研究者詳細 - 藤澤　真義

論文 - 藤澤　真義

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Tumor Microvessels with Specific Morphology as a Prognostic Factor in Esophageal Squamous Cell Carcinoma

Hnin Thida Tun, Masayoshi Fujisawa, Toshiaki Ohara, Seitaro Nishimura, Tomoyoshi Kunitomo, Kazuhiro Noma, Akihiro Matsukawa

Annals of Surgical Oncology 2025年7月

Expression of SPRED2 in the lung adenocarcinoma. 国際誌

Yoko Ota, Tong Gao, Masayoshi Fujisawa, I Wayan Sumardika, Masakiyo Sakaguchi, Shinichi Toyooka, Teizo Yoshimura, Akihiro Matsukawa

Pathology, research and practice 265 155721 - 155721 2024年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

SPRED2 (Sprouty-related, EVH1 domain-containing protein 2), a negative regulator of the ERK1/2 pathway, is downregulated in several cancers; however, the significance of SPRED2 expression in lung adenocarcinoma (LUAD) remains unclear. Here, we investigated the pathological expression of SPRED2 and its relationship with ERK1/2 activation (ERK1/2 phosphorylation), Ki67 index and clinicopathological features in 77 LUAD tissues from clinical patients. Immunohistochemically, SPRED2 expression was decreased in invasive adenocarcinoma (IA) compared to adenocarcinoma in situ (AIS). There was a negative correlation between SPRED2 expression and pERK1/2 levels and a positive correlation between SPRED2 expression and Ki67 index. In the database analysis, the survival probability was higher in patients with higher SPRED2 expression than in those with lower expression. In vitro, SPRED2 deletion increased cell proliferation, migration and invasion of three LUAD cell lines (A549:KRAS mutation, H1993:METamplification, and HCC4006:EGFR mutation), whereas SPRED2 overexpression decreased these responses. Thus, SPRED2 appears to be a regulator of LUAD progression and a potential target for the treatment of LUAD.

DOI： 10.1016/j.prp.2024.155721

Exosomal delivery of miR-200b-3p suppresses the growth of hepatocellular carcinoma cells by targeting ERG- and VEGF-mediated angiogenesis. 国際誌

Yuze Wang, Aye Moh-Moh-Aung, Tianyi Wang, Masayoshi Fujisawa, Toshiaki Ohara, Ken-Ichi Yamamoto, Masakiyo Sakaguchi, Teizo Yoshimura, Akihiro Matsukawa

Gene 148874 - 148874 2024年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited treatment options. Recent discoveries have highlighted the pivotal role of miRNAs in HCC progression. We previously reported that the expression of miR-200b-3p was decreased in HCC cells and exosomal miR-200b-3p from hepatocytes inhibited angiogenesis by suppressing the expression of the endothelial transcription factor ERG (erythroblast transformation-specific (ETS)-related gene), leading to the hypothesis that the delivery of this miRNA may inhibit angiogenesis and suppress HCC growth in vivo. Here, we tested this hypothesis by using human HCC inoculation models. First, we transfected the human HepG2 HCC cells and established a stable cell line that overexpressed a high level of miR-200b-3p. When miR-200b-3p-overexpressing cells were injected into severe combined immunedeficiency (SCID)-beige mice, tumor growth was significantly reduced compared to tumors of control cells, with a reduction in the expression of ERG and vascular endothelial growth factor (VEGF) and subsequent angiogenesis. Intra-tumoral injection of exosomes containing high levels of miR-200b-3p also reduced the growth of parental HepG2 tumors with reduced ERG and VEGF expression and angiogenesis. These results validate the inhibitory role of miR-200b-3p in tumor angiogenesis, thereby suppressing HCC tumor growth, and provide a novel insight into its potential therapeutic application.

DOI： 10.1016/j.gene.2024.148874

SPRED2 Is a Novel Regulator of Autophagy in Hepatocellular Carcinoma Cells and Normal Hepatocytes. 国際誌

Tianyi Wang, Tong Gao, Masayoshi Fujisawa, Toshiaki Ohara, Masakiyo Sakaguchi, Teizo Yoshimura, Akihiro Matsukawa

International journal of molecular sciences 25 ( 11 ) 2024年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Sprouty-related enabled/vasodilator-stimulated phosphoprotein homology 1 domain containing 2 (SPRED2) is an inhibitor of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway and has been shown to promote autophagy in several cancers. Here, we aimed to determine whether SPRED2 plays a role in autophagy in hepatocellular carcinoma (HCC) cells. The Cancer Genome Atlas (TCGA) Liver Cancer Database showed a negative association between the level of SPRED2 and p62, a ubiquitin-binding scaffold protein that accumulates when autophagy is inhibited. Immunohistochemically, accumulation of p62 was detected in human HCC tissues with low SPRED2 expression. Overexpression of SPRED2 in HCC cells increased the number of autophagosomes and autophagic vacuoles containing damaged mitochondria, decreased p62 levels, and increased levels of light-chain-3 (LC3)-II, an autophagy marker. In contrast, SPRED2 deficiency increased p62 levels and decreased LC3-II levels. SPRED2 expression levels were negatively correlated with translocase of outer mitochondrial membrane 20 (TOM20) expression levels, suggesting its role in mitophagy. Mechanistically, SPRED2 overexpression reduced ERK activation followed by the mechanistic or mammalian target of rapamycin complex 1 (mTORC1)-mediated signaling pathway, and SPRED2 deficiency showed the opposite pattern. Finally, hepatic autophagy was impaired in the liver of SPRED2-deficient mice with hepatic lipid droplet accumulation in response to starvation. These results indicate that SPRED2 is a critical regulator of autophagy not only in HCC cells, but also in hepatocytes, and thus the manipulation of this process may provide new insights into liver pathology.

DOI： 10.3390/ijms25116269

The specific shapes of capillaries are associated with worse prognosis in patients with invasive breast cancer. 国際誌

Hnin-Wint-Wint Swe, Masayoshi Fujisawa, Toshiaki Ohara, Yu Komatsubara, Teizo Yoshimura, Tadahiko Shien, Akihiro Matsukawa

Pathology international 2024年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Angiogenesis is considered essential for tumor progression; however, whether histological counting of blood vessel numbers, expressed as microvessel density (MVD), can be a prognostic factor in breast cancer remains controversial. It has been suggested that the specific morphology of blood vessels such as glomeruloid microvascular proliferation (GMP) is associated with clinical parameters. Here, we aimed to clarify the significance of MVD with revised immunohistochemistry and to identify new blood vessel shapes that predict prognosis in breast cancer. Four hundred and eleven primary breast cancer specimens were collected, and the sections were immunohistochemically stained with CD31 (single staining) and CD31 and Collagen IV (double staining). The prognosis of patients was examined based on the MVD value, and the presence of GMP and other blood vessels with other specific shapes. As a result, high MVD value and the presence of GMP were not associated with worse prognosis. By contrast, patients with deep-curved capillaries surrounding tumor cell nests (C-shaped) or excessively branched capillaries near tumor cell nests showed a significantly poor prognosis. The presence of these capillaries was also correlated with clinicopathological parameters such as Ki-67 index. Thus, the morphology of capillaries rather than MVD can be a better indicator of tumor aggressiveness.

DOI： 10.1111/pin.13442

SPRED2: A Novel Regulator of Epithelial-Mesenchymal Transition and Stemness in Hepatocellular Carcinoma Cells. 国際誌

Tong Gao, Xu Yang, Masayoshi Fujisawa, Toshiaki Ohara, Tianyi Wang, Nahoko Tomonobu, Masakiyo Sakaguchi, Teizo Yoshimura, Akihiro Matsukawa

International journal of molecular sciences 24 ( 5 ) 2023年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

The downregulation of SPRED2, a negative regulator of the ERK1/2 pathway, was previously detected in human cancers; however, the biological consequence remains unknown. Here, we investigated the effects of SPRED2 loss on hepatocellular carcinoma (HCC) cell function. Human HCC cell lines, expressing various levels of SPRED2 and SPRED2 knockdown, increased ERK1/2 activation. SPRED2-knockout (KO)-HepG2 cells displayed an elongated spindle shape with increased cell migration/invasion and cadherin switching, with features of epithelial-mesenchymal transition (EMT). SPRED2-KO cells demonstrated a higher ability to form spheres and colonies, expressed higher levels of stemness markers and were more resistant to cisplatin. Interestingly, SPRED2-KO cells also expressed higher levels of the stem cell surface markers CD44 and CD90. When CD44+CD90+ and CD44-CD90- populations from WT cells were analyzed, a lower level of SPRED2 and higher levels of stem cell markers were detected in CD44+CD90+ cells. Further, endogenous SPRED2 expression decreased when WT cells were cultured in 3D, but was restored in 2D culture. Finally, the levels of SPRED2 in clinical HCC tissues were significantly lower than those in adjacent non-HCC tissues and were negatively associated with progression-free survival. Thus, the downregulation of SPRED2 in HCC promotes EMT and stemness through the activation of the ERK1/2 pathway, and leads to more malignant phenotypes.

DOI： 10.3390/ijms24054996

Highly Metastatic Subpopulation of TNBC Cells Has Limited Iron Metabolism and Is a Target of Iron Chelators 査読

Yuze Wang, Toshiaki Ohara, Yuehua Chen, Yusuke Hamada, Chunning Li, Masayoshi Fujisawa, Teizo Yoshimura, Akihiro Matsukawa

Cancers 15 ( 2 ) 468 2023年1月

Exosomal Wnt7a from a low metastatic subclone promotes lung metastasis of a highly metastatic subclone in the murine 4t1 breast cancer. 国際誌

Chunning Li, Teizo Yoshimura, Miao Tian, Yuze Wang, Takamasa Kondo, Ken-Ichi Yamamoto, Masayoshi Fujisawa, Toshiaki Ohara, Masakiyo Sakaguchi, Akihiro Matsukawa

Breast cancer research : BCR 24 ( 1 ) 60 - 60 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Patients with triple-negative breast cancer (TNBC) often have poorer prognosis than those with other subtypes because of its aggressive behaviors. Cancer cells are heterogeneous, and only a few highly metastatic subclones metastasize. Although the majority of subclones may not metastasize, they could contribute by releasing factors that increase the capacity of highly metastatic cells and/or provide a favorable tumor microenvironment (TME). Here, we analyzed the interclonal communication in TNBC which leads to efficient cancer progression, particularly lung metastasis, using the polyclonal murine 4T1 BC model. METHODS: We isolated two 4T1 subclones, LM.4T1 and HM.4T1 cells with a low and a high metastatic potential, respectively, and examined the effects of LM.4T1 cells on the behaviors of HM.4T1 cells using the cell scratch assay, sphere-forming assay, sphere invasion assay, RT-qPCR, and western blotting in vitro. We also examined the contribution of LM.4T1 cells to the lung metastasis of HM.4T1 cells and TME in vivo. To identify a critical factor which may be responsible for the effects by LM.4T1 cells, we analyzed the data obtained from the GEO database. RESULTS: Co-injection of LM.4T1 cells significantly augmented lung metastases by HM.4T1 cells. LM.4T1-derived exosomes promoted the migration and invasion of HM.4T1 cells in vitro, and blocking the secretion of exosome abrogated their effects on HM.4T1 cells. Analyses of data obtained from the GEO database suggested that Wnt7a might be a critical factor responsible for the enhancing effects. In fact, a higher level of Wnt7a was detected in LM.4T1 cells, especially in exosomes, than in HM.4T1 cells, and deletion of Wnt7a in LM.4T1 cells significantly decreased the lung metastasis of HM.4T1 cells. Further, treatment with Wnt7a increased the spheroid formation by HM.4T1 cells via activation of the PI3K/Akt/mTOR signaling pathway. Finally, infiltration of αSMA-positive fibroblasts and angiogenesis was more prominent in tumors of LM.4T1 cells and deletion of Wnt7a in LM.4T1 cells markedly reduced angiogenesis. CONCLUSIONS: We demonstrated, for the first time, that a low metastatic subclone can enhance lung metastasis of highly metastatic subclone via exosomal Wnt7a and propose Wnt7a as a molecular target to treat TNBC patients.

DOI： 10.1186/s13058-022-01557-5

Thioredoxin interacting protein protects mice from fasting induced liver steatosis by activating ER stress and its downstream signaling pathways. 国際誌

Hiroyuki Miyahara, Kosei Hasegawa, Masato Yashiro, Toshiaki Ohara, Masayoshi Fujisawa, Teizo Yoshimura, Akihiro Matsukawa, Hirokazu Tsukahara

Scientific reports 12 ( 1 ) 4819 - 4819 2022年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Under normal conditions, fasting results in decreased protein disulfide isomerase (PDI) activity and accumulation of unfolded proteins, leading to the subsequent activation of the unfolded protein response (UPR)/autophagy signaling pathway to eliminate damaged mitochondria. Fasting also induces upregulation of thioredoxin-interacting protein (TXNIP) expression and mice deficient of this protein (TXNIP-KO mice) was shown to develop severe hypoglycemia, hyperlipidemia and liver steatosis (LS). In the present study, we aimed to determine the role of TXNIP in fasting-induced LS by using male TXNIP-KO mice that developed LS without severe hypoglycemia. In TXNIP-KO mice, fasting induced severe microvesicular LS. Examinations by transmission electron microscopy revealed mitochondria with smaller size and deformities and the presence of few autophagosomes. The expression of β-oxidation-associated genes remained at the same level and the level of LC3-II was low. PDI activity level stayed at the original level and the levels of p-IRE1 and X-box binding protein 1 spliced form (sXBP1) were lower. Interestingly, treatment of TXNIP-KO mice with bacitracin, a PDI inhibitor, restored the level of LC3-II after fasting. These results suggest that TXNIP regulates PDI activity and subsequent activation of the UPR/autophagy pathway and plays a protective role in fasting-induced LS.

DOI： 10.1038/s41598-022-08791-z

Spred2 controls the severity of Concanavalin A-induced liver damage by limiting interferon-gamma production by CD4+ and CD8+ T cells. 国際誌

Cuiming Sun, Masayoshi Fujisawa, Toshiaki Ohara, Qiuying Liu, Chen Cao, Xu Yang, Teizo Yoshimura, Steven L Kunkel, Akihiro Matsukawa

Journal of advanced research 35 71 - 86 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Introduction: Mitogen-activated protein kinases (MAPKs) are involved in T cell-mediated liver damage. However, the inhibitory mechanism(s) that controls T cell-mediated liver damage remains unknown. Objectives: We investigated whether Spred2 (Sprouty-related, EVH1 domain-containing protein 2) that negatively regulates ERK-MAPK pathway has a biological impact on T cell-mediated liver damage by using a murine model. Methods: We induced hepatotoxicity in genetically engineered mice by intravenously injecting Concanavalin A (Con A) and analyzed the mechanisms using serum chemistry, histology, ELISA, qRT-PCR, Western blotting and flow cytometry. Results: Spred2-deficient mice (Spred2-/-) developed more sever liver damage than wild-type (WT) mice with increased interferon-γ (IFNγ) production. Hepatic ERK phosphorylation was enhanced in Spred2-/- mice, and pretreatment of Spred2-/- mice with the MAPK/ERK inhibitor U0126 markedly inhibited the liver damage and reduced IFNγ production. Neutralization of IFNγ abolished the damage with decreased hepatic Stat1 activation in Spred2-/- mice. IFNγ was mainly produced from CD4+ and CD8+ T cells, and their depletion decreased liver damage and IFNγ production. Transplantation of CD4+ and/or CD8+ T cells from Spred2-/- mice into RAG1-/- mice deficient in both T and B cells caused more severe liver damage than those from WT mice. Hepatic expression of T cell attractants, CXCL9 and CXCL10, was augmented in Spred2-/- mice as compared to WT mice. Conversely, liver damage, IFNγ production and the recruitment of CD4+ and CD8+ T cells in livers after Con A challenge were lower in Spred2 transgenic mice, and Spred2-overexpressing CD4+ and CD8+ T cells produced lower levels of IFNγ than WT cells upon stimulation with Con A in vitro. Conclusion: We demonstrated, for the first time, that Spred2 functions as an endogenous regulator of T cell IFNγ production and Spred2-mediated inhibition of ERK-MAPK pathway may be an effective remedy for T cell-dependent liver damage.

DOI： 10.1016/j.jare.2021.03.014

Crosstalk between Cancer Cells and Fibroblasts for the Production of Monocyte Chemoattractant Protein-1 in the Murine 4T1 Breast Cancer. 国際誌

Mayu Imamura, Tiantian Li, Chunning Li, Masayoshi Fujisawa, Naofumi Mukaida, Akihiro Matsukawa, Teizo Yoshimura

Current issues in molecular biology 43 ( 3 ) 1726 - 1740 2021年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

The chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) is shown to promote the progression of breast cancer. We previously identified cancer cell-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) as a potential regulator of MCP-1 production in the murine 4T1 breast cancer, but it played a minimum role in overall MCP-1 production. Here, we evaluated the crosstalk between 4T1 cells and fibroblasts. When fibroblasts were co-cultured with 4T1 cells or stimulated with the culture supernatants of 4T1 cells (4T1-sup), MCP-1 production by fibroblasts markedly increased. 4T1 cells expressed mRNA for platelet-derived growth factor (PDGF)-a, b and c, and the PDGF receptor inhibitor crenolanib almost completely inhibited 4T1-sup-induced MCP-1 production by fibroblasts. However, PDGF receptor antagonists failed to reduce MCP-1 production in tumor-bearing mice. Histologically, 4T1 tumors contained a small number of αSMA-positive fibroblasts, and Mcp-1 mRNA was mainly associated with macrophages, especially those surrounding necrotic lesions on day 14, by in situ hybridization. Thus, although cancer cells have the capacity to crosstalk with fibroblasts via PDGFs, this crosstalk does not play a major role in MCP-1 production or cancer progression in this model. Unraveling complex crosstalk between cancer cells and stromal cells will help us identify new targets to help treat breast cancer patients.

DOI： 10.3390/cimb43030122

PolyI:C suppresses TGF-β1-induced Akt phosphorylation and reduces the motility of A549 lung carcinoma cells. 国際誌

Takahiro Yamaguchi, Teizo Yoshimura, Toshiaki Ohara, Masayoshi Fujisawa, Gao Tong, Akihiro Matsukawa

Molecular biology reports 48 ( 9 ) 6313 - 6321 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUNDS: Epithelial mesenchymal transition (EMT) is a critical process involved in the invasion and metastasis of cancer, including lung cancer (LC). Transforming growth factor (TGF)-β is one of factors capable of inducing EMT. Polyinosinic-polycytidylic acid (polyI:C), a synthetic agonist for toll-like receptor (TLR) 3, can enhance immune responses and has been used as an adjuvant for cancer vaccines; however, it remains unclear whether it influences other process, such as EMT. In the present study, we examined the effects of polyI:C on TGF-β-treated A549 human LC cells. METHODS AND RESULTS: By in vitro cell proliferation assay, polyI:C showed no effect on the growth of A549 cells treated with TGF-β1 at the concentration range up to 10 μg/ml; however, it markedly suppressed the motility in a cell scratch and a cell invasion assay. By Western blotting, polyI:C dramatically decreased TGF-β1-induced Ak strain transforming (Akt) phosphorylation and increased phosphatase and tensin homologue (PTEN) expression without affecting the Son of mothers against decapentaplegic (Smad) 3 phosphorylation or the expression level of E-cadherin, N-cadherin or Snail, indicating that polyI:C suppressed cell motility independently of the 'cadherin switching'. The Akt inhibitor perifosine inhibited TGF-β1-induced cell invasion, and the PTEN-specific inhibitor VO-OHpic appeared to reverse the inhibitory effect of polyI:C. CONCLUSION: PolyI:C has a novel function to suppress the motility of LC cells undergoing EMT by targeting the phosphatidylinositol 3-kinase/Akt pathway partly via PTEN and may prevent or reduce the metastasis of LC cells.

DOI： 10.1007/s11033-021-06625-1

Detection of cutaneous prion protein deposits could help diagnose GPI-anchorless prion disease with neuropathy 査読国際誌

European Journal of Neurology 28 ( 6 ) 2133 - 2137 2021年1月

Expression of Spred2 in the urothelial tumorigenesis of the urinary bladder. 国際誌

Shinsuke Oda, Masayoshi Fujisawa, Li Chunning, Toshihiro Ito, Takahiro Yamaguchi, Teizo Yoshimura, Akihiro Matsukawa

PloS one 16 ( 11 ) e0254289 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）

Aberrant activation of the Ras/Raf/ERK (extracellular-signal-regulated kinase)-MAPK (mitogen-activated protein kinase) pathway is involved in the progression of cancer, including urothelial carcinoma; but the negative regulation remains unclear. In the present study, we investigated pathological expression of Spred2 (Sprouty-related EVH1 domain-containing protein 2), a negative regulator of the Ras/Raf/ERK-MAPK pathway, and the relation to ERK activation and Ki67 index in various categories of 275 urothelial tumors obtained from clinical patients. In situ hybridization demonstrated that Spred2 mRNA was highly expressed in high-grade non-invasive papillary urothelial carcinoma (HGPUC), and the expression was decreased in carcinoma in situ (CIS) and infiltrating urothelial carcinoma (IUC). Immunohistochemically, membranous Spred2 expression, important to interact with Ras/Raf, was preferentially found in HGPUC. Interestingly, membranous Spred2 expression was decreased in CIS and IUC relative to HGPUC, while ERK activation and the expression of the cell proliferation marker Ki67 index were increased. HGPUC with membranous Spred2 expression correlated significantly with lower levels of ERK activation and Ki67 index as compared to those with negative Spred2 expression. Thus, our pathological findings suggest that Spred2 counters cancer progression in non-invasive papillary carcinoma possibly through inhibiting the Ras/Raf/ERK-MAPK pathway, but this regulatory mechanism is lost in cancers with high malignancy. Spred2 appears to be a key regulator in the progression of non-invasive bladder carcinoma.

DOI： 10.1371/journal.pone.0254289

Spred2-deficiency enhances the proliferation of lung epithelial cells and alleviates pulmonary fibrosis induced by bleomycin. 国際誌

Akina Kawara, Ryo Mizuta, Masayoshi Fujisawa, Toshihiro Ito, Chunning Li, Kaoru Nakamura, Cuiming Sun, Masaki Kuwabara, Masahiro Kitabatake, Teizo Yoshimura, Akihiro Matsukawa

Scientific reports 10 ( 1 ) 16490 - 16490 2020年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

The mitogen-activated protein kinase (MAPK) pathways are involved in many cellular processes, including the development of fibrosis. Here, we examined the role of Sprouty-related EVH-1-domain-containing protein (Spred) 2, a negative regulator of the MAPK-ERK pathway, in the development of bleomycin (BLM)-induced pulmonary fibrosis (PF). Compared to WT mice, Spred2-/- mice developed milder PF with increased proliferation of bronchial epithelial cells. Spred2-/- lung epithelial cells or MLE-12 cells treated with spred2 siRNA proliferated faster than control cells in vitro. Spred2-/- and WT macrophages produced similar levels of TNFα and MCP-1 in response to BLM or lipopolysaccharide and myeloid cell-specific deletion of Spred2 in mice had no effect. Spred2-/- fibroblasts proliferated faster and produced similar levels of MCP-1 compared to WT fibroblasts. Spred2 mRNA was almost exclusively detected in bronchial epithelial cells of naïve WT mice and it accumulated in approximately 50% of cells with a characteristic of Clara cells, 14 days after BLM treatment. These results suggest that Spred2 is involved in the regulation of tissue repair after BLM-induced lung injury and increased proliferation of lung bronchial cells in Spred2-/- mice may contribute to faster tissue repair. Thus, Spred2 may present a new therapeutic target for the treatment of PF.

DOI： 10.1038/s41598-020-73752-3

胎児期に一過性骨髄異常増殖症を発症し,胎盤にfetal vascular malperfusion を伴ったダウン症候群の1剖検例査読

濱崎友洋, 藤澤真義, 宮原宏幸, 伏見聡一郎, 堀田真智子, 和仁洋治, 松川昭博

診断病理 34 ( 4 ) 428 - 434 2020年10月

Decreased miR-200b-3p in cancer cells leads to angiogenesis in HCC by enhancing endothelial ERG expression 査読

Aye Moh-Moh-Aung, Masayoshi Fujisawa, Sachio Ito, Hiroshi Katayama, Toshiaki Ohara, Yoko Ota, Teizo Yoshimura, Akihiro Matsukawa 3

Scientific Reports 26 ( 10 ) 10418 2020年10月

Elastin and collagen IV double staining: A refined method to detect blood vessel invasion in breast cancer 査読国際誌

Masayoshi Fujisawa, Masako Omori, Hiroyoshi Doihara, Ye‐Min Than, Hnin Wint Wint Swe, Teizo Yoshimura, Akihiro Matsukawa

Pathology International 70 ( 9 ) 612 - 623 2020年9月

Decreased miR-200b-3p in cancer cells leads to angiogenesis in HCC by enhancing endothelial ERG expression. 査読国際誌

Aye Moh-Moh-Aung, Masayoshi Fujisawa, Sachio Ito, Hiroshi Katayama, Toshiaki Ohara, Yoko Ota, Teizo Yoshimura, Akihiro Matsukawa

Scientific reports 10 ( 1 ) 10418 - 10418 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Transcription factor ERG (erythroblast transformation-specific (ETS)-related gene) is essential in endothelial differentiation and angiogenesis, in which microRNA (miR)-200b-3p targeting site is expected by miRNA target prediction database. miR-200b is known decreased in hepatocellular carcinoma (HCC), however, the functional relation between ERG and miR-200b-3p, originating from pre-miR-200b, in HCC angiogenesis remains unclear. We investigated whether hepatocyte-derived miR-200b-3p governs angiogenesis in HCC by targeting endothelial ERG. Levels of miR-200b-3p in HCC tissues were significantly lower than those in adjacent non-HCC tissues. Poorly differentiated HCC cell line expressed lower level of miR-200b-3p compared to well-differentiated HCC cell lines. The numbers of ERG-positive endothelial cells were higher in HCC tissues than in adjacent non-HCC tissues. There was a negative correlation between the number of ERG-positive cells and miR-200b-3p expression in HCC tissues. Culture supernatants of HCC cell lines with miR-200b-3p-overexpression reduced cell migration, proliferation and tube forming capacity in endothelial cells relative to the control, while those with miR-200b-3p-inhibition augmented the responses. Exosomes isolated from HCC culture supernatants with miR-200b-3p overexpression suppressed endothelial ERG expression. These results suggest that exosomal miR-200b-3p from hepatocytes suppresses endothelial ERG expression, and decreased miR-200b-3p in cancer cells promotes angiogenesis in HCC tissues by enhancing endothelial ERG expression.

DOI： 10.1038/s41598-020-67425-4

THE RELATIONSHIP BETWEEN THE PD-L1 EXPRESSION OF SURGICAL RESECTED AND FINE-NEEDLE ASPIRATION SPECIMENS FOR PATIENTS WITH PANCREATIC CANCER 査読

Matsumoto Kazuyuki, Ohara Toshiaki, Fujisawa Masayoshi, Takaki Akinobu, Takahara Masahiro, Kato Hironari, Horiguchi Shigeru, Matsukawa Akihiro, Okada Hiroyuki

GASTROENTEROLOGY 156 ( 6 ) S758 2019年5月

Ovarian stromal cells as a source of cancer-associated fibroblasts in human epithelial ovarian cancer: A histopathological study. 査読国際誌

Fujisawa M, Aye Moh-Moh-Aung, Zeng Z, Wani Y, Matsukawa A.

PLoS One 13 ( 10 ) e0205494 2018年10月

Immunohistochemistry

Masayoshi Fujisawa

protocols.io 2018年9月

Immunohistochemistry v1

Masayoshi Fujisawa

2018年9月

Spred2 Deficiency Exacerbates D-Galactosamine/Lipopolysaccharide -induced Acute Liver Injury in Mice via Increased Production of TNFα. 査読国際誌

Yang X, Fujisawa M, Yoshimura T, Ohara T, Sato M, Mino M, San TH, Gao T, Kunkel SL, Matsukawa A

Scientific reports 8 ( 1 ) 188 - 188 2018年1月

Spred-2 deficiency exacerbates lipopolysaccharide (LPS)/D-galactosamine (D-GalN) induced acute liver injury

Yang Xu, Teizo Yoshimura, Masayoshi Fujisawa, Toshiaki Ohara, Cuiming Sun, Akihiro Matsukawa

CYTOKINE 100 137 - 137 2017年12月

Biphenotypic sinonasal sarcomaの1例

林詠子, 祇園由佳, 藤澤真義, 能島舞, 田中顕之, 田中健大, 柳井広之, 吉野正

診断病理 34 ( 4 ) 293 - 298 2017年10月

Molecular subtypes of breast cancers from Myanmar women: a study of 91 cases at two pathology centers.Asian Pacific Journal of Cancer Prevention 査読

San TH, Fujisawa M, Fushimi S, Soe L, Min NW, Yoshimura T, Ohara T, Yee MM, Oda S, Matsukawa A

Asian Pac J Cancer Prev. 18 ( 6 ) 1617 - 1621 2017年6月

Molecular subtypes of breast cancers from Myanmar women 査読

Thar Htet San,Masayoshi Fujisawa*,Soichiro Fushimi,Lamin Soe,Ngu Wah Min,Teizo Yoshimura*,Toshiaki Ohara*,Myint Myint Yee,Shinsuke Oda,Akihiro Matsukawa*

Asian Pacific Journal of Cancer Prevention, Asian Pacific journal of cancer prevention : APJCP 18 ( 6 ) 1617 - 1621 2017年6月

Low prevalence of human mammary tumor virus (HMTV) in breast cancer patients from Myanmar 査読国際誌

San TH, Fujisawa M, Fushimi S, Yoshimura T, Ohara T, Soe L, Min NW, Kyaw O, Yang X,?Matsukawa A

Infect Agent Cancer 12 ( 20 ) 20 - 20 2017年4月

Low prevalence of human mammary tumor virus (HMTV) in breast cancer patients from Myanmar 査読国際誌

Thar Htet San,Masayoshi Fujisawa*,Soichiro Fushimi,Teizo Yoshimura*,Toshiaki Ohara*,Lamin Soe,Ngu Wah Min,Ohnmar Kyaw,Xu Yang,Akihiro Matsukawa*

Infectious Agents and Cancer 12 ( 1 ) 60 - 66 2017年4月

前頭葉に発生し，てんかん原性を示した髄膜腫合併髄膜血管腫症の1例査読

河原明奈、伏見聡一郎、板倉淳哉、藤澤真義、小林勝弘、林裕美子、伊達勲、上利崇、柳井広之、松川昭博

診断病理 34 ( 1 ) 46 - 50 2017年1月

A Novel Role of Spred2 in the Colonic Epithelial Cell Homeostasis and Inflammation.（共著Scientific reports）査読国際誌

Scientific reports 21 ( 6 ) 37531 - 37531 2016年11月

大腿に発生した胞巣状軟部肉腫の1例（共著）査読

診断病理 33 ( 2 ) 158 - 162 2016年4月

Diffuse large B-cell lymphoma of the thyroid which caused esophageal fistula 査読

Tomoyasu Tachibana, Yorihisa Orita, Masayoshi Fujisawa, Yasushi Hiramatsu, Yuya Ogawara, Yuko Matsuyama, Iku Abe, Kaori Uchino, Hirofumi Morishita, Tetsuji Nobuhisa, Koichi Uesaka, Kazunori Nishizaki

Esophagus 12 ( 1 ) 77 - 81 2015年1月

Tracheal stenosis caused by unnoticed foreign bodies.（共著）査読

Ogawara Y, Tachibana T, Orita Y, Uchino K, Wani Y, Nagahiro I, Matsuyama Y, Abe I, Fujisawa M, Nishizaki

Acta Medica Okayama 68 ( 4 ) 249 - 252 2014年8月

Mucocele in the middle ear. 査読

Otology & neurotology 35 ( 2 ) 92 - 94 2014年2月

Factors that make it difficult to diagnose cervical tuberculous lymphadenitis

Tomoyasu Tachibana, Yorihisa Orita, Masayoshi Fujisawa, Michihiro Nakada, Yuya Ogawara, Yuko Matsuyama, Iku Abe, Yasuharu Sato, Koichi Uesaka, Kazunori Nishizaki

Journal of Infection and Chemotherapy 19 ( 6 ) 1015 - 1020 2013年12月

Oxaliplatin-induced liver injury mimicking metastatic tumor on images: a case report（共著）査読国際誌

Japanese journal of clinical oncology 43 ( 10 ) 1034 - 1038 2013年10月

A study on submandibular gland tumors

Tomoyasu Tachibana, Yuya Ogawara, Yuko Matsuyama, Iku Abe, Masayoshi Fujisawa, Kaori Uchino, Michihiro Nakada, Motoharu Fukazawa, Kinya Uno

Practica Oto-Rhino-Laryngologica 106 ( 8 ) 723 - 728 2013年8月

1型自己免疫性膵炎におけるマクロファージの分布の検討

内野かおり, 能登原憲司, 藤澤真義, 和仁洋治, 松川昭博

日本病理学会会誌 102 ( 1 ) 439 - 439 2013年4月

Papillary thyroid carcinoma arising from a median ectopic thyroid with no thyroglossal duct remnant

Tomoyasu Tachibana, Yorihisa Orita, Masayoshi Fujisawa, Yuya Ogawara

Acta Medica Okayama 67 ( 1 ) 61 - 64 2013年

Pathologic findings of autoimmune pancreatitis and IgG4-related disease

Kenji Notohara, Yoji Wani, Masayoshi Fujisawa

Current Immunology Reviews 7 ( 2 ) 212 - 220 2011年

Aberrant expression of an "intestinal marker" Cdx2 in pyloric gland adenoma of the gallbladder

Yoji Wani, Kenji Notohara, Masayoshi Fujisawa

Virchows Archiv 453 ( 5 ) 521 - 527 2008年11月

Solid pseudopapillary neoplasm: pathological diagnosis and distinction from other solid cellular tumours of the pancreas

Kenji Notohara, Yoji Wani, Masayoshi Fujisawa

Diagnostic Histopathology 14 ( 6 ) 266 - 274 2008年6月

Nonfunctioning endocrine pancreatic tumor examined with 18F-FDG PET/CT

Nobuyuki Toshikuni, Kyohei Kai, Masayoshi Fujisawa

Annals of Nuclear Medicine 22 ( 2 ) 133 - 137 2008年2月

CD56-positive cells with or without synaptophysin expression are recognized in the pancreatic duct epithelium: a study with adult and fetal tissues and specimens from chronic pancreatitis.

Fujisawa Masayoshi, Notohara Kenji, Tsukayama Choutatsu, Mizuno Ryuichirou, Okada Shigeru

Acta Medica Okayama 57 ( 6 ) 279 - 284 2003年12月

記述言語：英語出版者・発行元：Okayama University Medical School

<p>We observed the distribution of CD56+ epithelial cells in the pancreatic duct system using 25 fetal, one infantile, 3 normal adult, 4 diabetic, and 8 chronically inflamed pancreatic tissue samples. In the early stage of gestation (12 to 17 weeks), CD56+ cells were commonly seen in the immature tubular structures. They were often continuous to pancreatic islets, and their distribution was similar to that of synaptophysin (Syn)+ cells, suggesting that they are precursors of islet neogenesis. Their number decreased in proportion to gestational age. Instead, from 24 weeks of gestation, luminal cell clusters that were common in interlobular ducts revealed CD56+. These cell clusters were unrelated to islet neogenesis and Syn expression. Similar CD56+ luminal cell clusters were also observed in cases of chronic pancreatitis, whereas they were scarce in normal adult and diabetic tissues. CD56+ cells were also occasionally seen in intralobular ducts, intercalated ducts, and centroacinar cells in cases of chronic pancreatitis. We conclude that there are two types of CD56+ epithelial cells in the pancreatic duct system: CD56+ endocrine cells are numerous during the early stage of gestation, when islet neogenesis appears, while CD56+ luminal cells may represent developmental and regenerative changes of pancreatic ducts.</p>

DOI： 10.18926/AMO/32811

Effects of phlebotomy on the growth of ferric nitrilotriacetate-induced renal cell carcinoma.

Mizote Akiko, Hida Akira I, Hosako Mutsumi, Fujisawa Masayoshi, Kamekawa Mika, Okada Shigeru

Acta Medica Okayama 56 ( 4 ) 199 - 204 2002年8月

記述言語：英語出版者・発行元：Okayama University Medical School

<p>The ferric nitrilotriacetate-induced carcinogenesis model is unique in that reactive oxygen species-free radicals are involved in the carcinogenic process. But the effects of iron-withdrawal in the progression of renal cell carcinoma are not well understood. We performed repeated phlebotomies on animals that had been administered ferric nitrilotriacetate in the initiation stage of renal cell carcinoma (phlebotomy group), and compared the development of renal tumors with those not receiving repeated phlebotomies (non-phlebotomy group). Ferric nitrilotriacetate-treated male Wistar rats were randomly divided into 2 groups: a phlebotomy group (21 rats) and a non-phlebotomy group (17 rats). Ten age-adjusted normal rats were also observed as a normal group. Hematocrit was maintained under 25% in the phlebotomy group. Hematocrit levels in the normal group and in the non-phlebotomy group were not significantly different. As a result, the incidence of renal cell carcinoma was not significantly different between phlebotomy and non-phlebotomy animals. However, the total weight of the renal cell carcinoma was significantly heavier in the animals from non-phlebotomy group than in those from the phlebotomy group (23.64 g +/- 18.54 vs. 54.40 g +/- 42.40, P < 0.05). The present study demonstrated that phlebotomy after the administration of ferric nitrilotriacetate did not reduce the incidence of renal cell carcinoma. In addition, we showed that iron withdrawal at the promotion stage of carcinogenesis will retard tumor growth.</p>

DOI： 10.18926/AMO/31687

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