motoo Araki, Yasutomo Nasu, Zhengyan Tang, Peng Huang

    Molecular human reproduction   27 ( 1 )   2021年1月

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    担当区分:最終著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Accumulating evidence has shown that Wnt signaling is deeply involved in male reproductive physiology, and malfunction of the signal path can cause pathological changes in genital organs and sperm cells. These abnormalities are diverse in manifestation and have been constantly found in the knockout models of Wnt studies. Nevertheless, most of the research solely focused on a certain factor in the Wnt pathway, and there are few reports on the overall relation between Wnt signals and male reproductive physiology. In our review, Wnt findings relating to the reproductive system were sought and summarized in terms of Wnt ligands, Wnt receptors, Wnt intracellular signals and Wnt regulators. By sorting out and integrating relevant functions, as well as underlining the controversies among different reports, our review aims to offer an overview of Wnt signaling in male reproductive physiology and pathology for further mechanistic studies.

    DOI: 10.1093/molehr/gaaa085

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  • Exosomes Promote the Transition of Androgen-Dependent Prostate Cancer Cells into Androgen-Independent Manner Through Up-Regulating the Heme Oxygenase-1 査読

    Yiming Zhang, Binshen Chen, Naijin Xu, Peng Xu, Wenfeng Lin, Chunxiao Liu, Peng Huang

    International Journal of Nanomedicine   2021年1月

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    担当区分:最終著者, 責任著者   掲載種別:研究論文(学術雑誌)  

    DOI: 10.2147/IJN.S281710

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  • Dual-Functional PLGA Nanoparticles Co-Loaded with Indocyanine Green and Resiquimod for Prostate Cancer Treatment. 査読 国際誌

    Wenfeng Lin, Chaoming Li, Naijin Xu, Masami Watanabe, Ruizhi Xue, Abai Xu, Motoo Araki, Ruifen Sun, Chunxiao Liu, Yasutomo Nasu, Peng Huang

    International journal of nanomedicine   16   2775 - 2787   2021年

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    担当区分:最終著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Purpose: With the advance of screening techniques, there is a growing number of low-risk or intermediate-risk prostate cancer (PCa) cases, remaining a serious threat to men's health. To obtain better efficacy, a growing interest has been attracted to develop such emerging treatments as immunotherapy and focal therapy. However, few studies offer guidance on whether and how to combine these modalities against PCa. This study was designed to develop dual-functional nanoparticles (NPs) which combined photothermal therapy (PTT) with immunotherapy and determine the anti-tumor efficacy for PCa treatment. Methods: By a double emulsion technique, the drug nanocarrier, poly(lactic-co-glycolic acid) or PLGA, was applied for co-loading of a fluorescent dye, indocyanine green (ICG) and a toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) to synthesize PLGA-ICG-R848 NPs. Next, we determined their characteristic features and evaluated whether they inhibited the cell viability in multiple PCa cell lines. After treatment with PLGA-ICG-R848, the maturation markers of bone marrow-derived dendritic cells (BMDCs) were detected by flow cytometry. By establishing a subcutaneous xenograft model of mouse PCa, we explored both the anti-tumor effect and immune response following the NPs-based laser ablation. Results: With a mean diameter of 157.7 nm, PLGA-ICG-R848 exhibited no cytotoxic effect in PCa cells, but they significantly decreased RM9 cell viability to (3.9±1.0)% after laser irradiation. Moreover, PLGA-ICG-R848 promoted BMDCs maturation with the significantly elevated proportions of CD11c+CD86+ and CD11c+CD80+ cells. Following PLGA-ICG-R848-based laser ablation in vivo, the decreased bioluminescent signals indicated a significant inhibition of PCa growth, while the ratio of splenic natural killer (NK) cells in PLGA-ICG-R848 was (3.96±1.88)% compared with (0.99±0.10)% in PBS group, revealing the enhanced immune response against PCa. Conclusion: The dual-functional PLGA-ICG-R848 NPs under laser irradiation exhibit the anti-tumor efficacy for PCa treatment by combining PTT with immunotherapy.

    DOI: 10.2147/IJN.S301552

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  • Discovery and Validation of Nitroxoline as a Novel STAT3 Inhibitor in Drug-resistant Urothelial Bladder Cancer. 査読 国際誌

    Wenfeng Lin, Jingkai Sun, Takuya Sadahira, Naijin Xu, Koichiro Wada, Chunxiao Liu, Motoo Araki, Abai Xu, Masami Watanabe, Yasutomo Nasu, Peng Huang

    International journal of biological sciences   17 ( 12 )   3255 - 3267   2021年

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    担当区分:最終著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Repeated cycles of first-line chemotherapy drugs such as doxorubicin (DOX) and cisplatin (CIS) trigger frequent chemoresistance in recurrent urothelial bladder cancer (UBC). Nitroxoline (NTX), an antibiotic to treat urinary tract infections, has been recently repurposed for cancer treatment. Here we aimed to investigate whether NTX suppresses drug-resistant UBC and its molecular mechanism. The drug-resistant cell lines T24/DOX and T24/CIS were established by continual exposure of parental cell line T24 to DOX and CIS, respectively. T24/DOX and T24/CIS cells were resistant to DOX and CIS, respectively, but they were sensitive to NTX time- and dose-dependently. Overexpressions of STAT3 and P-glycoprotein (P-gp) were identified in T24/DOX and T24/CIS, which could be reversed by NTX. Western blot revealed that NTX downregulated p-STAT3, c-Myc, Cyclin D1, CDK4, CDK6, Bcl-xL, Mcl-1, and Survivin, which were further confirmed by Stattic, a selective STAT3 inhibitor. In vivo, NTX exhibited the significant anti-tumor effect in T24/DOX and T24/CIS tumor-bearing mice. These results suggested that NTX-induced P-gp reversal, G0/G1 arrest, and apoptosis in drug-resistant UBC were mediated by inhibition of STAT3 signaling. Our findings repurpose NTX as a novel STAT3 inhibitor to induce P-gp reversal, G0/G1 arrest, and apoptosis in drug-resistant UBC.

    DOI: 10.7150/ijbs.63125

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  • Repurposing of posaconazole as a hedgehog/SMO signaling inhibitor for embryonal rhabdomyosarcoma therapy. 査読 国際誌

    Jingkai Sun, Wenfeng Lin, Chaoming Li, Hideo Ueki, Ruizhi Xue, Takuya Sadahira, Hao Hu, Koichiro Wada, Na Li, Chunxiao Liu, Motoo Araki, Abai Xu, Peng Huang

    American journal of cancer research   11 ( 9 )   4528 - 4540   2021年

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    担当区分:最終著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Posaconazole (POS) is a novel antifungal agent, which has been repurposed as an anti-tumor drug for its potential inhibition of Hedgehog signaling pathway. Hedgehog pathway is reported to be abnormally activated in embryonal rhabdomyosarcoma (ERMS), this study aimed to reveal whether POS could inhibit Hedgehog signaling pathway in ERMS. Following POS treatment, XTT viability assay was used to determine the cell proliferation of ERMS cell lines. Protein changes related to Hedgehog signaling, cell cycle and autophagy were detected by Western blot. The cell cycle distribution was analyzed by flow cytometry. Moreover, a subcutaneous tumor mouse model of ERMS was established to assess the anti-tumor effect of POS. POS was found to inhibit tumor progression by inducing G0/G1 arrest and autophagy of RD, RMS-YM, and KYM-1 cells dose-dependently. Western blot demonstrated that POS downregulated the expressions of SMO, Gli1, c-Myc, CDK4, and CDK6, while upregulated the expressions of autophagy-related proteins. Immunofluorescence microscopy revealed a significant increase of LC3B puncta in POS-treated ERMS cells. Furthermore, POS treatment led to a significant inhibition of tumor growth in mice bearing ERMS. Our findings could provide a theoretical basis and have important clinical implications in developing POS as a promising agent against ERMS by targeting Hedgehog pathway.

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  • Reprogramming Prostate Cancer Cells into Induced Pluripotent Stem Cells: a Promising Model of Prostate Cancer Stem Cell Research. 査読 国際誌

    Yiming Zhang, Binshen Chen, Peng Xu, Chunxiao Liu, Peng Huang

    Cellular reprogramming   2020年8月

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    担当区分:最終著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Prostate cancer stem cells (PrCSCs) are responsible for the development of castration-resistant disease and are associated with poor outcomes; however, the origin of PrCSCs is still not known due to the lack of a suitable model. In the current study, the human prostate cancer cell line 22RV1 was used to generate induced pluripotent stem cells (iPSCs) via the exogenous expression of four classic transcription factors (OCT-4, SOX2, KLF4, and C-MYC). The iPSCs were analyzed by phase contrast microscopy, real-time polymerase chain reaction, immunofluorescence, alkaline phosphatase (AP) activity, and examined for karyotype and embryoid body and teratoma formation. The analyses demonstrated that the prostate cancer cells were successfully reprogrammed into iPSCs by characteristic human embryonic stem cell morphology, cell marker expression, AP activity, embryoid body, and pluripotency capability in generating all three embryonic germ layers. These results may provide a convenient and accessible model for studying the origin of PrCSCs and the process by which progenitor cells are transformed into PrCSCs.

    DOI: 10.1089/cell.2020.0032

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  • Tumor suppressor REIC/Dkk-3 and its interacting protein SGTA inhibit glucocorticoid receptor to nuclear transport. 査読 国際誌

    Takehiro Iwata, Takuya Sadahira, Kazuhiko Ochiai, Hideo Ueki, Takanori Sasaki, Peng Haung, Motoo Araki, Toyohiko Watanabe, Yasutomo Nasu, Masami Watanabe

    Experimental and therapeutic medicine   20 ( 2 )   1739 - 1745   2020年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    REIC/Dkk-3 is a tumor suppressor, and its expression is significantly downregulated in a variety of human cancer types. A previous study performed yeast two-hybrid screening and identified the small glutamine-rich tetratricopeptide repeat-containing protein α (SGTA), known as a negative modulator of cytoplasmic androgen receptor (AR) signaling, which is a novel interacting partner of REIC/Dkk-3. The previous study also indicated that the REIC/Dkk-3 protein interferes with the dimerization of SGTA and then upregulates the AR transport and signaling in human prostate cancer PC3 cells. Since the transport of some steroid receptors to nucleus is conducted similarly by dynein motor-dependent way, the current study aimed to investigate the role of SGTA and REIC/Dkk-3 in the transport of other glucocorticoid receptors (GR). In vitro reporter assays for the cytoplasmic GR transport were performed in human prostate cancer PC3 cells and 293T cells. As for the SGTA protein, a suppressive effect on the GR transport to the nucleus was observed in the cells. As for the REIC/Dkk-3 protein, an inhibitory effect was observed for the GR transport in PC3 cells. Under the depleted condition of SGTA by short-hairpin (sh)RNA, the downregulation of GR transport by REIC/Dkk-3 was significantly enhanced compared with the non-depleted condition in PC3 cells, suggesting a compensatory role of REIC/Dkk-3 in the SGTA mediated inhibition of GR transport. The current study therefore demonstrated that SGTA inhibited the cytoplasmic transport of GR in 293T and PC3 cells, and REIC/Dkk-3 also inhibited the cytoplasmic transport of GR in PC3 cells. These results may be used to gain novel insight into the GR transport and signaling in normal and cancer cells.

    DOI: 10.3892/etm.2020.8819

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  • Percutaneous Nephrolithotomy under Local Infiltration Anesthesia in Kneeling Prone Position for a Patient with Spinal Deformity. 査読

    Zhikang Yu, Wenfeng Lin, Abai Xu, Chunxiao Liu, Hulin Li, Peng Huang

    Acta medica Okayama   74 ( 2 )   175 - 178   2020年4月

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    記述言語:英語  

    Urolithiasis, a common condition in patients with spinal deformity, poses a challenge to surgical procedures and anesthetic management. A 51-year-old Chinese male presented with bilateral complex renal calculi. He was also affected by severe kyphosis deformity and spinal stiffness due to ankylosing spondylitis. Dr. Li performed the percutaneous nephrolithotomy under local infiltration anesthesia with the patient in a kneeling prone position, achieving satisfactory stone clearance with no severe complications. We found this protocol safe and effective to manage kidney stones in patients with spinal deformity. Local infiltration anesthesia may benefit patients for whom epidural anesthesia and intubation anesthesia are difficult.

    DOI: 10.18926/AMO/58278

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  • Nitroxoline inhibits bladder cancer progression by reversing EMT process and enhancing anti-tumor immunity. 査読 国際誌

    Naijin Xu, Wenfeng Lin, Jingkai Sun, Takuya Sadahira, Abai Xu, Masami Watanabe, Kai Guo, Motoo Araki, Gonghui Li, Chunxiao Liu, Yasutomo Nasu, Peng Huang

    Journal of Cancer   11 ( 22 )   6633 - 6641   2020年

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    担当区分:最終著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Nitroxoline is considered to be an effective treatment for the urinary tract infections. Recently, it has been found to be effective against several cancers. However, few studies have examined the anti-tumor activity of nitroxoline in bladder cancer. The purpose of the study was to reveal the possible mechanisms how nitroxoline inhibited bladder cancer progression. In vitro assay, we demonstrated that nitroxoline inhibited bladder cancer cell growth and migration in a concentration-related manner. Western blot analysis demonstrated that nitroxoline downregulated the expressions of epithelial mesenchymal transition (EMT)-related proteins. Furthermore, treatment with nitroxoline in the C3H/He mice bladder cancer subcutaneous model resulted in significant inhibition of tumor growth. Moreover, the percentage of myeloid-derived suppressor cells (MDSC) in peripheral blood cells significantly decreased after treatment of nitroxoline. Taken together, our results suggested that nitroxoline may be used as a potential drug for bladder cancer.

    DOI: 10.7150/jca.47025

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  • [Role of outer dense fiber in multiple morphological abnormalities of the sperm flagella in Akap4 gene defect mice]. 査読 国際誌

    Linglong Huang, Peng Huang

    Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences   44 ( 12 )   1367 - 1375   2019年12月

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    担当区分:最終著者, 責任著者   記述言語:中国語  

    OBJECTIVE: To determine the role of outer dense fiber (ODF) in multiple morphological abnormalities of the sperm flagella in Akap4 gene defect mice.
 Methods: Akap4 knock-out (KO) mouse model was established by using gene editing technology. Akap4-KO male mice were identified by genotype. Seven sexually mature male Akap4-KO mice served as an experimental group, and 7 sexually mature wild-type (WT) male mice served as a control group. The changes in body weight and testicular weight were measured. Computer aided sperm analysis (CASA) was used to detect sperm motility. Sperm morphology was detected by modified Periodic Acid-Schif (PAS) staining. The ultra-structure of sperm was observed under the scanning and transmission electron microscope. Sperm flagella associated protein expression and localization were detected by immunofluorescence. Spermatogenesis function of testis was evaluated by HE and PAS staining. Ultra-structure of seminiferous tubules was observed under the transmission electron microscope.
 Results: Akap4-KO mice had no natural fertility. The sperm motility of Akap4-KO male mice was lower than that of WT male mice (8.81% vs 46.02%, P<0.01). In Akap4-KO male mice the percentage of sperm, with shortened tail and coiled tail was 91.18% which was higher than that of WT male mice (P<0.01). There was no statistically significance in the testicular weight, spermatogensis function, and sperm count between the 2 groups (P>0.01). The longitudinal column of fibrous sheath in Akap4-KO male mice was absent, and the residues of transverse rib remained, which was consistent with the immunofluorescence localization of AKAP3 protein. No. 3 and No. 8 ODF in the principal piece were disordered, which was in consistent with ectopic localization of ODF2 protein.
 Conclusion: Multiple morphological abnormalities of the sperm flagella in mice are resulted from disorder of "9+2" microtubules and the abnormally expanded lumen at the proximal of the principal piece via causing dysplasia of the transverse rib due to Akap4 gene defect, and separation of the ODF of No. 3 and No. 8 via loss of longitudinal column.

    DOI: 10.11817/j.issn.1672-7347.2019.190546

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  • Proteomics and single-cell RNA analysis of Akap4-knockout mice model confirm indispensable role of Akap4 in spermatogenesis. 査読 国際誌

    Xiang Fang, Ling-Long Huang, Jian Xu, Cai-Qi Ma, Zhi-Heng Chen, Zhan Zhang, Cai-Hua Liao, Shu-Xin Zheng, Peng Huang, Wen-Ming Xu, Na Li, Ling Sun

    Developmental biology   454 ( 2 )   118 - 127   2019年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Sperm fibrous sheath, a unique cytoskeletal structure, is implicated in various sperm physiological functions, such as sperm maturation, motility and capacitation. AKAP4 has been described to be required for structural and functional integrity of the fibrous sheath. We generated Akap4-knockout mice line using CRISPR-Cas9 system. Cytomorphology and motility of sperm and testes were studied, confirming loss of Akap4 led to abnormal sperm morphology, motility and infertility. The proteomic components of testes were studied and Akap4 was found to be significantly decreased in the Akap4-knockout mice. Testis single-cell RNA sequencing and analysis revealed three genes with significant change in the general cell population, i.e., Akap4, Haspin, and Ccdc38. The single-cell RNA expression profiles also showed that the major difference between Akap4-knockout and wild-type testes existed in the elongating cell cluster, where in the Akap4-knockout testes, a subgroup of elongating cells with marker genes involved in cell adhesion and migration were increased, while a subgroup of elongating cells marked by mitochondrial sheath genes were decreased. Our results revealed the complex and well-coordinated procedures of spermatogenesis, and substantiated Akap4's indispensable roles in the integrity of sperm flagellum and the step-wise maturation of spermatozoa.

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  • The Novel Combination of Nitroxoline and PD-1 Blockade, Exerts a Potent Antitumor Effect in a Mouse Model of Prostate Cancer. 査読 国際誌

    Naijin Xu, Linglong Huang, Xiezhao Li, Masami Watanabe, Chaoming Li, Abai Xu, Chunxiao Liu, Qiang Li, Motoo Araki, Koichiro Wada, Yasutomo Nasu, Peng Huang

    International journal of biological sciences   15 ( 5 )   919 - 928   2019年

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    担当区分:最終著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Programmed cell death protein 1 (PD-1) blockade is a promising therapeutic strategy against prostate cancer. Nitroxoline has been found to have effective anticancer properties in several cancer types. We investigated the efficacy of a combination therapy involving nitroxoline and PD-1 blockade in a prostate cancer mouse model. In our in vitro analysis, we found that nitroxoline inhibited the viability and proliferation of the mouse prostate cancer cell line RM9-Luc-PSA. Additionally, nitroxoline downregulated the expressions of phospho-PI3 kinase, phospho-Akt (Thr308), phospho-Akt (Ser473), phospho-GSK-3β, Bcl-2, and Bcl-xL. Nitroxoline also downregulated programmed death-ligand 1 (PD-L1) expression levels in prostate cancer cell line and tumor tissue. In our murine prostate cancer orthotopic model, nitroxoline plus PD-1 blockade synergistically suppressed tumor growth when compared with nitroxoline or PD-1 blockade alone, leading to reductions in tumor weight, bioluminescence tumor signals, and serum prostate-specific antigen levels. Furthermore, fluorescence-activated cell sorting analysis showed that the combination strategy significantly enhanced antitumor immunity by increasing CD44+CD62L+CD8+ memory T cell numbers and reducing myeloid-derived suppressor cell numbers in peripheral blood. In conclusion, our findings suggest that nitroxoline plus PD-1 blockade may be a promising treatment strategy in patients with prostate cancer.

    DOI: 10.7150/ijbs.32259

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  • Bufalin suppresses the proliferation and metastasis of renal cell carcinoma by inhibiting the PI3K/Akt/mTOR signaling pathway. 査読 国際誌

    Jinlin Xie, Wenfeng Lin, Linglong Huang, Naijin Xu, Abai Xu, Binshen Chen, Masami Watanabe, Chunxiao Liu, Peng Huang

    Oncology letters   16 ( 3 )   3867 - 3873   2018年9月

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    担当区分:最終著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Bufalin, one of the active ingredients of the Chinese drug Chan su, exhibits significant antitumor activity against various cancer types. However, the role of bufalin in renal cell carcinoma (RCC) remains unclear. In the present study, it was demonstrated that bufalin inhibited cell proliferation, blocked the cell cycle in the G2/M phase, and reduced the metastasis of human RCC ACHN cells via the upregulation of p21waf/cip1 and E-cadherin and the downregulation of cyclin dependent kinase 1, cyclin B1, N-cadherin, and hypoxia-inducible factor-1α (HIF-1α). Further mechanistic study revealed that bufalin reduced the expression of phosphorylated (phospho)-Akt and phospho-mammalian target of rapamycin (mTOR). Moreover, HIF-1α expression may be regulated through the inhibition of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mTOR signaling pathway. Thus, the present results suggest that bufalin induces cell cycle arrest and suppresses metastasis; this process may be associated with the PI3K/Akt/mTOR signaling pathway. Accordingly, it is suggested that bufalin is a therapeutic agent for RCC.

    DOI: 10.3892/ol.2018.9111

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  • Programmed death ligand 1 expression in bladder. 査読

    Peng Zhou, Qiongren Wang, Chongshan Wang, Xiezhao L, Wei Du, Chunxiao Liu, Masami Watanabe, Peng Huang, Abai Xu

    Int J Clin Exp Pathol   2018年4月

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    担当区分:責任著者   記述言語:英語  

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  • Induction of cells with prostate cancer stem-like properties from mouse induced pluripotent stem cells via conditioned medium. 査読 国際誌

    Naijin Xu, Xiezhao Li, Masami Watanabe, Hideo Ueki, Hao Hu, Na Li, Motoo Araki, Koichiro Wada, Abai Xu, Chunxiao Liu, Yasutomo Nasu, Peng Huang

    American journal of cancer research   8 ( 8 )   1624 - 1632   2018年

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    担当区分:最終著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cancer stem cells (CSCs) that closely correlated with tumor growth, metastasis, provide a plausible explanation for chemoresistance and cancer relapse. CSCs are usually isolated and enriched from carcinoma cells, which is inconvenient, low-efficient, and even unreliable. Here, we converted mouse induced pluripotent stem cells (miPSCs) into prostate cancer stem-like cells with carcinoma microenvironment following exposure to conditioned medium (CM) derived from RM9, a mouse prostate cancer cell line. These transformed cells, termed as miPS-RM9CM, displayed CSCs properties, including spheroids morphology and expression of both stemness genes and cancer stem cells surface markers, such as Oct3/4, Sox2, Nanog, Klf-4, c-Myc, CD44, and CD133. In addition, in vivo transplantation experiment was performed to confirm the tumorigenicity. Furthermore, we used the model to assess conventional chemotherapeutic agent, docetaxel. The results showed that miPS-RM9CM cells exhibited increased resistance to docetaxel, however, high susceptibility to the cancer cell stemness inhibitor I (BBI-608). Our current study demonstrates that CM from cultured RM9 cells play a crucial role in the determination of cell fate from miPSCs to cancer stem-like cells and provide a potentially valuable system for the study of CSCs.

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  • Glaucocalyxin A induces G2/M cell cycle arrest and apoptosis through the PI3K/Akt pathway in human bladder cancer cells. 査読 国際誌

    Wenfeng Lin, Jinlin Xie, Naijin Xu, Linglong Huang, Abai Xu, Hulin Li, Chaoming Li, Yubo Gao, Masami Watanabe, Chunxiao Liu, Peng Huang

    International journal of biological sciences   14 ( 4 )   418 - 426   2018年

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    担当区分:最終著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Glaucocalyxin A (GLA), a major component isolated from Rabdosia japonica, has been proven to show anti-bacterial and anti-tumor biological characteristics according to previous studies. However, its potential effect on bladder cancer remains unknown. The present research aims to investigate the underlying mechanism in treating bladder cancer in vivo and in vitro. Cell proliferation was analyzed by CCK-8 assay and colony formation. Flow cytometry was used to measure the cell cycle distribution and apoptosis. The expressions of the cell cycle and apoptosis-related proteins were detected by western blotting and immunofluorescence staining. Meanwhile, the in vivo study was performed to evaluate the anti-tumor effect on a UMUC3 subcutaneous tumor of NOD/SCID mice model. GLA suppressed colony-formation ability, triggered G2/M arrest and promoted apoptosis of UMUC3 cells in a dose-dependent manner. Furthermore, western blotting showed that GLA downregulated the expressions of PI3K p85, p-Akt, Bcl-2, CDK1, Cyclin B1 whereas upregulated the levels of PTEN, Bax, Cleaved Caspase-3. In vivo, GLA at a dosage of 20 mg/kg significantly inhibited tumor growth compared with the control group by intraperitoneal injection. These results suggested that GLA-related G2/M arrest and apoptosis in UMUC3 cells were mediated by a suppressed PI3K/Akt signaling pathway, which regulated p21Waf1/Cip1 as well as intrinsic caspase cascade. Collectively, our observations could help to develop new drugs targeting the PI3K/Akt pathway for the treatment of bladder cancer.

    DOI: 10.7150/ijbs.23602

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  • Exogenous DKK-3/REIC inhibits Wnt/β-catenin signaling and cell proliferation in human kidney cancer KPK1. 査読 国際誌

    Jiaqi Xu, Takuya Sadahira, Rie Kinoshita, Shun-Ai Li, Peng Huang, Koichiro Wada, Motoo Araki, Kazuhiko Ochiai, Hirofumi Noguchi, Masakiyo Sakaguchi, Yasutomo Nasu, Masami Watanabe

    Oncology letters   14 ( 5 )   5638 - 5642   2017年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The third member of the Dickkopf family (DKK-3), also known as reduced expression in immortalized cells (REIC), is a tumor suppressor present in a variety of tumor cells. Regarding the regulation of the Wnt/β-catenin signaling pathway, exogenous DKK-1 and DKK-2 are reported to inhibit Wnt signaling by binding the associated effectors. However, whether exogenous DKK-3 inhibits Wnt signaling remains unclear. A recombinant protein of human full-length DKK-3 was used to investigate the exogenous effects of the protein in vitro in KPK1 human renal cell carcinoma cells. It was demonstrated that the expression of phosphorylated (p-)β-catenin (inactive form as the transcriptional factor) was increased in KPK1 cells treated with the exogenous DKK-3 protein. The levels of non-p-β-catenin (activated form of β-catenin) were consistently decreased. It was revealed that the expression of transcription factor (TCF) 1 and c-Myc, the downstream transcription factors of the Wnt/β-catenin signaling pathway, was inhibited following treatment with DKK-3. A cancer cell viability assay confirmed the anti-proliferative effects of exogenous DKK-3 protein, which was consistent with a suppressed Wnt/β-catenin signaling cascade. In addition, as low-density lipoprotein receptor-related protein 6 (LRP6) is a receptor of DKK-1 and DKK-2 and their interaction on the cell surface inhibits Wnt/β-catenin signaling, it was examined whether the exogenous DKK-3 protein affects LRP6-mediated Wnt/β-catenin signaling. The LRP6 gene was silenced and the effects of DKK-3 on the time course of the upregulation of p-β-catenin expression were subsequently analyzed. Notably, LRP6 depletion elevated the base level of p-β-catenin; however, there was no significant effect on its upregulation course or expression pattern. These findings indicate that exogenous DKK-3 upregulates p-β-catenin and inhibits Wnt/β-catenin signaling in an LRP6-independent manner. Therefore, exogenous DKK-3 protein may inhibit the proliferation of KPK1 cells via inactivating Wnt/β-catenin signaling.

    DOI: 10.3892/ol.2017.6833

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  • Synergistic effects of the immune checkpoint inhibitor CTLA-4 combined with the growth inhibitor lycorine in a mouse model of renal cell carcinoma. 査読 国際誌

    Xiezhao Li, Peng Xu, Chongshan Wang, Naijin Xu, Abai Xu, Yawen Xu, Takuya Sadahira, Motoo Araki, Koichiro Wada, Eiji Matsuura, Masami Watanabe, Junxia Zheng, Pinghua Sun, Peng Huang, Yasutomo Nasu, Chunxiao Liu

    Oncotarget   8 ( 13 )   21177 - 21186   2017年3月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Renal cell carcinoma (RCC) management has undergone a major transformation over the past decade; immune checkpoint inhibitors are currently undergoing clinical trials and show promising results. However, the effectiveness of immune checkpoint inhibitors in patients with metastatic RCC (mRCC) is still limited. Lycorine, an alkaloid extracted from plants of the Amaryllidaceae family, is touted as a potential anti-cancer drug because of its demonstrative growth inhibition capacity (induction of cell cycle arrest and inhibition of vasculogenic mimicry formation). Moreover, T cell checkpoint blockade therapy with antibodies targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4) has improved outcomes in cancer patients. However, the anti-tumor efficacy of combined lycorine and anti-CTLA-4 therapy remains unknown. Thus, we investigated a combination therapy of lycorine hydrochloride and anti-CTLA-4 using a murine RCC model. As a means of in vitro confirmation, we found that lycorine hydrochloride inhibited the viability of various RCC cell lines. Furthermore, luciferase-expressing Renca cells were implanted in the left kidney and the lung of BALB/c mice to develop a RCC metastatic mouse model. Lycorine hydrochloride and anti-CTLA-4 synergistically decreased tumor weight, lung metastasis, and luciferin-staining in tumor images. Importantly, the observed anti-tumor effects of this combination were dependent on significantly suppressing regulatory T cells while upregulating effector T cells; a decrease in regulatory T cells by 31.43% but an increase in effector T cells by 31.59% were observed in the combination group compared with those in the control group). We suggest that a combination of lycorine hydrochloride and anti-CTLA-4 is a viable therapeutic option for RCC patients.

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  • Ligation-free technique for dorsal vascular complex control during laparoscopic radical prostatectomy: a single-center experience from China. 査読 国際誌

    Peng Xu, Abai Xu, Binshen Chen, Shaobo Zheng, Yawen Xu, Hulin Li, Bingkun Li, Peng Huang, Yiming Zhang, Yukun Ge, Chunxiao Liu

    World journal of urology   35 ( 3 )   395 - 402   2017年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: To illustrate a ligation-free technique and compare perioperative and postoperative outcomes of this technique versus the standard suture method. PATIENTS AND METHODS: This study is a retrospective review of 233 consecutive patients with localized prostate cancer who underwent ligation-free technique (n = 180, Group 1) or standard ligation (n = 53, Group 2) at an academic institution from February 2010 to January 2014. RESULTS AND LIMITATIONS: Operative time was significantly shorter in Group 1 than in Group 2 (148.47 vs. 164.25 min, p = 0.000). No difference in EBL was noted between the groups (191.11 vs. 185.06 mL, p = 0.055). Postoperative continence rates at 3, 6, and 12 months in Groups 1 and 2 were 40.0 versus 24.5, 54.4 versus 37.7, and 73.9 versus 71.7 %, respectively. These differences were statistically significant. No patient in either group had a positive apical surgical margin. During follow-up, tumor recurrence or metastasis was not observed in any patient. Limitations of the study include this retrospective study of a single-center experience and lack of potency appraisal. CONCLUSIONS: This present ligation-free technique showed a statistically significant shorter interval to recovery of continence and higher continence rates in short-term postoperative results by contrast to conventional suture ligation, but no significant difference was revealed in long-term urinary control. We offer this technique and the correlative data to provide more information for deeply understanding the precise construction of the dorsal vascular complex and the mechanism of urinary control.

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  • Lycorine induces apoptosis of bladder cancer T24 cells by inhibiting phospho-Akt and activating the intrinsic apoptotic cascade. 査読 国際誌

    Chongshan Wang, Qiongren Wang, Xiezhao Li, Zhong Jin, Peng Xu, Naijin Xu, Abai Xu, Yawen Xu, Shaobo Zheng, Junxia Zheng, Chunxiao Liu, Peng Huang

    Biochemical and biophysical research communications   483 ( 1 )   197 - 202   2017年1月

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    担当区分:最終著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Lycorine, an alkaloid extracted from Amaryllidaceae genera, exhibits antitumor activities against several human solid-tumor and leukemia cells with extensive influence on various cell signaling molecules. However, the effect of lycorine on bladder cancer has not yet been investigated. In this study, we demonstrated that lycorine induced apoptosis in human bladder cancer T24 cells, an effect that is mediated via inhibition of phospho-Akt expression and the consequent activation of caspase-3 and Bax in vitro. In an in vivo experiment, T24 cells were subcutaneously implanted in the right rear flank of nu/nu mice. Lycorine treatment for 14 days significantly inhibited tumor growth compared with that in controls. Collectively, our findings suggest that lycorine suppressed the Akt pathway and activated the intrinsic apoptotic cascade, leading to the apoptosis of bladder cancer cells. We suggest that lycorine can be a viable therapeutic option for bladder cancer patients.

    DOI: 10.1016/j.bbrc.2016.12.168

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  • Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies 査読 国際誌

    Ken Suzawa, Kazuhiko Shien, Huang Peng, Masakiyo Sakaguchi, Masami Watanabe, Shinsuke Hashida, Yuho Maki, Hiromasa Yamamoto, Shuta Tomida, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Yasutomo Nasu, Hiromi Kumon, Shinichiro Miyoshi, Shinichi Toyooka

    ANTICANCER RESEARCH   37 ( 1 )   301 - 307   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:INT INST ANTICANCER RESEARCH  

    Background: Reduced expression in immortalized cell (REIC)/Dickkoph-3 (DKK3) is a tumor-suppressor gene, and its overexpression by adenovirus vector (Ad-REIC) exhibits a remarkable therapeutic effect on various human cancer types through a mechanism triggered by endoplasmic reticulum stress. Materials and Methods: We examined the direct anti-tumor effect of Ad-REIC gene therapy on lung cancer and malignant mesothelioma cell lines in vitro, and the distant bystander effect using immunocompetent mouse allograft models with bilateral flank tumors. Results: Ad-REIC treatment showed antitumor effect in many lung cancer and malignant mesothelioma cell lines in vitro. In an in vivo model, Ad-REIC treatment inhibited the growth not only of directly treated tumors but also of distant untreated tumors. By immunohistochemical analysis, infiltration of T-cells and natural killer (NK) cells and expression of the major histocompatibility complex (MHC) class I molecules were observed in bilateral tumors. Conclusion: Ad-REIC treatment not only had a direct antitumor effect but also an indirect bystander effect through stimulation of the immune system.

    DOI: 10.21873/anticanres.11321

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  • Development of Sialic Acid-coated Nanoparticles for Targeting Cancer and Efficient Evasion of the Immune System. 査読 国際誌

    Young-Hwa Kim, Kyung Hyun Min, Zhantong Wang, Jihoon Kim, Orit Jacobson, Peng Huang, Guizhi Zhu, Yijing Liu, Bryant Yung, Gang Niu, Xiaoyuan Chen

    Theranostics   7 ( 4 )   962 - 973   2017年

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    記述言語:英語  

    Evading the reticuloendothelial system (RES) remains a critical challenge in the development of efficient delivery and diagnostic systems for cancer. Sialic acid (N-acetylneuraminic acid, Neu5Ac) is recognized as a "self" marker by major serum protein complement factor H and shows reduced interaction with the innate immune system via sialic acid-binding immunoglobulin-like lectin (Siglec), which is known as one of the significant regulators of phagocytic evasion. Accordingly, we prepared different surface-modified gold nanoparticles (AuNPs) and investigated the effects of sialic acid on cellular and immune responses of nanoparticles in vitro and in vivo. Sialic acid modification not only facilitates evasion of the RES by suppressing the immune response, but also enhances tumor accumulation via its active targeting ability. Therefore, sialic acid modification presents a promising strategy to advance nanotechnology towards the prospect of clinical translation.

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  • Programmed death ligand 1 expression in bladder rhabdomyosarcoma and its association with clinicopathological features. 査読 国際誌

    Peng Zhou, Qiongren Wang, Chongshan Wang, Xiezhao Li, Wei Du, Chunxiao Liu, Masami Watanabe, Peng Huang, Abai Xu

    International journal of clinical and experimental pathology   10 ( 10 )   10565 - 10570   2017年

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The aim of this study was to detect PD-L1 expression in bladder rhabdomyosarcoma and its association with clinicopathological features and patient prognosis. PD-L1 expression was detected in paraffin-embedded sections obtained from 34 patients with bladder rhabdomyosarcoma via immunohistochemistry. Immunohistochemistry results were statistically analyzed to determine their association with patient clinicopathological features and survival outcomes. PD-L1-positive staining was observed in 47.1% (16/34) of patients. Metastatic tumor cells in the lymph nodes of two patients were positive for PD-L1 expression. PD-L1 expression was significantly different with regard to muscularis invasion, but the expression did not affect patient survival outcomes. We confirmed PD-L1 expression in bladder rhabdomyosarcoma, suggesting that PD-1/PD-L1 inhibitors are potential therapeutic agents for patients with bladder rhabdomyosarcoma.

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  • A convenient and effective strategy for the enrichment of tumor-initiating cell properties in prostate cancer cells. 査読 国際誌

    Yiming Zhang, Yiqiang Huang, Zhong Jin, Xiezhao Li, Bingkun Li, Peng Xu, Peng Huang, Chunxiao Liu

    Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine   37 ( 9 )   11973 - 11981   2016年9月

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    担当区分:責任著者   記述言語:英語  

    Stem-like prostate cancer (PrCa) cells, also called PrCa stem cells (PrCSCs) or PrCa tumor-initiating cells (PrTICs), are considered to be involved in the mediation of tumor metastasis and may be responsible for the poor prognosis of PrCa patients. Currently, the methods for PrTIC sorting are mainly based on cell surface marker or side population (SP). However, the rarity of these sorted cells limits the investigation of the molecular mechanisms and therapeutic strategies targeting PrTICs. For PrTIC enrichment, we induced cancer stem cell (CSC) properties in PrCa cells by transducing three defined factors (OCT3/4, SOX2, and KLF4), followed by culture with conventional serum-containing medium. The CSC properties in the transduced cells were evaluated by proliferation, cell cycle, SP assay, drug sensitivity technology, in vivo tumorigenicity, and molecular marker analysis of PrCSCs compared with parental cells and spheroids. After culture with serum-containing medium for 8 days, the PrCa cells transduced with the three factors showed significantly enhanced CSC properties in terms of marker gene expression, sphere formation, chemoresistance to docetaxel, and tumorigenicity. The percentage of CD133+/CD44+ cells was ninefold higher in the transduced cell population than in the adherent PC3 cell population (2.25 ± 0.62 vs. 0.25 ± 0.12 %, respectively), and the SP increased to 1.22 ± 0.18 % in the transduced cell population, but was undetectable in the adherent population. This method can be used to obtain abundant PrTIC material and enables a complete understanding of PrTIC biology and development of novel therapeutic agents targeting PrTICs.

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  • MCAM, as a novel receptor for S100A8/A9, mediates progression of malignant melanoma through prominent activation of NF-κB and ROS formation upon ligand binding. 査読 国際誌

    I Made Winarsa Ruma, Endy Widya Putranto, Eisaku Kondo, Hitoshi Murata, Masami Watanabe, Peng Huang, Rie Kinoshita, Junichiro Futami, Yusuke Inoue, Akira Yamauchi, I Wayan Sumardika, Chen Youyi, Ken-Ichi Yamamoto, Yasutomo Nasu, Masahiro Nishibori, Toshihiko Hibino, Masakiyo Sakaguchi

    Clinical & experimental metastasis   33 ( 6 )   609 - 27   2016年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The dynamic interaction between tumor cells and their microenvironment induces a proinflammatory milieu that drives cancer development and progression. The S100A8/A9 complex has been implicated in chronic inflammation, tumor development, and progression. The cancer microenvironment contributes to the up-regulation of this protein complex in many invasive tumors, which is associated with the formation of pre-metastatic niches and poor prognosis. Changing adhesive preference of cancer cells is at the core of the metastatic process that governs the reciprocal interactions of cancer cells with the extracellular matrices and neighboring stromal cells. Cell adhesion molecules (CAMs) have been confirmed to have high-level expression in various highly invasive tumors. The expression and function of CAMs are profoundly influenced by the extracellular milieu. S100A8/A9 mediates its effects by binding to cell surface receptors, such as heparan sulfate, TLR4 and RAGE on immune and tumor cells. RAGE has recently been identified as an adhesion molecule and has considerably high identity and similarity to ALCAM and MCAM, which are frequently over-expressed on metastatic malignant melanoma cells. In this study, we demonstrated that ALCAM and MCAM also function as S100A8/A9 receptors as does RAGE and induce malignant melanoma progression by NF-κB activation and ROS formation. Notably, MCAM not only activated NF-κB more prominently than ALCAM and RAGE did but also mediated intracellular signaling for the formation of lung metastasis. MCAM is known to be involved in malignant melanoma development and progression through several mechanisms. Therefore, MCAM is a potential effective target in malignant melanoma treatment.

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  • [Antitumor activity of lycorine in renal cell carcinoma ACHN cell line and its mechanism]. 査読 国際誌

    Yi-Qiang Huang, Yi-Ming Zhang, Zhong Jin, Xie-Zhao Li, Chong-Shan Wang, Kai Xu, Peng Huang, Chun-Xiao Liu

    Nan fang yi ke da xue xue bao = Journal of Southern Medical University   36 ( 6 )   857 - 62   2016年6月

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    記述言語:中国語  

    OBJECTIVE: To investigate the antitumor effect of lycorine on renal cell carcinoma ACHN cells and explore the possible mechanism. METHODS: We used flow cytometry to examine the effect of lycorine on ACHN cell cycle and apoptosis. The cell proliferation, migration and invasion were assessed with MTS assay, wound healing assay, and Transwell assay, respectively. Colony forming assay was performed, and the mRNA and protein levels of Bax, Bcl-2, survivin, caspase-3, cyclin D1 and CDK4 were measured with qRT-PCR and Western blotting. RESULTS: Lycorine obviously inhibited the proliferation of ACHN cells with an IC(50) of 24.34 µmol/L. Lycorine also induced apoptosis of ACHN cells, caused cell cycle arrest at G(0)/G(1) phase, and suppressed the colony forming ability of the cells in a dose-dependent manner. The migration and invasion of ACHN cells were significantly inhibited by 5 µmol/L lycorine. Lycorine up-regulated the mRNA levels of CDK4, Bax, caspase-3 while down-regulated the levels of survivin, Bcl-2 and Cyclin D1; the protein levels of CDK4 and Bax were increased and cyclin D1, Bcl-2 and surviving expressions were decreased, but caspase-3 expression showed no significant changes following the treatment. CONCLUSION: Lycorine has obvious antitumor effect against ACHN cells, suggesting its value as a new therapeutic agent for renal cell carcinoma.

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  • Real-time monitoring of tumor progression and drug responses in a preclinical mouse model of prostate cancer. 査読 国際誌

    Peng Xu, Naijin Xu, Kai Guo, Abai Xu, Fumiaki Takenaka, Eiji Matsuura, Chunxiao Liu, Hiromi Kumon, Peng Huang

    Oncotarget   7 ( 22 )   33025 - 34   2016年5月

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    担当区分:最終著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Monitoring disease progression through imaging is playing an increasingly important role in the treatment of prostate cancer. Here, we report that primary mouse prostate cancer cell lines stably expressing luciferase and tumor biomarkers can be monitored through bioluminescence imaging along with assays of serum biomarkers and immune function. Tumorigenesis in immunocompetent C57BL/6 mice can be monitored in by collecting samples from the dorsal flank, dorsolateral prostate, and tail vein to obtain real-time subcutaneous, orthotopic, and metastasis indicators, respectively. We used this technique to confirm the therapeutic effect of immune checkpoint blockade. Our findings suggest the presented indicators are ideally suited for real-time tracking of drug responses, tumor progression and immune function.

    DOI: 10.18632/oncotarget.8846

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  • Influence of a single-nucleotide polymorphism of the DNA mismatch repair-related gene exonuclease-1 (rs9350) with prostate cancer risk among Chinese people. 査読 国際誌

    Yiming Zhang, Pengju Li, Abai Xu, Jie Chen, Chao Ma, Akiko Sakai, Liping Xie, Lei Wang, Yanqun Na, Haruki Kaku, Peng Xu, Zhong Jin, Xiezhao Li, Kai Guo, Haiyan Shen, Shaobo Zheng, Hiromi Kumon, Chunxiao Liu, Peng Huang

    Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine   37 ( 5 )   6653 - 9   2016年5月

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    担当区分:最終著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    In this study, we aimed to identify the influence of exonuclease 1 (EXO1) single-nucleotide polymorphism rs9350, which is involved in DNA mismatch repair, on prostate cancer risk in Chinese people. In our hospital-based case-control study, 214 prostate cancer patients and 253 cancer-free control subjects were enrolled from three hospitals in China. Genotyping for rs9350 was performed by the SNaPshot(®) method using peripheral blood samples. Consequently, a significantly higher prostate cancer risk was observed in patients with the CC genotype [odds ratio (OR) = 1.678, 95 % confidence interval (CI) = 1.130-2.494, P = 0.010] than in those with the CT genotype. Further, the CT/TT genotypes were significantly associated with increased prostate cancer risk (adjusted OR = 1.714, 95 % CI = 1.176-2.500, P = 0.005), and the C allele had a statistically significant compared with T allele (P = 0.009) of EXO1 (rs9350). Through stratified analysis, significant associations were revealed for the CT/TT genotype in the subgroup with diagnosis age >72 (adjusted OR = 1.776, 95 % CI = 1.051-3.002, P = 0.032) and in patients with localized disease subgroup (adjusted OR = 1.798, 95 % CI = 1.070-3.022, P = 0.027). In addition, we observed that patients with prostate-specific antigen (PSA) levels of ≤10 ng/mL were more likely to have the CT/TT genotypes than those with PSA levels of >10 ng/mL (P = 0.006). For the first time, we present evidence that the inherited EXO1 polymorphism rs9350 may have a substantial influence on prostate cancer risk in Chinese people. We believe that the rs9350 could be a useful biomarker for assessing predisposition for and early diagnosis of prostate cancer.

    DOI: 10.1007/s13277-015-4298-x

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  • New antibacterial isocoumarin glycosides from a wetland soil derived fungal strain Metarhizium anisopliae. 査読 国際誌

    Jie-Feng Tian, Peng-Ju Li, Xiao-Xia Li, Ping-Hua Sun, Hao Gao, Xing-Zhong Liu, Peng Huang, Jin-Shan Tang, Xin-Sheng Yao

    Bioorganic & medicinal chemistry letters   26 ( 5 )   1391 - 6   2016年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Eight new isocoumarin glycosides (1-8) were obtained from the solid culture of the wetland soil-derived fungus Metarhizium anisopliae (No. DTH12-10). Their chemical structures were elucidated by analyses of HR ESI-TOF MS, (1)H, (13)C NMR, (1)H-(1)H COSY, HSQC, and HMBC spectra. The absolute configurations were determined by single crystal X-ray diffraction, circular dichroism (CD) spectrum, and chemical derivatization methods. In addition, inhibition of the biofilm formation and the secretion of virulence factor of the new isocoumarin glycosides against Pseudomonas aeruginosa strain PAOA (clinical isolates) were evaluated. The result revealed that compound 1 showed antibacterial activity comparable with (Z)-4-bromo-5-(bromomethylene)-2(5H)-furanone (BF).

    DOI: 10.1016/j.bmcl.2016.01.074

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  • Remarkable Pathologic Change in Advanced Prostate Cancer Patient Using Dendritic Cell-Cytokine-Induced Killer Combined Therapy: A Case Report. 査読 国際誌

    Peng Xu, Peng Ju Li, Kai Guo, Yanjie He, Chao Ma, Zhong Jin, Yiming Zhang, Yukun Ge, Abai Xu, Shaobo Zheng, Yuhua Li, Chunxiao Liu, Peng Huang

    Clinical genitourinary cancer   13 ( 5 )   e379-83   2015年10月

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    担当区分:最終著者, 責任著者   記述言語:英語  

    DOI: 10.1016/j.clgc.2015.04.006

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  • Distant Bystander Effect of REIC/Dkk-3 Gene Therapy through Immune System Stimulation in a Murine Model of Thoracic Malignancies 査読

    Ken Suzawa, Kazuhiko Shien, Peng Huang, Masakiyo Sakaguchi, Masami Watanabe, Shinsuke Hashida, Junichi Soh, Hiromasa Yamamoto, Yuho Maki, Hiroaki Asano, Kazunori Tsukuda, Yasutomo Nasu, Hiromi Kumon, Shinichiro Miyoshi, Shinichi Toyooka

    JOURNAL OF THORACIC ONCOLOGY   10 ( 9 )   S599 - S599   2015年9月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE INC  

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  • A combination of YM-155, a small molecule survivin inhibitor, and IL-2 potently suppresses renal cell carcinoma in murine model. 査読 国際誌

    Kai Guo, Peng Huang, Naijin Xu, Peng Xu, Haruki Kaku, Shaobo Zheng, Abai Xu, Eiji Matsuura, Chunxiao Liu, Hiromi Kumon

    Oncotarget   6 ( 25 )   21137 - 47   2015年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    YM155, a small molecule inhibitor of the antiapoptotic protein survivin, has been developed as a potential anti-cancer drug. We investigated a combination therapy of YM155 and interleukin-2 (IL-2) in a mouse model of renal cell carcinoma (RCC). YM155 caused cell cycle arrest and apoptosis in renal cancer (RENCA) cells. Next, luciferase-expressing RENCA cells were implanted in the left kidney and the lung of BALB/c mice to develop RCC metastatic model. In this orthotopic renal and metastatic lung tumors models, YM155 and IL-2 additively decreased tumor weight, lung metastasis, and luciferin-stained tumor images. Also, the combination significantly suppressed regulatory T cells and myeloid-derived suppressor cells compared with single agent treatment. We suggest that a combination of YM155 and IL-2 can be tested as a potential therapeutic modality in patients with RCC.

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  • The cysteine-rich core domain of REIC/Dkk-3 is critical for its effect on monocyte differentiation and tumor regression. 査読 国際誌

    Rie Kinoshita, Masami Watanabe, Peng Huang, Shun-Ai Li, Masakiyo Sakaguchi, Hiromi Kumon, Junichiro Futami

    Oncology reports   33 ( 6 )   2908 - 14   2015年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Reduced expression in immortalized cells (REIC)/Dickkopf (Dkk)-3 is a tumor-suppressor gene and has been studied as a promising therapeutic gene for cancer gene therapy. Intratumoral injection of an adenovirus vector carrying the human REIC/Dkk-3 gene (Ad-REIC) elicits cancer cell-specific apoptosis and anticancer immune responses. The cytokine-like effect of secretory REIC/Dkk-3 on the induction of dendritic cell (DC)-like cell differentiation from monocytes plays a role in systemic anticancer immunity. In the present study, we generated recombinant full-length and N-terminally truncated REIC/Dkk-3 to characterize the biological activity of the protein. During the purification procedure, we identified a 17 kDa cysteine-rich stable product (C17-REIC) showing limited degradation. Further analysis showed that the C17-REIC domain was sufficient for the induction of DC-like cell differentiation from monocytes. Concomitant with the differentiation of DCs, the REIC/Dkk-3 protein induced the phosphorylation of glycogen synthase kinase 3β (GSK-3β) and signal transducers and activators of transcription (STAT) at a level comparable to that of granulocyte/macrophage colony-stimulating factor. In a mouse model of subcutaneous renal adenocarcinoma, intraperitoneal injection of full-length and C17-REIC proteins exerted anticancer effects in parallel with the activation of immunocompetent cells such as DCs and cytotoxic T lymphocytes in peripheral blood. Taken together, our results indicate that the stable cysteine-rich core region of REIC/Dkk-3 is responsible for the induction of anticancer immune responses. Because REIC/Dkk-3 is a naturally circulating serum protein, the upregulation REIC/Dkk-3 protein expression could be a promising option for cancer therapy.

    DOI: 10.3892/or.2015.3885

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  • Efficacy of intravesical Bacillus Calmette-Guérin therapy against tumor immune escape in an orthotopic model of bladder cancer. 査読 国際誌

    Peng Huang, Chao Ma, Peng Xu, Kai Guo, Abai Xu, Chunxiao Liu

    Experimental and therapeutic medicine   9 ( 1 )   162 - 166   2015年1月

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    記述言語:英語  

    The aim of this study was to evaluate the antitumor immune response of the Bacillus Calmette-Guérin (BCG) in an orthotopic bladder cancer model. The murine bladder cancer cell line MBT-2 was transurethrally implanted in the bladder of syngeneic female C3H/He mice. The animals were randomly divided into three treatment groups: Phosphate-buffered saline (PBS), low-dose BCG and high-dose BCG. The analyses of luciferin-stained tumor images 28 days after each treatment showed significant tumor growth inhibition in the high-dose group in comparison with that in the low-dose- or PBS-treated groups. In addition, the percentage of myeloid-derived suppressor cells in the high-dose group was significantly suppressed in comparison with that in the PBS and low-dose agent treatment groups. These findings are notable in terms of the clinical evaluations of this therapy for patients with bladder cancer. The outcomes of this study also provide important implications regarding antitumor immune responses in human cancer.

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  • Increased expression of metastasis-associated in colon cancer-1 in renal cell carcinoma is associated with poor prognosis. 査読 国際誌

    Zhong Jin, Naijin Xu, Kai Guo, Peng Xu, Pengju Li, Yiming Zhang, Xiezhao Li, Shaobo Zheng, Chunxiao Liu, Abai Xu, Peng Huang

    International journal of clinical and experimental pathology   8 ( 4 )   3857 - 63   2015年

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    記述言語:英語  

    Metastasis-associated in colon cancer-1 (MACC1) expression in tumor specimens is an independent prognostic indicator of metastasis, which has recently gained considerable attention in cancer research, due to its overexpression in several types of carcinoma. However, MACC1 expression patterns and its possible role in renal cell carcinoma remain unknown. This study aimed to investigate MACC1 expression in renal cell carcinoma via immunohistochemical analysis and determine the relationship between MACC1 expression and cancer prognosis. Positive MACC1 expression was found to significantly correlate with distant metastasis and TNM stage (P < 0.05). A Kaplan-Meier survival analysis revealed that patients with higher MACC1 expression had a significantly lower disease-free rate (P < 0.05). These results indicate that MACC1 expression is significantly associated with prognosis in patients with renal cell carcinoma. To the best of our knowledge, this is the first study on the significance of MACC1 as a prognostic marker in renal cell carcinoma. MACC1 expression may be a useful target for the development of new therapeutic approaches, including molecular targeted therapeutic agents, for renal cell carcinoma.

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  • Significant association between the Axin2 rs2240308 single nucleotide polymorphism and the incidence of prostate cancer. 査読 国際誌

    Chao Ma, Chunxiao Liu, Peng Huang, Haruki Kaku, Jie Chen, Kai Guo, Hideo Ueki, Akiko Sakai, Yasutomo Nasu, Hiromi Kumon, Kenji Shimizu, Masami Watanabe

    Oncology letters   8 ( 2 )   789 - 794   2014年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The Wnt signaling pathway plays a crucial role in human cancer development, and axis inhibition protein 2 (Axin2) is a master scaffold protein involved in Wnt signaling. Axin2 negatively regulates Wnt signaling and acts as a tumor suppressor protein. The present study evaluated the association between the Axin2 single nucleotide polymorphism (SNP) rs2240308 [guanine (G)/adenine (A)] and the incidence of prostate cancer. In total, 103 patients with prostate cancer and 100 cancer-free control males were included in this case-control study, and were genotyped using the genomic DNA extracted from peripheral blood samples. The results revealed a higher incidence of prostate cancer in the subjects with the homozygous GG genotype and a reduced cancer incidence in the patients with the GA genotype of the rs2240308 SNP (G/A) in the Axin2 gene. The adjusted odds ratio for carriers with the GA genotype was 0.377 (95% CI, 0.206-0.688; P=0.001) and that for the AA genotype was 0.830 (95% CI, 0.309-2.232; P=0.712) compared with the GG genotype. Therefore, the GA genotype was found to exhibit a protective effect that decreased the risk of prostate cancer. To the best of our knowledge, this is the first study to demonstrate the significant association between this SNP (rs2240308, G/A) and the risk of prostate cancer. This association indicates the possibility that the variations in the Axin2 gene in this position may play a significant role in promoting the development of cancer in the prostate. We believe that the Axin2 SNP (rs2240308) could be a useful biomarker for the predisposition and early diagnosis of the disease.

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  • Dramatic increase in expression of a transgene by insertion of promoters downstream of the cargo gene. 査読 国際誌

    Masakiyo Sakaguchi, Masami Watanabe, Rie Kinoshita, Haruki Kaku, Hideo Ueki, Junichiro Futami, Hitoshi Murata, Yusuke Inoue, Shun-Ai Li, Peng Huang, Endy Widya Putranto, I Made Winarsa Ruma, Yasutomo Nasu, Hiromi Kumon, Nam-Ho Huh

    Molecular biotechnology   56 ( 7 )   621 - 30   2014年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    For expression of genes in mammalian cells, various vectors have been developed using promoters including CMV, EF-1α, and CAG promoters and have been widely used. However, such expression vectors sometimes fail to attain sufficient expression levels depending on the nature of cargo genes and/or on host cell types. In the present study, we aimed to develop a potent promoter system that enables high expression levels of cargo genes ubiquitously in many different cell types. We found that insertion of an additional promoter downstream of a cargo gene greatly enhanced the expression levels. Among the constructs we tested, C-TSC cassette (C: CMV-RU5' located upstream; TSC: another promoter unit composed of triple tandem promoters, hTERT, SV40, and CMV, located downstream of the cDNA plus a polyadenylation signal) had the most potent capability, showing far higher efficiency than that of potent conventional vector systems. The results indicate that the new expression system is useful for production of recombinant proteins in mammalian cells and for application as a gene therapeutic measure.

    DOI: 10.1007/s12033-014-9738-0

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  • Immunological aspects of REIC/Dkk-3 gene therapy : the mechanism of the robust anti-tumor effects. 査読

    Masami Watanabe, Peng Huang, Fernando Abarzua, Haruki Kaku, Katsumi Sasaki, Hideo Ueki, Toyohiko Wananabe, Yasutomo Nasu, Hiromi Kumon

    JOURNAL OF GENE MEDICINE   16 ( 7-8 )   226 - 227   2014年7月

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    記述言語:英語   出版者・発行元:WILEY-BLACKWELL  

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  • A novel gene expression system strongly enhances the anticancer effects of a REIC/Dkk-3-encoding adenoviral vector. 査読 国際誌

    Masami Watanabe, Masakiyo Sakaguchi, Rie Kinoshita, Haruki Kaku, Yuichi Ariyoshi, Hideo Ueki, Ryuta Tanimoto, Shin Ebara, Kazuhiko Ochiai, Junichiro Futami, Shun-Ai Li, Peng Huang, Yasutomo Nasu, Nam-Ho Huh, Hiromi Kumon

    Oncology reports   31 ( 3 )   1089 - 95   2014年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Gene expression systems with various promoters, including the cytomegalovirus (CMV) promoter, have been developed to increase the gene expression in a variety of normal and cancer cells. In particular, in the clinical trials of cancer gene therapy, a more efficient and robust gene expression system is required to achieve sufficient therapeutic outcomes. By inserting the triple translational enhancer sequences of human telomerase reverse transcriptase (hTERT), Simian virus 40 (SV40) and CMV downstream of the sequence of the BGH polyA, we were able to develop a novel gene expression system that significantly enhances the expression of the genes of interest. We termed this novel gene expression cassette the super gene expression (SGE) system, and herein verify the utility of the SGE cassette for a replication-deficient adenoviral vector. We newly developed an adenoviral vector expressing the tumor suppressor, reduced expression in immortalized cells (REIC)/Dickkopf-3 (Dkk-3), based on the CMV promoter-driven SGE system (Ad-SGE-REIC) and compared the therapeutic utility of Ad-SGE-REIC with that of the conventional adenoviral vectors (Ad-CMV-REIC or Ad-CAG-REIC). The results demonstrated that the CMV promoter-SGE system allows for more potent gene expression, and that the Ad-SGE-REIC is superior to conventional adenoviral systems in terms of the REIC protein expression and therapeutic effects. Since the SGE cassette can be applied for the expression of various therapeutic genes using various vector systems, we believe that this novel system will become an innovative tool in the field of gene expression and gene therapy.

    DOI: 10.3892/or.2013.2958

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  • N'-[4-(dipropylamino)benzylidene]-2-hydroxybenzohydrazide is a dynamin GTPase inhibitor that suppresses cancer cell migration and invasion by inhibiting actin polymerization. 査読 国際誌

    Hiroshi Yamada, Tadashi Abe, Shun-Ai Li, Shota Tago, Peng Huang, Masami Watanabe, Satoru Ikeda, Naohisa Ogo, Akira Asai, Kohji Takei

    Biochemical and biophysical research communications   443 ( 2 )   511 - 7   2014年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Dynasore, a specific dynamin GTPase inhibitor, suppresses lamellipodia formation and cancer cell invasion by destabilizing actin filaments. In search for novel dynamin inhibitors that suppress actin dynamics more efficiently, dynasore analogues were screened. N'-[4-(dipropylamino)benzylidene]-2-hydroxybenzohydrazide (DBHA) markedly reduced in vitro actin polymerization, and dose-dependently inhibited phosphatidylserine-stimulated dynamin GTPase activity. DBHA significantly suppressed both the recruitment of dynamin 2 to the leading edge in U2OS cells and ruffle formation in H1299 cells. Furthermore, DBHA suppressed both the migration and invasion of H1299 cells by approximately 70%. Furthermore, intratumoral DBHA delivery significantly repressed tumor growth. DBHA was much less cytotoxic than dynasore. These results strongly suggest that DBHA inhibits dynamin-dependent actin polymerization by altering the interactions between dynamin and lipid membranes. DBHA and its derivative may be potential candidates for potent anti-cancer drugs.

    DOI: 10.1016/j.bbrc.2013.11.118

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  • Clinical significance of CD24 as a predictor of bladder cancer recurrence. 査読 国際誌

    Chunxiao Liu, Shaobo Zheng, Haiyan Shen, Kai Xu, Jie Chen, Hulin Li, Yawen Xu, Abai Xu, Binshen Chen, Haruki Kaku, Yasutomo Nasu, Hiromi Kumon, Peng Huang, Masami Watanabe

    Oncology letters   6 ( 1 )   96 - 100   2013年7月

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    記述言語:英語  

    Cluster of differentiation (CD)24 was originally described as a B lymphocyte marker and has recently received considerable attention in cancer research as its overexpression has been observed in several types of carcinoma. The CD24 molecule is a glycosyl-phosphatidylinositol-linked cell surface protein that appears to be associated with aggressive cancers involving invasion and metastasis. However, the expression of CD24 in human bladder cancer and its clinical significance remains largely unknown and no association has been reported between CD24 overexpression and human bladder tumor recurrence. In the present study, the CD24 expression in cancer tissues obtained during transurethral surgery and the subsequent intra-bladder tumor recurrence following surgery were assessed. Immunohistochemical staining was performed and the intensity of CD24 staining was semi-quantitatively evaluated. CD24 expression was observed more frequently in high-grade bladder tumors (G2-G3) than low-grade tumors (G1). Positive CD24 expression was significantly associated with intra-bladder tumor recurrence following surgery and increased staining intensity was also correlated with recurrence. The positive association between CD24 expression and tumor recurrence was observed in each tumor category (stages Ta and T1, low and high grade). The results demonstrated that CD24 expression is significantly associated with bladder tumor recurrence. To the best of our knowledge, this is the first study to reveal the significance of CD24 as a predictor of bladder cancer recurrence. These insights may lead to future therapeutic strategies targeting CD24 to prevent the dissemination of bladder cancer cells and tumor recurrence.

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  • [Expression of myeloid-derived suppressor cells in the peripheral blood and its clinical significance in renal carcinoma]. 査読 国際誌

    Songqing Feng, Chunxiao Liu, Shaobo Zheng, Peng Huang, Binshen Chen, Kai Guo

    Nan fang yi ke da xue xue bao = Journal of Southern Medical University   33 ( 4 )   550 - 3   2013年4月

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    記述言語:中国語  

    OBJECTIVE: To investigate the expression of CD33⁺ HLA-DR⁻ myeloid-derived suppressor cells (MDSCs) in the peripheral blood of patients with renal carcinoma and its correlation with the clinicopathological features of renal cancer. METHODS: Forty-four patients with renal carcinoma treated in our hospital between June, 2011 and October, 2012 and 18 healthy volunteers were enrolled in this study. Flow cytometry was performed to detect CD33⁺ HLA-DR⁻ MDSCs in the peripheral blood, and its correlation with the clinicopathological features of the patients were analyzed. RESULTS: The positivity rate of CD33⁺ HLA-DR⁻ MDSCs in the peripheral blood was significantly higher in the cancer patients than in the healthy controls [(1.91 ± 0.66)% vs (0.62 ± 0.22)%, P<0.001]. The expression levels of CD33⁺ HLA-DR⁻ MDSCs in patients with renal carcinoma showed significant differences between stage I+II [(1.46 ± 0.44)%] and stage III [(2.04 ± 0.35)%] patients (P<0.01) and between stage III and stage IV patients [(2.50 ± 0.64)%] (P<0.05), but did not differ significantly in respect of age or gender. CONCLUSION: CD33⁺ HLA-DR⁻ MDSCs expression in the peripheral blood is associated with tumor stage and differentiation in renal carcinoma and may play an important role in predicting the prognosis and tumor immunology of renal carcinoma.

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  • Cancer stem cell-like characteristics of a CD133+ subpopulation in the J82 human bladder cancer cell line. 査読 国際誌

    Peng Huang, Masami Watanabe, Haruki Kaku, Hideo Ueki, Hirofumi Noguchi, Morito Sugimoto, Takeshi Hirata, Hiroshi Yamada, Kohji Takei, Shaobo Zheng, Kai Xu, Yasutomo Nasu, Yasuyuki Fujii, Chunxiao Liu, Hiromi Kumon

    Molecular and clinical oncology   1 ( 1 )   180 - 184   2013年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cancer stem cells (CSCs) are thought to be crucial for understanding the biological roots of cancer, and are of increasing importance as a target for new anticancer agents. According to an expression analysis of the cell surface antigens of various types of cancer, CD133 is considered to be a potential marker of cancer stemness. In this study, a human urinary bladder cancer cell line (J82) was used to analyze the cancer stem cell-like characteristics of CD133+ bladder cancer cells in vitro and in vivo. The CD133 expression in the J82 cells was examined and the cells were immunomagnetically categorized into positive and negative subsets. The CD133- and CD133+ subsets were phenotypically divergent with regard to the cell growth pattern, while CD133+ cells tended to colonize during their growth. In CD133+ cells, the pluripotent stem cell factors Oct-4 and Sox-2 were upregulated, and a statistically significant proliferation increase was observed when compared to CD133- cells. The CD133+ subpopulation was more tolerant to the chemotherapeutic agent cisplatin, and Bacillus Calmette-Guérin (BCG), an agent instilled intravesically to treat bladder cancer. In addition, CD133+ J82 cells were more resistant to radiation treatment when compared to CD133- cells. The in vivo tumorigenesis of the CD133- and CD133+ subsets of J82 cancer cells was also examined by subcutaneously injecting them into nude mice. The tumor growth was more aggressive in the CD133+ subpopulation, showing a significant difference in the tumorigenic potential in these subsets. In conclusion, J82 human bladder cancer cells include CD133- and CD133+ subpopulations, while the CD133 molecule is a potential marker of the potential malignancy of human bladder cancer. In the present study, the CD133+ subpopulation was herein demonstrated to have certain characteristics consistent with those of cancer stem cells.

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  • A novel gene expression system for detecting viable bladder cancer cells. 査読 国際誌

    Hideo Ueki, Masami Watanabe, Haruki Kaku, Peng Huang, Shun-Ai Li, Kazuhiko Ochiai, Takeshi Hirata, Hirofumi Noguchi, Hiroshi Yamada, Kohji Takei, Yasutomo Nasu, Yuji Kashiwakura, Hiromi Kumon

    International journal of oncology   41 ( 1 )   135 - 40   2012年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A novel transcriptional system was developed that can robustly enhance cancer-specific gene expression. In the system, hTERT promoter-driven gene expression was enhanced by an advanced two-step transcriptional amplification (TSTA). This construct was used to develop a novel system for detection of bladder cancer cells. The current study evaluated the advanced TSTA system by examining the cancer-specific gene transcription in various bladder cancer cell lines. The system significantly enhanced cancer-specific luciferase gene expression in the bladder cancer cell lines in comparison to the previous expression system of one-step or conventional TSTA. The fold gain of the enhancement was significantly correlated to the telomerase activity of the cell lines. A green fluorescent protein (GFP) gene encoding plasmid vector was constructed where hTERT promoter-driving transcription is enhanced by the advanced TSTA to utilize the system for the imaging and detection of viable bladder cancer cells. The advanced TSTA-hTERT-GFP plasmid successfully induced cancer-specific gene expression, showing robust GFP expression in human bladder cancer cell lines, but no visible GFP expression in normal bladder urothelial cells. The control GFP plasmid with a CMV promoter yielded GFP expression in both normal bladder cells and cancer cells. The advanced TSTA-hTERT-GFP plasmid allowed selective visualization of viable human bladder cancer cells in mixed cell culture containing 10- and 100-fold more normal bladder urothelial cells. These findings indicate that the advanced TSTA-hTERT expressional system is a valuable tool for detecting viable bladder cancer cells. The current system can be applied for in vitro detection of bladder cancer cells in urine and other types of cancer cells disseminated in vivo.

    DOI: 10.3892/ijo.2012.1417

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  • Implications of transcriptional factor, OCT-4, in human bladder malignancy and tumor recurrence. 査読 国際誌

    Peng Huang, Jie Chen, Lei Wang, Yanqun Na, Haruki Kaku, Hideo Ueki, Katsumi Sasaki, Ken Yamaguchi, Kai Zhang, Takashi Saika, Yasutomo Nasu, Masami Watanabe, Hiromi Kumon

    Medical oncology (Northwood, London, England)   29 ( 2 )   829 - 34   2012年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OCT-4, which is also known as POU5f1, is a key regulator of self-renewal in embryonic stem cells. The new cancer stem cell concept proposes that the expression of such genes is potentially correlated with tumorigenesis and can affect some aspects of the cancer behavior, such as recurrence or metastasis. This study investigated the association between OCT-4 expression in cancer tissues obtained by transurethral surgery and the clinical data to clarify the involvement of OCT-4 in human bladder malignancy. Immunohistochemical analysis demonstrated that a positive rate of OCT-4 expression was significantly associated with the higher-grade cancer (G2 and G3) in comparison with that of the lower grade (G1). In addition, positive OCT-4 expression was significantly associated with the intra-bladder tumor recurrence after the operation. The staining intensity of OCT-4 expression was also correlated with tumor recurrence. These data indicate that positive OCT-4 expression may be involved in the development of high-grade bladder cancer and with the bladder cancer recurrence. This is the first study showing a correlation between the expression of OCT-4 and bladder cancer recurrence. OCT-4 may be a valuable clinical marker for the progression of bladder cancer and may be an attractive therapeutic target for the development of new medicines for the treatment of malignancy.

    DOI: 10.1007/s12032-011-9962-4

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  • [Expression of OCT4 protein in bladder cancer and its clinicopathological implications]. 査読 国際誌

    Pengpeng Zhao, Chunxiao Liu, Kai Xu, Shaobo Zheng, Hulin Li, Yawen Xu, Abai Xu, Bingkun Li, Peng Huang

    Nan fang yi ke da xue xue bao = Journal of Southern Medical University   32 ( 5 )   643 - 6   2012年5月

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    記述言語:中国語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: To study the expression of OCT4 protein in bladder cancer and its correlation to the clinicopathologic features and prognosis of bladder cancer. METHODS: OCT4 mRNA and protein expression was detected in 5 bladder cancer cell lines (RT-4, Tcc-Sup, KK47, T24, and 5637) and 1 normal bladder cell lines by real-time PCR and Western blotting, respectively. Immunohistochemical analysis was used to detect the expression of OCT4 protein in 46 bladder cancer samples. RESULTS: All the 5 bladder cancer cell lines expressed detectable levels of OCT4 mRNA and proteins, whereas the normal bladder cell line SV-HUC-1 was negative for OCT4 expression. The clinical bladder cancer tissues showed a high positivity rate of OCT4 expression (76.1%), which was not detected in normal bladder tissues. Specific OCT-4 signals were localized mainly in the nuclei of the cancer cells. The expression rate of OCT4 protein was significantly higher in bladder cancer tissue than in normal bladder epithelium (P<0.05), and showed a positive correlation to the grade of tumor differentiation and metastasis (P<0.05) but not to the patients' age, gender or TNM stage. CONCLUSION: OCT4 protein expression is associated with tumor differentiation and metastasis in bladder cancer and may play an important role in the early diagnosis and prognostic evaluation of bladder cancer.

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  • Preclinical safety and efficacy of in situ REIC/Dkk-3 gene therapy for prostate cancer. 査読

    Keiichiro Kawauchi, Masami Watanabe, Haruki Kaku, Peng Huang, Kasumi Sasaki, Masakiyo Sakaguchi, Kazuhiko Ochiai, Nam-Ho Huh, Yasutomo Nasu, Hiromi Kumon

    Acta medica Okayama   66 ( 1 )   7 - 16   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The preclinical safety and therapeutic efficacy of adenoviral vectors that express the REIC/Dkk-3 tumor suppressor gene (Ad-REIC) was examined for use in prostate cancer gene therapy. The Ad-human (h) and mouse (m) REIC were previously demonstrated to induce strong anti-cancer effects in vitro and in vivo, and we herein report the results of two in vivo studies. First, intra-tumor Ad-hREIC administration was examined for toxicity and therapeutic effects in a subcutaneous tumor model using the PC3 prostate cancer cell line. Second, intra-prostatic Ad-mREIC administration was tested for toxicity in normal mice. The whole-body and spleen weights, hematological and serum chemistry parameters, and histological evaluation of tissues from throughout the body were analyzed. Both experiments indicated that there was no significant difference in the examined parameters between the Ad-REIC-treated group and the control (PBS- or Ad-LacZ-treated) group. In the in vitro analysis using PC3 cells, a significant apoptotic effect was observed after Ad-hREIC treatment. Confirming this observation, the robust anti-tumor efficacy of Ad-hREIC was demonstrated in the in vivo subcutaneous prostate cancer model. Based on the results of these preclinical experiments, we consider the adenovirus-mediated REIC/Dkk-3 in situ gene therapy to be safe and useful for the clinical treatment of prostate cancer.

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  • Advanced two-step transcriptional amplification as a novel method for cancer-specific gene expression and imaging. 査読 国際誌

    Masami Watanabe, Hideo Ueki, Kazuhiko Ochiai, Peng Huang, Yasuyuki Kobayashi, Yasutomo Nasu, Katsumi Sasaki, Haruki Kaku, Yuji Kashiwakura, Hiromi Kumon

    Oncology reports   26 ( 4 )   769 - 75   2011年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The two-step transcriptional amplification (TSTA) system was previously reported to enhance the tissue-specific gene expression driven by weak promoters, but the enhancement of the gene expression is limited to use in in vitro and in vivo experimental situations. To achieve robust tissue-specific gene expression using the TSTA system, we developed an advanced TSTA system which includes polyglutamines and rat glucocorticoid receptor sequences between the GAL4 and VP16 sequences in the region of the first step of transcription. We evaluated the advanced TSTA system as a method to enhance the human telomerase reverse transcriptase (hTERT) promoter-driving cancer-specific transcription in various cancer cell lines. As a result, the advanced TSTA enhanced cancer-specific luciferase gene expression in all of the examined cancer cell lines, when compared with both the one-step and conventional TSTA systems (an ~6- and ~17-fold enhancement, respectively). Notably, the enhancement of the hTERT driven expression by the conventional TSTA system was modest and even inferior to the one-step system in several cancer cell lines. We then constructed a luciferase gene encoding the adeno-associated virus vector in which the hTERT promoter-mediated expression was driven by the advanced TSTA or control systems. In an orthotopic liver tumor model, mice were treated with the vector via tail vein injection. An optical imaging device was used to visualize the in vivo luciferase expression in the orthotopic tumor. The advanced TSTA system significantly enhanced the luciferase expression compared with the one-step and conventional TSTA systems (18.0±1.0- and 15.9±0.85-fold gain, respectively). Therefore, the advanced TSTA system significantly improves hTERT-dependent cancer-specific gene expression both in vitro and in vivo when compared with the previous systems. Since the advanced TSTA method can also be applied to other site-specific gene expression systems using tissue-specific promoters, this approach is expected to become a valuable tool enabling in vivo site-specific targeting in the field of gene therapy and molecular imaging.

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  • Single nucleotide polymorphism WRN Leu1074Phe is associated with prostate cancer susceptibility in Chinese subjects. 査読

    Lei Wang, Haruki Kaku, Peng Huang, Kexin Xu, Kai Yang, Jiheng Zhang, Ming Li, Liping Xie, Xiaofeng Wang, Akiko Sakai, Masami Watanabe, Yasutomo Nasu, Kenji Shimizu, Hiromi Kumon, Yanqun Na

    Acta medica Okayama   65 ( 5 )   315 - 23   2011年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Deficiencies in the human DNA repair gene WRN are the cause of Werner syndrome, a rare autosomal recessive disorder characterized by premature aging and a predisposition to cancer. This study evaluated the association of WRN Leu1074Phe (rs1801195), a common missense single nucleotide polymorphism in WRN, with prostate cancer susceptibility in Chinese subjects. One hundred and forty-seven prostate cancer patients and 111 male cancer-free control subjects from 3 university hospitals in China were included. Blood samples were obtained from each subject, and the single nucleotide polymorphism WRN Leu1074Phe was genotyped by using a Snapshot assay. The results showed that WRN Leu1074Phe was associated with the risk of prostate cancer in Chinese men and that the TG/GG genotype displayed a decreased prevalence of prostate cancer compared with the TT genotype (OR=0.58, 95%CI:0.35-0.97, p=0.039). Through stratified analysis, more significant associations were revealed for the TG/GG genotype in the subgroup with diagnosis age ≤ 72 yr (OR=0.27, 95%CI:0.12-0.61, p=0.002) and in patients with localized diseases (OR=0.36, 95%CI:0.19-0.70, p=0.003). However, no statistically significant difference was found in the subgroup with age >72 yr or in patients with advanced diseases. We concluded that the genetic variant Leu1074Phe in the DNA repair gene WRN might play a role in the risk of prostate cancer in Chinese subjects.

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  • Tumor suppressor REIC/Dkk-3 interacts with the dynein light chain, Tctex-1. 査読 国際誌

    Kazuhiko Ochiai, Masami Watanabe, Hideo Ueki, Peng Huang, Yasuyuki Fujii, Yasutomo Nasu, Hirofumi Noguchi, Takeshi Hirata, Masakiyo Sakaguchi, Nam-Ho Huh, Yuji Kashiwakura, Haruki Kaku, Hiromi Kumon

    Biochemical and biophysical research communications   412 ( 2 )   391 - 5   2011年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    REIC/Dkk-3 is a member of the Dickkopf family proteins known as Wnt-antagonists, and REIC/Dkk-3 expression is downregulated in a broad range of cancer types. REIC/Dkk-3 acts as a tumor suppressor in multiple cancer cell lines by inducing apoptosis through endoplasmic reticulum (ER) stress signaling. However, the intracellular interaction partners of REIC/Dkk-3 have not been fully elucidated. By employing yeast two-hybrid screening, we identified the human dynein light chain, Tctex-1, as a novel interaction partner of REIC/Dkk-3. We further disclosed that the interaction involves the 136-157 amino acid region of REIC/Dkk-3 by using the mammalian two-hybrid system. Interestingly, this binding region of REIC/Dkk-3 with Tctex-1 contains an amino acid sequence motif [-E-X-G-R-R-X-H-] which was previously reported as the Tctex-1 binding domain of dynein intermediate chain (DIC). Immunocytochemistry demonstrated that both REIC/Dkk-3 and Tctex-1 were localized around the ER of human fibroblasts, and the similar distribution pattern of the proteins suggests that their interaction occurs around the ER. This is the first study showing the interaction of a Dickkopf family protein with a dynein motor complex protein. The link between REIC/Dkk-3 and Tctex-1 may be of significance for understanding the molecular functions of the proteins in ER stress signaling and intracellular dynein motor dynamics, respectively.

    DOI: 10.1016/j.bbrc.2011.07.109

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  • 【前立腺癌(第2版)-基礎・臨床研究のアップデート-】臨床 前立腺癌の治療 遺伝子治療 REIC/Dkk-3遺伝子治療

    渡部 昌実, 賀来 春紀, 黄 鵬, 那須 保友, 公文 裕巳

    日本臨床   69 ( 増刊5 前立腺癌 )   559 - 563   2011年6月

  • REIC/Dkk-3遺伝子治療 (前立腺癌(第2版)--基礎・臨床研究のアップデート) -- (臨床 前立腺癌の治療) 査読

    渡部 昌実, 賀来 春紀, 黄 鵬

    日本臨床   69 ( 0 )   559 - 563   2011年6月

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    記述言語:日本語   出版者・発行元:日本臨床社  

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    その他リンク: http://search.jamas.or.jp/link/ui/2011251185

  • Expression pattern of REIC/Dkk-3 in various cell types and the implications of the soluble form in prostatic acinar development. 査読 国際誌

    Kai Zhang, Masami Watanabe, Yuji Kashiwakura, Shun-Ai Li, Kohei Edamura, Peng Huang, Ken Yamaguchi, Yasutomo Nasu, Yasuyuki Kobayashi, Masakiyo Sakaguchi, Kazuhiko Ochiai, Hiroshi Yamada, Kohji Takei, Hideo Ueki, Nam-Ho Huh, Ming Li, Haruki Kaku, Yanqun Na, Hiromi Kumon

    International journal of oncology   37 ( 6 )   1495 - 501   2010年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The tumor suppressor REIC/Dkk-3 is a secretory protein which was originally identified to be downregulated in human immortalized cells. In the present study, we investigated the expression pattern of REIC/Dkk-3 in various cell types to characterize its physiological functions. We first examined the expression level of REIC/Dkk-3 in a broad range of cancer cell types and confirmed that it was significantly downregulated in all of the cell types. We also examined the tissue distribution pattern in a variety of normal mouse organs. Ubiquitous REIC/Dkk-3 protein expression was observed in the organs. The expression was abundant in the liver, heart and brain tissue, but was absent in the spleen and peripheral blood mononuclear cells. The immunohistochemical analyses revealed that the subcellular localization of REIC/Dkk-3 had a punctate pattern around the nucleus, indicating its association with secretory vesicles. In cancer cells stably transfected with REIC/Dkk-3, the protein was predominantly localized to the endoplasmic reticulum (ER) under observation with confocal microscopy. Because REIC/Dkk-3 was found to be abundantly expressed in the acinar epithelial cells of the mouse prostate, we analyzed the effects of recombinant REIC/Dkk-3 protein on the acinar morphogenesis of RWPE-1 cells, which are derived from human normal prostate epithelium. Statistically significant acinar growth was observed in the culture condition with 10 µg/ml REIC/Dkk-3 protein, implicating the soluble form in prostatic acinar development. Current results suggest that REIC/Dkk-3 may play a role in regulating the morphological process of normal tissue architecture through an autocrine and/or paracrine manner.

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  • Potent antitumor effects of combined therapy with a telomerase-specific, replication-competent adenovirus (OBP-301) and IL-2 in a mouse model of renal cell carcinoma 査読

    P. Huang, H. Kaku, J. Chen, Y. Kashiwakura, T. Saika, Y. Nasu, Y. Urata, T. Fujiwara, M. Watanabe, H. Kumon

    CANCER GENE THERAPY   17 ( 7 )   484 - 491   2010年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    OBP-301 (a telomerase-specific, replication-competent adenovirus with hTERT promoter) was constructed in a previous study and it showed a strong anticancer effect by inducing cell lysis in human lung and prostate cancer cells. This study investigated the effectiveness of a combination therapy of OBP-301 and interleukin-2 (IL-2) in a mouse model of renal cell carcinoma (RCC). The cell-killing effect of OBP-301 was confirmed in vitro in the RENCA cancer cells. In in vivo experiment, luciferase-expressing RENCA cells were implanted in the left kidney and lung of BALB/c mice to prepare the RCC metastatic model. The animals were randomly divided into four treatment groups: PBS, IL-2 alone, OBP-301 alone and the combination. The analyses of orthotopic tumor weight, lung metastasis and luciferin-stained tumor images 14 days after each treatment showed significant tumor growth inhibition in the combination group in comparison with that in the OBP-301- or IL-2-treated groups. In addition, the percentage of regulatory T-cells (Tregs) in the combination group was significantly suppressed in comparison with that in the PBS and single-agent treatment groups. The outcomes of this study suggest that tumor-specific oncolytic immunovirotherapy may become an attractive strategy for the treatment of human RCC. Cancer Gene Therapy (2010) 17, 484-491; doi:10.1038/cgt.2010.5; published online 19 February 2010

    DOI: 10.1038/cgt.2010.5

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  • REIC/Dkk-3 stable transfection reduces the malignant phenotype of mouse prostate cancer RM9 cells. 査読 国際誌

    Jie Chen, Masami Watanabe, Peng Huang, Masakiyo Sakaguchi, Kazuhiko Ochiai, Yasutomo Nasu, Mamoru Ouchida, Nam-Ho Huh, Kenji Shimizu, Yuji Kashiwakura, Haruki Kaku, Hiromi Kumon

    International journal of molecular medicine   24 ( 6 )   789 - 94   2009年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The reduced expression in immortalized cells (REIC)/Dickkopf (Dkk)-3, a member of the Dkk gene family, is a tumor suppressor in a broad range of cancers. REIC/Dkk-3 transfected stable clones of mouse prostate cancer RM9 cells (RM9-REIC) and the empty vector-transfected control clone cells (RM9-EV) were established. Clones were used to evaluate the anti-cancer effects and a proteomics analysis of REIC/Dkk-3 continuous expression was performed. The RM9-REIC cells show a feeble appearance and the cell membrane shows irregular buds known as blebs. In vitro cell proliferation was significantly suppressed in RM9-REIC clones in comparison to the control. The apoptosis assay was done under standard culture conditions and RM9-REIC showed a higher incidence of apoptosis. The RM9-EV and RM9-REIC cells were orthotopically implanted into a C57BL/6 mouse prostate. After 2 weeks, the tumor growth was significantly inhibited in RM9-REIC cells in comparison to the control. Two-dimensional gel electrophoresis was used to examine the modification of protein expression by the gene transfection. The analysis with mass spectrometry disclosed that expression of peroxiredoxin-1, GST-P1, transgelin-2, MRP-L12, ARD, GRP78 and Sorcin were increased and eEF1A-1 and cyclophilin-40 protein were decreased in RM9-REIC cells. Therefore, REIC/Dkk-3 stable transfectants show a reduction of malignancy in mouse prostate cancer RM9 cells in vitro and in vivo. The result of the proteomics analysis might provide important clues to clarify the anti-cancer molecular mechanism of REIC/Dkk-3 gene transfer.

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  • Immunological aspects of REIC/Dkk-3 in monocyte differentiation and tumor regression. 査読 国際誌

    Masami Watanabe, Yuji Kashiwakura, Peng Huang, Kazuhiko Ochiai, Junichiro Futami, Shun-Ai Li, Munenori Takaoka, Yasutomo Nasu, Masakiyo Sakaguchi, Nam-Ho Huh, Hiromi Kumon

    International journal of oncology   34 ( 3 )   657 - 63   2009年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The REIC/Dkk-3 gene has been reported to be a tumor suppressor and the expression is significantly down-regulated in a broad range of cancer cell types. The protein is secretory, but the physiological function remains unclear. This study demonstrated that recombinant REIC/Dkk-3 protein induced the differentiation of human CD14+ monocytes into a novel cell type (REIC/Dkk-3Mo). REIC/Dkk-3Mo resembles immature dendritic cells generated with IL-4 and GM-CSF. Both these cell populations exhibit similar proportions of CD11c+, CD40+, CD86+ and HLA-DR+ cells and endocytic capacity, but REIC/Dkk-3Mo is negative for CD1a antigen. An analysis of the signal transducers and activators of transcription (STAT) pathways revealed that REIC/Dkk-3 induces phosphorylation of STAT 1 and STAT 3. Furthermore, intratumoral administration of REIC/Dkk-3 protein significantly suppressed tumor growth with CD11c+ and CD8+ (dendritic and killer T cell marker, respectively) cell accumulation and enhanced anti-cancer cytolytic activity of splenocytes. These data indicated a cytokine-like role of REIC/Dkk-3 protein in monocyte differentiation that might be exploited therapeutically.

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  • A comparison of proteomic profiles changes during 17β-estradiol treatment in human prostate cancer PC-3 cell line 査読

    Jie Chen, Peng Huang, Haruki Kaku, Kai Zhang, Masami Watanabe, Takashi Saika, Yasutomo Nasu, Hiromi Kumon

    Cancer Genomics and Proteomics   6 ( 6 )   331 - 335   2009年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Institute of Anticancer Research  

    Human telomerase reverse transcriptase (hTERT) is overexpressed in prostate cancer. Estrogen plays a central role in the development of prostate cancer. hTERT activity has been shown to be increased after estrogen treatment. Although significant efforts have been made to understand the role of estrogen, the telomerase connection with estrogen is poorly understood. In this report, we describe a proteomics approach for investigating the global changes in protein expression in estrogen-treated human prostate cancer PC-3 cells. PC-3 cells were seeded in medium and then treated with estrogen
    the protein extract from these cells was used for two-dimensional (2D) gel electrophoresis. The protein spots were subjected to comparative analysis by liquid chromatography/mass spectrometry (LC/MS). We observed that the expression of 17 proteins, including stress-induced phosphoprotein 1 and lamin-A/C was down-regulated, and that the expression of proteins such as subunit a of T-complex protein 1, tubulin alpha-1B, and other 13 proteins was up-regulated. These proteins may have been closely associated with estrogen-induced hTERT activity. The expression level of these proteins could be a useful parameter for evaluating the estrogen-induced hTERT activity in clinical specimens of human prostate cancer.

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  • 再燃進行前立腺がんの治療の現状と展望 再燃前立腺がんに対する遺伝子治療の現況と展望 査読

    那須 保友, 賀来 春紀, 渡部 昌実, 枝村 康平, 谷本 竜太, Abaruz Fernando, 黄 鵬, 佐々木 克己, 雑賀 隆史, 公文 裕巳

    泌尿器外科   21 ( 8 )   1049 - 1051   2008年8月

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    記述言語:日本語   出版者・発行元:医学図書出版(株)  

    再燃前立腺がんに対する新たな治療法として遺伝子治療の基礎研究は分子生物学の進歩に伴いその成果を挙げてきた。さらにこれらの基礎研究の成果を臨床に還元するための研究(トランスレーショナルリサーチ)としてわれわれは遺伝子治療臨床研究を実施してきた。われわれが実施してきた自殺遺伝子としてのHSV-tk遺伝子、Interleukin-12遺伝子、腫瘍融解アデノウイルス、新規がん抑制遺伝子REICを用いた遺伝子治療研究の成果を概説することで再燃前立腺がんに対する遺伝子治療の現況とその展望を述べた。(著者抄録)

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  • Direct and distant antitumor effects of a telomerase-selective oncolytic adenoviral agent, OBP-301, in a mouse prostate cancer model 査読

    P. Huang, M. Watanabe, H. Kaku, Y. Kashiwakura, J. Chen, T. Saika, Y. Nasu, T. Fujiwara, Y. Urata, H. Kumon

    CANCER GENE THERAPY   15 ( 5 )   315 - 322   2008年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    We previously constructed OBP-301 ( Telomelysin, a telomerase-specific replication-competent adenovirus with human telomerase reverse transcriptase ( hTERT) promoter), which showed a strong anticancer effect by inducing cell lysis of human non-small cell lung cancer and colorectal cancer cells. To investigate the utility of OBP-301 for prostate cancer treatment, we herein evaluate the cell killing and antitumor effects. First, in vitro hTERT-specific adenovirus transduction in human prostate cancer cells ( LNCaP, PC3, DU145) was confirmed using OBP-401 ( Telomelysin-green fluorescent protein ( GFP)). There was no detectable GFP transduction in the human prostate normal cells ( PrEC, PrSC). Consistently, the cell-killing effect of OBP-301 was observed only in the cancer cells. Second, using an in vivo subcutaneous LNCaP tumor model in nude mice, we demonstrated that three intratumoral OBP-301 injections ( 10(7) PFU per tumor x 3 days) were sufficient to eradicate the detectable LNCaP prostate tumor. We also demonstrated that the ispilateral treatment with OBP-301 significantly suppressed contralateral LNCaP tumor growth in both sides of the tumor model. Histological and immunohistochemical analyses revealed diffuse oncolytic degeneration and adenoviral E1A protein expression in both sides of the tumors. Therefore, in situ OBP-301 administration could be a promising therapeutic strategy against prostate cancer and its metastatic lesions.

    DOI: 10.1038/cgt.2008.3

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  • 岡山大学における前立腺癌遺伝子治療研究の現況と展望 : ベーシックリサーチからトランスレーショナルリサーチへ

    賀来 春紀, 藤原 俊義, 公文 裕巳, 渡部 昌実, 黄 鵬, 陳 潔, 谷本 竜太, アバルスア フェルナンド, 枝村 康平, 真鍋 大輔, 江原 伸, 雑賀 隆史, 那須 保友, 公文 裕巳

    西日本泌尿器科   69 ( 4 )   221 - 229   2007年4月

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    記述言語:日本語   出版者・発行元:日本泌尿器科学会西日本支部  

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  • PP-245 Telomerase-Specific Replication-Selective Virotherapy for Prostate Cancer

    黄 鵬, 渡部 昌実, 陳 潔, 賀来 春紀, 那須 保友, 雑賀 隆史, 藤原 俊義, 浦田 泰生, 公文 裕巳

    日本泌尿器科学会雑誌   98 ( 2 )   458 - 458   2007年

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    記述言語:英語   出版者・発行元:一般社団法人 日本泌尿器科学会  

    DOI: 10.5980/jpnjurol.98.458_1

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MISC

  • Tracking and Imaging of Tumor Progression and Immune Function in a Preclinical Mouse Model

    Peng Huang, Naijin Xu, Eiji Matsuura, Masami Watanbe, Hiromi Kumon, Yasutomo Nasu, Chunxiao Liu

    MOLECULAR THERAPY   25 ( 5 )   98 - 98   2017年5月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:CELL PRESS  

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  • REAL-TIME MONITORING OF TUMOR PROGRESSION AND DRUG RESPONSES IN A PRECLINICAL MOUSE MODEL OF PROSTATE CANCER

    Peng Huang, Peng Xu, Xiezhao Li, Naijin Xu, Abai Xu, Masami Watanabe, Hiromi Kumon, Chunxiao Liu, Yasutomo Nasu

    JOURNAL OF UROLOGY   197 ( 4 )   E598 - E598   2017年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER SCIENCE INC  

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  • IMMUNE CHECKPOINT INHIBITOR COMBINED WITH THE GROWTH INHIBITOR LYCORINE SYNERGISTICALLY FUNCTION TO MEDIATE ANTI-TUMOR EFFECTS IN A MOUSE MODEL OF RENAL CELL CARCINOMA

    Xiezhao Li, Naijin Xu, Aibai Xu, Masami Watanabe, Peng Huang, Yasutomo Nasu, Chunxiao Liu

    JOURNAL OF UROLOGY   197 ( 4 )   E963 - E963   2017年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER SCIENCE INC  

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  • INDUCTION OF PROSTATE CANCER STEM CELL PROPERTIES IN MOUSE INDUCED PLURIPOTENT STEM CELLS VIA DEFINED CARCINOMA NICHE AND TRACKING DRUG RESPONSE IN PRECLINICAL RESEARCH

    Naijin Xu, Xiezhao Li, Aibai Xu, Masami Watanabe, Peng Huang, Yasutomo Nasu, Chunxiao Liu

    JOURNAL OF UROLOGY   197 ( 4 )   E540 - E540   2017年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER SCIENCE INC  

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  • Advanced two-step transcriptional amplification as a novel method for cancer-specific gene expression and imaging

    H. Kaku, H. Ueki, Y. Ariyoshi, S. Li, P. Huang, Y. Nasu, H. Kumon, M. Watanabe

    HUMAN GENE THERAPY   24 ( 12 )   A154 - A154   2013年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:MARY ANN LIEBERT, INC  

    Web of Science

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  • REIC/DKK-3 STABLE TRANSFECTANT INDICATES ANTI-TUMOR PHENOTYPE IN MOUSE PROSTATE CANCER RM9 CELLS

    Haruki Kaku, Jie Chen, Masami Watanabe, Peng Huang, Yuji Kashiwakura, Fernando Abarzua, Takashi Saika, Yasutomo Nasu, Hiromi Kumon

    JOURNAL OF GENE MEDICINE   11 ( 12 )   1182 - 1182   2009年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:JOHN WILEY & SONS LTD  

    Web of Science

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  • Telomerase-specific replication-selective virotherapy for prostate cancer

    Haruki Kaku, Yasutomo Nasu, Peng Huang, Takashi Saika, Shunsuke Kagawa, Toshiyoshi Fujiwara, Hiromi Kumon, Yasuo Urata

    JOURNAL OF GENE MEDICINE   8 ( 12 )   1454 - 1454   2006年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:JOHN WILEY & SONS LTD  

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産業財産権

  • トリアゾール誘導体の用途

    黄 鵬, 渡部昌実, 林 文鋒

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    出願人:国立大学法人岡山大学

    出願番号:特願2021-053244  出願日:2021年3月26日

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  • ニトロキソリンおよびその類似体と、化学療法剤および免疫療法剤との、がんの治療における、組合せの使用

    Ke PAN, Peng HUANG, Qiang LI

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    出願人:Asieris Pharmaceutical Technologies Co., Ltd.

    出願番号:特願16089800  出願日:2017年3月31日

    公開番号:特開20190275025  公開日:2019年9月12日

    特許番号/登録番号:特許WO/2017/173278  登録日:2017年3月31日  発行日:2017年10月5日

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  • 遺伝子導入リンパ球の移植による細胞療法における治療効果及びGVHDを可視化するPETイメージング技術

    松浦栄次, 阪口政清, 公文裕巳, 黄鵬, 竹中文章

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    出願人:国立大学法人岡山大学

    出願番号:特願2016-066068  出願日:2016年3月29日

    公開番号:特開2017-178818  公開日:2017年10月5日

    特許番号/登録番号:特許6707256  登録日:2020年5月22日 

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受賞

  • ベストポスター賞(2018)

    2018年5月   アメリカ泌尿器科総会  

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共同研究・競争的資金等の研究

  • 骨髄由来免疫抑制細胞の抗癌免疫逃避機構の解明に基づく革新的癌創薬の探索

    研究課題/領域番号:21K09371  2021年04月 - 2024年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    黄 鵬, 渡部 昌実, 荒木 元朗, 植木 英雄

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

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  • 治療抵抗性前立腺癌における癌化-ステロイドシグナルaxisの機構解明

    研究課題/領域番号:21K09423  2021年04月 - 2024年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    小林 泰之, 那須 保友, 荒木 元朗, 定平 卓也, 黄 鵬

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    配分額:3900000円 ( 直接経費:3000000円 、 間接経費:900000円 )

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  • 細胞骨格ダイナミクスに基づく分子輸送制御システムの解明と革新的癌創薬への新展開

    研究課題/領域番号:19H01064  2019年04月 - 2024年03月

    日本学術振興会  科学研究費助成事業 基盤研究(A)  基盤研究(A)

    渡部 昌実, 那須 保友, 竹居 孝二, 竹田 哲也, 野口 洋文, 山田 浩司, 黄 鵬, 定平 卓也

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    配分額:40300000円 ( 直接経費:31000000円 、 間接経費:9300000円 )

    各種癌細胞を入手すると同時に、より普遍性の高い研究を遂行する為、独自のマウス間葉系幹細胞を樹立した。各種癌細胞において、細胞骨格因子が関わる細胞内分子輸送システムに重要と考えられるタンパク質群の発現を網羅的に解析した。特に、REIC/Dkk-3、SGTA、Tctex-1、Dyneinモーター、Dynaminおよびその他の細胞骨格(制御)因子に着目して、それら関連分子を含め発現を解析した。一部のタンパク質においてはその発現を認めず、免疫組織学的な解析を行うべく準備を進めた。これまでの男性ホルモンレセプターの核内移行に基づく実験系に加え、糖質コルチコイドレセプターの核内移行に基づく表現型解析系を立ち上げた。また癌創薬の観点から複数のDynamin阻害薬に関する検討を行い、in vivo投与での作用機序解明に係る動物実験での解析系の立ち上げを行った。

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  • 制限増殖型アデノウィルスを用いた次世代遺伝子治療の基盤研究

    研究課題/領域番号:18K09194  2018年04月 - 2021年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    小林 泰之, 黄 鵬, 那須 保友, 定平 卓也, 植木 英雄

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    癌に対するウイルスベクター投与治療の研究開発では、新たな薬剤創製、そして臨床効果の検証と効果増強法への展開が中心的課題となっている。我々は「癌治療遺伝子REIC/Dkk-3 を用いた前立腺癌に対する in-situ 遺伝子治療」の臨床研究において、腫抗腫瘍効果を確認しさらに「癌細胞の選択的アポトーシス」の誘導を実証している。本研究は、癌治療遺伝子REIC(Reduced Expression in Immortalized Cells)を制限増殖型アデノウイルスベクター(Oncolytic Adenovirus)で超高発現させることにより、抗腫瘍効果と抗癌免疫活性を著明に高める治療法に関する研究である。すなわち、強力なOncolyticシステムを REIC 遺伝子治療薬に組み込んだ新規のアデノウイルスベクター治療剤を用いることにより、尿路癌における当該治療法の治療効果の最大化および最適化を目指す研究を実施している。従来の研究により当該Oncolytic Ad-REICの各種癌細胞に対する抗腫瘍メカニズム・有効性が検証され、その局所投与による作用機序として「腫瘍局所での癌選択的細胞死による大量の癌抗原の提示」と「樹状細胞の分化誘導による抗癌免疫の同時活性化」が報告されている。そこで本年度の本申請研究では、アデノウイルスベクターの腫瘍内局所投与方法に関して基盤となる研究を実施した。また同様の観点から、前立腺癌のみならず膀胱癌に対する次世代遺伝子治療の基盤の確立を目指した研究を実施した。

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  • 前立腺癌幹細胞を標的とした新規遺伝子治療戦略の確立

    研究課題/領域番号:17K11138  2017年04月 - 2020年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    黄 鵬, 那須 保友, 定平 卓也, 植木 英雄

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    平成29年に引き続き、外源性REICより小胞体ストレス応答に基づく癌幹細胞に標的治療のメカニズムの一端を解明するため、癌幹細胞マウスモデルに対するREIC/DKK3遺伝子の有効性を検証した。さらに、我々の確立したREIC/Dkk-3ノックアウト(KO)マウスを用いた実験系では、生体内の内在性・機能的REIC/Dkk-3タンパク質の影響を回避することが可能となり、以下の研究を行った。平成30年度、REIC遺伝子発現アデノウイルスベクターのin vivoでのオートファジー誘導腫瘍増殖抑制効果を行った。具体的には、GFPとPSAを恒常発現する前立腺癌幹細胞株(mice ips-RM-9))を用いて同所移植モデル、肺転移モデル等を作製し、REIC遺伝子発現アデノウイルスベクターを投与した場合の全身の転移に対するオートファジー誘導され治療効果を解析した。
    さらに、REIC遺伝子発現アデノウイルスベクターを用いて治療を行った腫瘍内における抗癌免疫担当細胞の出現動態、特に抗癌免疫に強く関わるとされる、MDSC、樹状細胞、細胞傷害性Tリンパ球(CTL)、制御性Tリンパ球、ヘルパーTリンパ球、ナチュラルキラー(NK)細胞等の細胞について、それぞれの細胞表面マーカーに基づき免疫組織学的に解析を行った。特に当該治療効果については、in vitro 検証したkey分子に関する検証も行った。

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  • 前立腺癌における悪性形質およびアンドロゲン不応性の一元的制御機構の解明

    研究課題/領域番号:15H04297  2015年04月 - 2019年03月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    渡部 昌実, 黄 鵬, 野口 洋文, 植木 英雄

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    配分額:16510000円 ( 直接経費:12700000円 、 間接経費:3810000円 )

    REIC/Dkk-3遺伝子を癌細胞内で強制発現することにより、アポトーシスが誘導される。本研究により、REIC/Dkk-3はAndrogen標的性を持つ前立腺癌において、RasおよびAndrogenシグナルの両方を制御し、Androgen除去療法抵抗性前立腺癌の発生に関与すると考えられた。またREIC/Dkk-3のこれらの機能と、細胞内に張り巡らされた細胞骨格に基づく分子輸送システムとの関連を示唆する知見を得た。

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  • 癌増悪因子:CD147 Emmprinを標的とした新規の抗癌免疫療法の基盤の確立

    研究課題/領域番号:15K10590  2015年04月 - 2018年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    小林 泰之, 黄 鵬, 渡部 昌実, 植木 英雄

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    CD147癌抗原-サイトカイン融合タンパク質群を独自に作成し、担癌モデルマウスにおける治療実験系を確立し、CD147癌抗原を発現する腫瘍に特異的な抗腫瘍効果を確認した。また、癌増殖抑制タンパク質:REIC/Dkk-3と癌増悪タンパク質CD147タンパク質の相互関係を示唆する所見として、REIC/Dkk-3の発現が癌増悪因子であるCD147の発現をダウンレギュレーションしていることが明らかとなった。今回の研究成果として、CD147タンパク質が各種サイトカインやREIC/Dkk-3に基づく癌免疫・ワクチン療法において有望な標的となり得ることが示された。

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  • 腫瘍融解性Ad-REICを用いた新規癌ワクチン療法の開発

    研究課題/領域番号:15K20093  2015年04月 - 2017年03月

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    黄 鵬, 公文 裕巳, 那須 保友, 渡部 昌実, 植木 英雄

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    配分額:3900000円 ( 直接経費:3000000円 、 間接経費:900000円 )

    REIC/Dkk-3遺伝子を基盤シーズとする日本発の癌標的治療の創出基盤を強化し、泌尿器科領域の癌のみならず、多くの難治固形癌に対する、癌免疫逃避の抑制および癌ワクチン化を目的とした、次世代REIC遺伝子発現制限増殖型アデノウイルスベクター(腫瘍融解性Ad-REIC)遺伝子治療の抗腫瘍免疫学的な展開基盤になるものと判断される。

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  • 癌抑制遺伝子REICの抗癌免疫逃避機構の解析

    研究課題/領域番号:25861425  2013年04月 - 2015年03月

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    黄 鵬

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    配分額:3770000円 ( 直接経費:2900000円 、 間接経費:870000円 )

    癌抑制遺伝子REIC/Dkk-3を治療遺伝子とする固形癌に対するin-situ遺伝子治療は、「癌細胞の選択的アポトーシス」と「抗癌免疫の活性化」による相乗的効果増強作用(自己癌ワクチン化)を誘導し、原発巣のみならず転移巣に対しても顕著な治療効果を示すことが複数の動物モデルで実証されている。本申請研究では、広範な抗癌免疫担当細胞の抑制作用を示すMDSCの分化をREIC/Dkk-3タンパク質が阻害するメカニズムが明らかとなっており、次世代癌免疫逃避の抑制および癌ワクチン化療法としてのREIC遺伝子治療の抗腫瘍免疫学的基盤の確立につながることが示唆された。

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  • 尿路癌に対する次世代癌免疫療法の創成

    研究課題/領域番号:25462479  2013年04月 - 2015年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    賀来 春紀, 黄 鵬, 那須 保友, 植木 英雄

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    癌標的医療の近年の研究開発においては、新たな分子標的薬の探索とともに癌ワクチンの創製、特に、その臨床効果の検証と効果増強法の解明が中心課題となっている。申請者らは新規の癌免疫療法「癌治療遺伝子REIC/Dkk-3 を用いた前立腺癌に対するin-situ 遺伝子治療」の臨床研究において、既にPSA 低下を伴う抗腫瘍効果を確認し、さらに「癌細胞の選択的アポトーシス」と「抗癌免疫の活性化」による相乗的効果増強作用(自己癌ワクチン化)が誘導されることを実証しつつある。また、近年、申請者らは極めて強力な遺伝子発現を実現する新規の超高効率遺伝子発現(SGE)システムの開発に成功した。本研究では、この超高効率遺伝子発現技術をREICアデノウイルスベクターに組み込んだAd-SGE-REIC剤を用いて、尿路癌を中心とした複数の癌種においてAd-SGE-REIC剤の殺癌細胞効果を検証した。また、現存の超高効率遺伝子発現システム(発現遺伝子の直ぐ下流に3つのエンハンサー配列 [hTERT、SV40、CMV] を挿入)を更に改良する為の基盤研究を実施した。まずプラスミドベクターレベルでSGE システムの優位性をさらに向上させる目的で、発現遺伝子の直ぐ下流に各種エンハンサー群を挿入し、それぞれの場合の遺伝子発現について「SGE 遺伝子発現システムの最適化」の観点から解析した。この結果を踏まえて、各尿路性器癌に最も適したSGEシステムを決定し、各癌における自己癌ワクチン化を目指したREIC遺伝子治療の最適化につなげていく方針である。
    本研究により、複数の癌種においてAd-SGE-REIC剤の殺癌細胞効果の優位性(従来のAd-REICと比較した際の)を確認した。得られたin vitro実験での知見を踏まえて、今後はin vivo投与実験等へ研究を進め、さらに、SGE 遺伝子発現システムの最適化に関する研究を継続して実施する。

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  • PETイメージングによるがん遺伝子治療評価モデルの構築

    2012年04月 - 2013年03月

    科学技術振興機構(JST)  研究成果最適展開支援プログラム(A-STEP)  探索タイプ

    黄 鵬

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    担当区分:研究代表者 

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  • 尿路性器癌に対するテロメラーゼ活性を標的とした新規ウイルス療法の開発研究

    研究課題/領域番号:18591754  2006年 - 2008年

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    賀来 春紀, 那須 保友, 藤原 俊義, 香川 俊輔, 黄 鵬

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    配分額:3970000円 ( 直接経費:3400000円 、 間接経費:570000円 )

    本研究は尿路性器癌に対するテロメラーゼ活性を標的とした新規ウイルス療法の開発研究を目的とした。研究期間内に転移癌を含む前立腺癌、腎癌に対する有効性、他の療法との併用効果の増強が確認された。一方、Telomelysinと新規癌抑制遺伝子REICとの併用効果は癌種によって効果は一定ではなく、新規ウイルスArmed-Telomelysin(Telomelysin-REIC)の作製に至らなかった。

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