Updated on 2022/07/01

写真a

 
OKADA Nobuhiro
 
Organization
Faculty of Interdisciplinary Science and Engineering in Health Systems Assistant Professor
Position
Assistant Professor
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Degree

  • 博士(理学) ( 大阪大学 )

Research Interests

  • 分子生物学

  • 腫瘍生物学

Research Areas

  • Life Science / Tumor biology

  • Life Science / Molecular biology

Education

  • 大阪大学大学院   生命機能研究科   5年一貫制博士課程

    2005.4 - 2010.3

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  • Meiji University   農学部   生命科学科

    2001.4 - 2005.3

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Research History

  • Okayama University   ヘルスシステム統合科学研究科ナノバイオシステム分子設計学分野   Assistant Professor

    2018

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  • Kanazawa University   Cancer Research Institute

    2016 - 2018

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  • 京都大学大学院   特定助教

    2014 - 2016

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  • University of California, Berkeley

    2010 - 2014

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Professional Memberships

 

Papers

  • Treatment of Retinoblastoma 1-Intact Hepatocellular Carcinoma With Cyclin-Dependent Kinase 4/6 Inhibitor Combination Therapy. Reviewed International journal

    Jindan Sheng, Susumu Kohno, Nobuhiro Okada, Nobuyuki Okahashi, Kana Teranishi, Fumio Matsuda, Hiroshi Shimizu, Paing Linn, Naoko Nagatani, Minako Yamamura, Kenichi Harada, Shin-Ichi Horike, Hiroshi Inoue, Seiji Yano, Sharad Kumar, Shunsuke Kitajima, Itsuki Ajioka, Chiaki Takahashi

    Hepatology (Baltimore, Md.)   74 ( 4 )   1971 - 1993   2021.10

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    BACKGROUND AND AIMS: Synthetic cyclin-dependent kinase (CDK) 4/6 inhibitors exert antitumor effects by forcing RB1 in unphosphorylated status, causing not only cell cycle arrest but also cellular senescence, apoptosis, and increased immunogenicity. These agents currently have an indication in advanced breast cancers and are in clinical trials for many other solid tumors. HCC is one of promising targets of CDK4/6 inhibitors. RB family dysfunction is often associated with the initiation of HCC; however, this is revivable, as RB family members are not frequently mutated or deleted in this malignancy. APPROACH AND RESULTS: Loss of all Rb family members in transformation related protein 53 (Trp53)-/- mouse liver resulted in liver tumor reminiscent of human HCC, and re-expression of RB1 sensitized these tumors to a CDK4/6 inhibitor, palbociclib. Introduction of an unphosphorylatable form of RB1 (RB7LP) into multiple liver tumor cell lines induced effects similar to palbociclib. By screening for compounds that enhance the efficacy of RB7LP, we identified an I kappa B kinase (IKK)β inhibitor Bay 11-7082. Consistently, RB7LP expression and treatment with palbociclib enhanced IKKα/β phosphorylation and NF-κB activation. Combination therapy using palbociclib with Bay 11-7082 was significantly more effective in hepatoblastoma and HCC treatment than single administration. Moreover, blockade of IKK-NF-κB or AKT pathway enhanced effects of palbociclib on RB1-intact KRAS Kirsten rat sarcoma viral oncogene homolog mutated lung and colon cancers. CONCLUSIONS: In conclusion, CDK4/6 inhibitors have a potential to treat a wide variety of RB1-intact cancers including HCC when combined with an appropriate kinase inhibitor.

    DOI: 10.1002/hep.31872

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  • Signaling Inhibitors Accelerate the Conversion of mouse iPS Cells into Cancer Stem Cells in the Tumor Microenvironment. Reviewed International journal

    Juan Du, Yanning Xu, Saki Sasada, Aung Ko Ko Oo, Ghmkin Hassan, Hafizah Mahmud, Apriliana Cahya Khayrani, Md Jahangir Alam, Kazuki Kumon, Ryo Uesaki, Said M Afify, Hager M Mansour, Neha Nair, Maram H Zahra, Akimasa Seno, Nobuhiro Okada, Ling Chen, Ting Yan, Masaharu Seno

    Scientific reports   10 ( 1 )   9955 - 9955   2020.6

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    Cancer stem cells (CSCs) are a class of cancer cells characterized by self-renewal, differentiation and tumorigenic potential. We previously established a model of CSCs by culturing mouse induced pluripotent stem cells (miPSCs) for four weeks in the presence of a conditioned medium (CM) of cancer cell lines, which functioned as the tumor microenvironment. Based on this methodology of developing CSCs from miPSCs, we assessed the risk of 110 non-mutagenic chemical compounds, most of which are known as inhibitors of cytoplasmic signaling pathways, as potential carcinogens. We treated miPSCs with each compound for one week in the presence of a CM of Lewis lung carcinoma (LLC) cells. However, one-week period was too short for the CM to convert miPSCs into CSCs. Consequently, PDO325901 (MEK inhibitor), CHIR99021 (GSK-3β inhibitor) and Dasatinib (Abl, Src and c-Kit inhibitor) were found to confer miPSCs with the CSC phenotype in one week. The tumor cells that survived exhibited stemness markers, spheroid formation and tumorigenesis in Balb/c nude mice. Hence, we concluded that the three signal inhibitors accelerated the conversion of miPSCs into CSCs. Similarly to our previous study, we found that the PI3K-Akt signaling pathway was upregulated in the CSCs. Herein, we focused on the expression of relative genes after the treatment with these three inhibitors. Our results demonstrated an increased expression of pik3ca, pik3cb, pik3r5 and pik3r1 genes indicating class IA PI3K as the responsible signaling pathway. Hence, AKT phosphorylation was found to be up-regulated in the obtained CSCs. Inhibition of Erk1/2, tyrosine kinase, and/or GSK-3β was implied to be involved in the enhancement of the PI3K-AKT signaling pathway in the undifferentiated cells, resulting in the sustained stemness, and subsequent conversion of miPSCs into CSCs in the tumor microenvironment.

    DOI: 10.1038/s41598-020-66471-2

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  • Upregulated CCL20 and CCR6 in Cancer Stem Cells Converted from Mouse iPS Cells

    Juan Du, Akimasa Seno, Saki Sasada, Yanning Xu, Aung Ko Ko Oo, Ghmkin Hassan, Shunsuke Ueno, Said M. Afify, Maram H. Zahra, Nobuhiro Okada, Ling Chen, Xiaoying Fu, Heizo Tokutaka, Ting Yan, Masaharu Seno

    JOURNAL OF RESEARCH IN MEDICAL AND DENTAL SCIENCE   8 ( 1 )   200 - 207   2020

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:AMBER PUBLICATION  

    Background: Cancer stem cells (CSCs) as a class of malignant cancer cells play an important role in tumor progression. Previous studies by our group have demonstrated the establishment of the model of CSCs converting mouse iPS cells (miPSCs) into CSCs by treating the miPSCs with a conditioned medium (CM) of Lewis Lung Carcinoma (LLC) cells with or without the non-mutagenic chemical compounds. CSCs converted from miPSCs developed highly malignant adenocarcinoma when subcutaneously transplanted into the nude mice.Methods: The miPSCs were treated with each compound for 1 week in the presence of a CM of LLC cells. We evaluated the gene expression in the resultant CSCs comparing that in miPSCs by microarray analysis. And the expression of chemokine (C-C motif) ligand 20 (CCL20) and C-C chemokine receptor type 6 (CCR6) in converted cells were evaluated by rt-qPCR. The CCR6 expression in converted cells and primary cells were determined by flow cytometry.Results: As the result, the expression of CCL20 was found upregulated in the presence of CM supplemented with PD0325901. Then we assessed the expression of CCR6, which was considered to be stimulated by CCL20. Then the expression of CCR6 was also found up-regulated. Interestingly, IL17A expression was also observed only in the CSCs from the primary tumor implying the effect of tumor microenvironment. Moreover, significantly high level of CCR6 was showed in flow cytometric analysis.Conclusion: These results suggest that a model of CSCs with CCL20-CCR6 autocrine loop was obtained as the result of the conversion of iPSCs. This CSC should be a good model to study targeting CCR6 as a G protein-coupled receptor (GPCR).

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  • Hematopoietic Cells Derived from Cancer Stem Cells Generated from Mouse Induced Pluripotent Stem Cells. Reviewed International journal

    Ghmkin Hassan, Said M Afify, Neha Nair, Kazuki Kumon, Amira Osman, Juan Du, Hager Mansour, Hagar A Abu Quora, Hend M Nawara, Ayano Satoh, Maram H Zahra, Nobuhiro Okada, Akimasa Seno, Masaharu Seno

    Cancers   12 ( 1 )   2019.12

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    Cancer stem cells (CSCs) represent the subpopulation of cancer cells with the ability to differentiate into other cell phenotypes and initiated tumorigenesis. Previously, we reported generating CSCs from mouse induced pluripotent stem cells (miPSCs). Here, we investigated the ability of the CSCs to differentiate into hematopoietic cells. First, the primary cells were isolated from malignant tumors that were formed by the CSCs. Non-adherent cells (NACs) that arose from adherent cells were collected and their viability, as well as the morphology and expression of hematopoietic cell markers, were analyzed. Moreover, NACs were injected into the tail vein of busulfan conditioned Balb/c nude mice. Finally, CSCs were induced to differentiate to macrophages while using IL3 and SCF. The round nucleated NACs were found to be viable, positive for hematopoietic lineage markers and CD34, and expressed hematopoietic markers, just like homing to the bone marrow. When NACs were injected into mice, Wright-Giemsa staining showed that the number of white blood cells got higher than those in the control mice after four weeks. CSCs also showed the ability to differentiate toward macrophages. CSCs were demonstrated to have the potential to provide progenies with hematopoietic markers, morphology, and homing ability to the bone marrow, which could give new insight into the tumor microenvironment according to the plasticity of CSCs.

    DOI: 10.3390/cancers12010082

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  • Hematopoietic Cells Derived from Cancer Stem Cells Generated from Mouse Induced Pluripotent Stem Cells

    Ghmkin Hassan, Said M. Afify, Neha Nair, Kazuki Kumon, Amira Osman, Juan Du, Hager Mansour, Hagar A Abu Quora, Hend M Nawara, Ayano Satoh, Maram H. Zahra, Nobuhiro Okada, Akimasa Seno, Masaharu Seno

    Cancers   12 ( 1 )   82 - 82   2019.12

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    Publishing type:Research paper (scientific journal)   Publisher:MDPI AG  

    Cancer stem cells (CSCs) represent the subpopulation of cancer cells with the ability to differentiate into other cell phenotypes and initiated tumorigenesis. Previously, we reported generating CSCs from mouse induced pluripotent stem cells (miPSCs). Here, we investigated the ability of the CSCs to differentiate into hematopoietic cells. First, the primary cells were isolated from malignant tumors that were formed by the CSCs. Non-adherent cells (NACs) that arose from adherent cells were collected and their viability, as well as the morphology and expression of hematopoietic cell markers, were analyzed. Moreover, NACs were injected into the tail vein of busulfan conditioned Balb/c nude mice. Finally, CSCs were induced to differentiate to macrophages while using IL3 and SCF. The round nucleated NACs were found to be viable, positive for hematopoietic lineage markers and CD34, and expressed hematopoietic markers, just like homing to the bone marrow. When NACs were injected into mice, Wright–Giemsa staining showed that the number of white blood cells got higher than those in the control mice after four weeks. CSCs also showed the ability to differentiate toward macrophages. CSCs were demonstrated to have the potential to provide progenies with hematopoietic markers, morphology, and homing ability to the bone marrow, which could give new insight into the tumor microenvironment according to the plasticity of CSCs.

    DOI: 10.3390/cancers12010082

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  • Method to Convert Stem Cells into Cancer Stem Cells. International journal

    Said M Afify, Ling Chen, Ting Yan, Anna Sanchez Calle, Neha Nair, Chikae Murakami, Maram H Zahra, Nobuhiro Okada, Yoshiaki Iwasaki, Akimasa Seno, Masahura Seno

    Methods and protocols   2 ( 3 )   2019.8

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    The cancer stem cell (CSC) hypothesis suggests that tumors are sustained exclusively by a small population of the cells with stem cell properties. CSCs have been identified in most tumors and are responsible for the initiation, recurrence, and resistance of different cancers. In vitro CSC models will be of great help in revisiting the mechanism of cancer development, as well as the tumor microenvironment and the heterogeneity of cancer and metastasis. Our group recently described the generation of CSCs from induced pluripotent stem cells (iPSCs), which were reprogrammed from normal cells, and/or embryonic stem cells (ESCs). This procedure will improve the understanding of the essential niche involved in cancer initiation. The composition of this cancer-inducing niche, if identified, will let us know how normal cells convert to malignant in the body and how, in turn, cancer prevention could be achieved. Further, once developed, CSCs demonstrate the ability to differentiate into endothelial cells, cancer-associated fibroblasts, and other phenotypes establishing the CSC niche. These will be good materials for developing novel cancer treatments. In this protocol, we describe how to handle mouse iPSCs/ESCs and how to choose the critical time for starting the conversion into CSCs. This CSC generation protocol is essential for understanding the role of CSC in cancer initiation and progress.

    DOI: 10.3390/mps2030071

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  • Retinoblastoma Inactivation Induces a Protumoral Microenvironment via Enhanced CCL2 Secretion. Reviewed International journal

    Fengkai Li, Shunsuke Kitajima, Susumu Kohno, Akiyo Yoshida, Shoichiro Tange, Soichiro Sasaki, Nobuhiro Okada, Yuuki Nishimoto, Hayato Muranaka, Naoko Nagatani, Misa Suzuki, Sayuri Masuda, Tran C Thai, Takumi Nishiuchi, Tomoaki Tanaka, David A Barbie, Naofumi Mukaida, Chiaki Takahashi

    Cancer research   79 ( 15 )   3903 - 3915   2019.8

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    Cancer cell-intrinsic properties caused by oncogenic mutations have been well characterized; however, how specific oncogenes and tumor suppressors impact the tumor microenvironment (TME) is not well understood. Here, we present a novel non-cell-autonomous function of the retinoblastoma (RB) tumor suppressor in controlling the TME. RB inactivation stimulated tumor growth and neoangiogenesis in a syngeneic and orthotropic murine soft-tissue sarcoma model, which was associated with recruitment of tumor-associated macrophages (TAM) and immunosuppressive cells such as Gr1+CD11b+ myeloid-derived suppressor cells (MDSC) or Foxp3+ regulatory T cells (Treg). Gene expression profiling and analysis of genetically engineered mouse models revealed that RB inactivation increased secretion of the chemoattractant CCL2. Furthermore, activation of the CCL2-CCR2 axis in the TME promoted tumor angiogenesis and recruitment of TAMs and MDSCs into the TME in several tumor types including sarcoma and breast cancer. Loss of RB increased fatty acid oxidation (FAO) by activating AMP-activated protein kinase that led to inactivation of acetyl-CoA carboxylase, which suppresses FAO. This promoted mitochondrial superoxide production and JNK activation, which enhanced CCL2 expression. These findings indicate that the CCL2-CCR2 axis could be an effective therapeutic target in RB-deficient tumors. SIGNIFICANCE: These findings demonstrate the cell-nonautonomous role of the tumor suppressor retinoblastoma in the tumor microenvironment, linking retinoblastoma loss to immunosuppression.

    DOI: 10.1158/0008-5472.CAN-18-3604

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  • Targeting Ovarian Cancer Cells Overexpressing CD44 with Immunoliposomes Encapsulating Glycosylated Paclitaxel. Reviewed International journal

    Apriliana Cahya Khayrani, Hafizah Mahmud, Aung Ko Ko Oo, Maram H Zahra, Miharu Oze, Juan Du, Md Jahangir Alam, Said M Afify, Hagar A Abu Quora, Tsukasa Shigehiro, Anna Sanchez Calle, Nobuhiro Okada, Akimasa Seno, Koki Fujita, Hiroki Hamada, Yuhki Seno, Tadakatsu Mandai, Masaharu Seno

    International journal of molecular sciences   20 ( 5 )   2019.2

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    Paclitaxel (PTX) is one of the front-line drugs approved for the treatment of ovarian cancer. However, the application of PTX is limited due to the significant hydrophobicity and poor pharmacokinetics. We previously reported target-directed liposomes carrying tumor-selective conjugated antibody and encapsulated glycosylated PTX (gPTX-L) which successfully overcome the PTX limitation. The tubulin stabilizing activity of gPTX was equivalent to that of PTX while the cytotoxic activity of gPTX was reduced. In human ovarian cancer cell lines, SK-OV-3 and OVK18, the concentration at which cell growth was inhibited by 50% (IC50) for gPTX range from 15⁻20 nM, which was sensitive enough to address gPTX-L with tumor-selective antibody coupling for ovarian cancer therapy. The cell membrane receptor CD44 is associated with cancer progression and has been recognized as a cancer stem cell marker including ovarian cancer, becoming a suitable candidate to be targeted by gPTX-L therapy. In this study, gPTX-loading liposomes conjugated with anti-CD44 antibody (gPTX-IL) were assessed for the efficacy of targeting CD44-positive ovarian cancer cells. We successfully encapsulated gPTX into liposomes with the loading efficiency (LE) more than 80% in both of gPTX-L and gPTX-IL with a diameter of approximately 100 nm with efficacy of enhanced cytotoxicity in vitro and of convenient treatment in vivo. As the result, gPTX-IL efficiently suppressed tumor growth in vivo. Therefore gPTX-IL could be a promising formulation for effective ovarian cancer therapies.

    DOI: 10.3390/ijms20051042

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  • A distinct function of the retinoblastoma protein in the control of lipid composition identified by lipidomic profiling Reviewed

    H. Muranaka, A. Hayashi, K. Minami, S. Kitajima, S. Kohno, Y. Nishimoto, N. Nagatani, M. Suzuki, L. A. N. Kulathunga, N. Sasaki, N. Okada, T. Matsuzaka, H. Shimano, H. Tada, C. Takahashi

    ONCOGENESIS   6   e350   2017.6

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    Here, by combining lipidomics with transcriptome analysis, we demonstrate that Rb depletion in mouse embryonic fibroblastss induces significant alterations in their lipid composition. We discovered that Rb depletion induced increase in lysophosphatidylserine, diacylglycerol (DAG), fatty acid (FA), acylcarnitine, phosphatidylcholine (PC), arachidonoyl ethanolamine, and decrease in phosphatidylglycerol, monoacylglycerol, without change in total lipid per protein levels. Analysis of the acyl chain composition of DAG, PC and phosphatidylserine revealed increase of saturated and mono-unsaturated acyl chains with specific carbon chain length. Consistently, we observed that Rb depletion increased the levels of fatty acids with the corresponding carbon chain length and number of carbon-carbon double bondssuch as myristic acid (14:0), palmitic acid (16:0), stearic acid (18:0) and all forms of FA 18:1. Microarray analysis revealed that Rb depletion induced significant upregulation of enzymes involved in elongation and desaturation of fatty acids. Among these, we found that elongation of long chain fatty acid family member 6 (Elovl6) and stearoyl-CoA desaturase 1 (Scd1) are the most robustly controlled by Rb possibly through E2F and sterol regulatory element-binding protein transcription factors. Depletion of Elovl6 or Scd1 significantly suppressed colony formation, sphere formation and xenograft tumor growth of Rb-deficient tumor cells. Suppression of self-renewal by the SCD1 inhibitor was rescued upon supplementation of the mono-unsaturated fatty acids generated by this enzyme. This study suggests a novel role for Rb in suppressing the malignant progression of tumors by controlling the lipid composition.

    DOI: 10.1038/oncsis.2017.51

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  • A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression Reviewed International journal

    Nobuhiro Okada, Chao-Po Lin, Marcelo C. Ribeiro, Anne Biton, Gregory Lai, Xingyue He, Pengcheng Bu, Hannes Vogel, David M. Jablons, Andreas C. Keller, J. Erby Wilkinson, Biao He, Terry P. Speed, Lin He

    GENES & DEVELOPMENT   28 ( 5 )   438 - 450   2014.3

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT  

    As bona fide p53 transcriptional targets, miR-34 microRNAs ( miRNAs) exhibit frequent alterations in many human tumor types and elicit multiple p53 downstream effects upon overexpression. Unexpectedly, miR-34 deletion alone fails to impair multiple p53-mediated tumor suppressor effects in mice, possibly due to the considerable redundancy in the p53 pathway. Here, we demonstrate that miR-34a represses HDM4, a potent negative regulator of p53, creating a positive feedback loop acting on p53. In a Kras-induced mouse lung cancer model, miR-34a deficiency alone does not exhibit a strong oncogenic effect. However, miR-34a deficiency strongly promotes tumorigenesis when p53 is haploinsufficient, suggesting that the defective p53-miR-34 feedback loop can enhance oncogenesis in a specific context. The importance of the p53/ miR-34/ HDM4 feedback loop is further confirmed by an inverse correlation between miR-34 and full-length HDM4 in human lung adenocarcinomas. In addition, human lung adenocarcinomas generate an elevated level of a short HDM4 isoform through alternative polyadenylation. This short HDM4 isoform lacks miR-34-binding sites in the 39 untranslated region ( UTR), thereby evading miR-34 regulation to disable the p53-miR-34 positive feedback. Taken together, our results elucidated the intricate cross-talk between p53 and miR-34 miRNAs and revealed an important tumor suppressor effect generated by this positive feedback loop.

    DOI: 10.1101/gad.233585.113

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  • Lats2 phosphorylates p21/CDKN1A after UV irradiation and regulates apoptosis Reviewed International journal

    Hirokazu Suzuki, Norikazu Yabuta, Nobuhiro Okada, Kosuke Torigata, Yael Aylon, Moshe Oren, Hiroshi Nojima

    JOURNAL OF CELL SCIENCE   126 ( 19 )   4358 - 4368   2013.10

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    LATS2 (Large tumor suppressor 2), a member of the conserved AGC Ser/Thr (S/T) kinase family, is a human tumor suppressor gene. Here, we show that in response to ultraviolet radiation, Lats2 is phosphorylated by Chk1 at Ser835 (S835), which is located in the kinase domain of Lats2. This phosphorylation enhances Lats2 kinase activity. Subsequently, Lats2 phosphorylates p21 at S146. p21 (CDKN1A) is a cyclin-dependent kinase (CDK) inhibitor, which not only regulates the cell cycle by inhibition of CDK, but also inhibits apoptosis by binding to procaspase-3 in the cytoplasm. Phosphorylation by Lats2 induces degradation of p21 and promotes apoptosis. Accordingly, Lats2 overexpression induces p21 degradation, activation of caspase-3 and caspase-9, and apoptosis. These findings describe a novel Lats2-dependent mechanism for induction of cell death in response to severe DNA damage.

    DOI: 10.1242/jcs.125815

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  • N-terminal truncation of Lats1 causes abnormal cell growth control and chromosomal instability Reviewed International journal

    Norikazu Yabuta, Satomi Mukai, Ayumi Okamoto, Daisuke Okuzaki, Hirokazu Suzuki, Kosuke Torigata, Kaori Yoshida, Nobuhiro Okada, Daisaku Miura, Akihiko Ito, Masahito Ikawa, Masaru Okabe, Hiroshi Nojima

    JOURNAL OF CELL SCIENCE   126 ( 2 )   508 - 519   2013.1

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    The tumor suppressors Lats1 and Lats2 are mediators of the Hippo pathway that regulates tissue growth and proliferation. Their N-terminal non-kinase regions are distinct except for Lats conserved domains 1 and 2 (LCD1 and LCD2), which may be important for Lats1/2-specific functions. Lats1 knockout mice were generated by disrupting the N-terminal region containing LCD1 (Lats1(Delta N/Delta N)). Some Lats1(Delta N/Delta N) mice were born safely and grew normally. However, mouse embryonic fibroblasts (MEFs) from Lats1(Delta N/Delta N) mice displayed mitotic defects, centrosomal overduplication, chromosomal misalignment, multipolar spindle formation, chromosomal bridging and cytokinesis failure. They also showed anchorage-independent growth and continued cell cycles and cell growth, bypassing cell-cell contact inhibition similar to tumor cells. Lats1(Delta N/Delta N) MEFs produced tumors in nude mice after subcutaneous injection, although the tumor growth rate was much slower than that of ordinary cancer cells. Yap, a key transcriptional coactivator of the Hippo pathway, was overexpressed and stably retained in Lats1(Delta N/Delta N) MEFs in a cell density independent manner, and Lats2 mRNA expression was downregulated. In conclusion, N-terminally truncated Lats1 induced Lats2 downregulation and Yap protein accumulation, leading to chromosomal instability and tumorigenesis.

    DOI: 10.1242/jcs.113431

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  • miR-34 miRNAs provide a barrier for somatic cell reprogramming Reviewed International journal

    Yong Jin Choi, Chao-Po Lin, Jaclyn J. Ho, Xingyue He, Nobuhiro Okada, Pengcheng Bu, Yingchao Zhong, Sang Yong Kim, Margaux J. Bennett, Caifu Chen, Arzu Ozturk, Geoffrey G. Hicks, Greg J. Hannon, Lin He

    NATURE CELL BIOLOGY   13 ( 11 )   1353 - U154   2011.11

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    Somatic reprogramming induced by defined transcription factors is a low-efficiency process that is enhanced by p53 deficiency(1-5). So far, p21 is the only p53 target shown to contribute to p53 repression of iPSC (induced pluripotent stem cell) generation(1,3), indicating that additional p53 targets may regulate this process. here, we demonstrate that miR-34 microRNAs (miRNAs), particularly miR-34a, exhibit p53-dependent induction during reprogramming. Mir34a deficiency in mice significantly increased reprogramming efficiency and kinetics, with miR-34a and p21 cooperatively regulating somatic reprogramming downstream of p53. Unlike p53 deficiency, which enhances reprogramming at the expense of iPSC pluripotency, genetic ablation for Mir34a promoted iPSC generation without compromising self-renewal or differentiation. Suppression of reprogramming by miR-34a was due, at least in part, to repression of pluripotency genes, including Nanog, Sox2 and Mycn (also known as N-Myc). This post-transcriptional gene repression by miR-34a also regulated iPSC differentiation kinetics. miR-34b and c similarly repressed reprogramming; and all three miR-34 miRNAs acted cooperatively in this process. taken together, our findings identified miR-34 miRNAs as p53 targets that play an essential role in restraining somatic reprogramming.

    DOI: 10.1038/ncb2366

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  • The tumor suppressor Lats2 is pivotal in Aurora A and Aurora B signaling during mitosis Reviewed International journal

    Norikazu Yabuta, Satomi Mukai, Nobuhiro Okada, Yael Aylon, Hiroshi Nojima

    CELL CYCLE   10 ( 16 )   2724 - 2736   2011.8

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:LANDES BIOSCIENCE  

    Accurate coordination between chromosome segregation and cytokinesis by various mitotic kinases, such as Aurora, prevent tetraploidization and subsequent tumorigensis. The tumor suppressors Lats1 and Lats2 are serine/threonine kinases that localize to the centrosome and regulate cell cycle progression and apoptosis. In the present study, Aurora A was demonstrated to phosphorylate Lats2 on serine 380 (S380) during mitosis. Immunocytochemical observations revealed that the subcellular localization of Lats2 was distinct during the cell cycle and depended on which site was phosphorylated. Interestingly, the S380-phosphorylated Lats2 protein (pS380) colocalized at the central spindle with Aurora B. Physical interactions were observed between Aurora A, Lats2, Lats1 and Aurora B. The Lats1 kinase was shown to phosphorylate Aurora B. Cells expressing a nonphosphorylated mutant (S380A) of Lats2 caused chromosome missegregation and cytokinesis failure, similar to the cells with aberrantly expressed Aurora B. Together, the results suggest that the Aurora A-Lats1/2-Aurora B axis might be a novel pathway that regulates accurate mitotic progression by ensuring the proper mitotic localization of Lats2.

    DOI: 10.4161/cc.10.16.16873

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  • A novel Chk1/2-Lats2-14-3-3 signaling pathway regulates P-body formation in response to UV damage Reviewed International journal

    Nobuhiro Okada, Norikazu Yabuta, Hirokazu Suzuki, Yael Aylon, Moshe Oren, Hiroshi Nojima

    JOURNAL OF CELL SCIENCE   124 ( 1 )   57 - 67   2011.1

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    Proper response to DNA damage is essential for maintaining the integrity of the genome. Here we show that in response to ultraviolet (UV) radiation, the Lats2 tumor suppressor protein is phosphorylated predominantly by Chk1 and weakly by Chk2 at S408 in vivo, and that this process occurs at all stages of the cell cycle and leads to phosphorylation of 14-3-3 gamma on S59 by Lats2. Interaction of Lats2 and 14-3-3 gamma in vivo was confirmed by immunoprecipitation and western blot analysis. Phosphorylated 14-3-3 gamma translocates to the P-body, where mRNA degradation, translational repression and mRNA surveillance take place. Depletion of Lats2 or 14-3-3 gamma by siRNA inhibits P-body formation in response to UV, newly implicating Lats2 and 14-3-3 as regulators of P-body formation. By contrast, siRNA-mediated depletion of Lats1, a mammalian paralog of Lats2, showed no such effect. On the basis of these findings, we propose that the Chk1/2-Lats2-14-3-3 axis identified here plays an important role in connecting DNA damage signals to P-body assembly.

    DOI: 10.1242/jcs.072918

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  • Lats2 is an essential mitotic regulator required for the coordination of cell division Reviewed International journal

    Norikazu Yabuta, Nobuhiro Okada, Akihiko Ito, Toshiya Hosomi, Souichi Nishihara, Yuya Sasayama, Azumi Fujimori, Daisuke Okuzaki, Hanjun Zhao, Masahito Ikawa, Masaru Okabe, Hiroshi Nojima

    JOURNAL OF BIOLOGICAL CHEMISTRY   282 ( 26 )   19259 - 19271   2007.6

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    Tumor suppressor Lats2 is a member of the conserved Dbf2 kinase family. It localizes to the centrosome and has been implicated in regulation of the cell cycle and apoptosis. However, the in vivo function of this kinase remains unclear. Here, we show that complete disruption of the gene encoding Lats2 in mice causes developmental defects in the nervous system and embryonic lethality. Furthermore, mutant cells derived from total LATS2-knock-out embryos exhibit mitotic defects including centrosome fragmentation and cytokinesis defects, followed by nuclear enlargement and multinucleation. We show that the Mob1 family, a regulator of mitotic exit, associates with Lats2 to induce its activation. We also show that the complete LATS2-knock-out cells exhibit an acceleration of exit from mitosis and marked down-regulation of critical mitotic regulators. These results suggest that Lats2 plays an essential mitotic role in coordinating accurate cytokinesis completion, governing the stabilization of other mitotic regulators.

    DOI: 10.1074/jbc.M608562200

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MISC

  • キナーゼ阻害剤と組み合わせたCDK4/6阻害剤によるHCCの新しい併用療法

    盛金丹, 高橋智聡, 河野晋, 岡田宣宏

    日本分子生物学会年会プログラム・要旨集(Web)   43rd   2020

  • 脂肪酸合成制御を介したNFYAによる乳がん悪性化機構への影響

    植木ちひろ, 辻本剛己, 河野晋, 高橋智聡, 岡田宣宏

    日本分子生物学会年会プログラム・要旨集(Web)   43rd   2020

  • Antitumor effect of gluconeogenesis induced by NFYA

    辻本剛己, 高橋智聡, 岡田宣宏

    日本癌学会学術総会抄録集(Web)   79th   2020

  • NFYA splicing variant regulates the malignant progression of breast cancer

    岡田宣宏, 辻本剛己, 吉川清次, 高橋智聡

    日本癌学会学術総会抄録集(Web)   79th   2020

  • Elucidation of the mechanism of cancer heterogeneity for preemptive breast cancer therapy

    岡田宣宏

    Annual Report of the Okayama Foundation for Science and Technology   ( 29 )   2020

  • 乳がん細胞系譜転換における脂質代謝制御機構の解明

    岡田宣宏, 辻本剛己

    金沢大学がん進展制御研究所がんの転移・薬剤耐性に関わる先導的共同研究拠点   2019   2020

  • 増強されたCCR6/CCL20/IL17軸の発現はmiPS細胞の癌幹細胞への変換に関与する。

    上野舜介, 杜娟, 佐々田沙紀, HUSSEIN ZAKY ZAHRA Maram, 岡田宣宏, 妹尾彬正, 妹尾昌治

    日本分子生物学会年会プログラム・要旨集(Web)   42nd   2019

  • ヒトグリオブラストーマ由来細胞株U251MG細胞からのがん幹細胞の単離

    三村祐稀, CAHYA Apriliana, MARAM Zahra Zaky, 妹尾彬正, 岡田宣宏, 妹尾昌治

    日本分子生物学会年会プログラム・要旨集(Web)   42nd   2019

  • NFYA regulates the acquisition of drug resistance in breast cancer

    岡田宣宏, 村中勇人, 吉川清次, 妹尾昌治, 高橋智聡

    日本癌学会学術総会抄録集(Web)   78th   2019

  • マウス人工多能性幹細胞のがん幹細胞化におけるプロスタグランジンE2の関与

    峯松秀希, 峯松秀希, 杉原有貴, 大谷敬亨, 杜娟, MARAM Zahara Zaky, 妹尾彬正, 岡田宣宏, 妹尾昌治

    日本分子生物学会年会プログラム・要旨集(Web)   42nd   2019

  • がん幹細胞モデルにおけるCpGアイランドの低メチル化とPI3K-Aktシグナルの活性化

    妹尾昌治, OO Aung Ko Ko, 妹尾彬正, ZAHRA Maram Hussein Zaky, 岡田宣宏, 岩崎良章

    日本分子生物学会年会プログラム・要旨集(Web)   41st   2018

  • ヒトiPS細胞を用いた膵臓がん幹細胞モデルの作成

    小瀬みはる, 妹尾彬正, ZAHRA Maram Hussein Zaky, 岡田宣弘, 岩崎良章, 妹尾昌治

    日本分子生物学会年会プログラム・要旨集(Web)   41st   2018

  • トリプルネガティブ乳癌とグリオブラストーマにおけるMETによる分化療法の検討

    吉川清次, 酒井浩旭, 嶋崎雅広, 岡田宣宏, 松本純明, 戸井雅和, 戸井雅和

    日本癌治療学会学術集会(Web)   53rd   2015

  • miR-34aはp53とのポジティブフィードバックを形成し,肺癌腫瘍形成を抑制する

    岡田宣宏, LIN He

    日本分子生物学会年会プログラム・要旨集(Web)   36th   2013

  • Lats1キナーゼのN末端領域は染色体安定性、腫瘍抑制に重要である

    向井 智美, 藪田 紀一, 岡本 歩, 鈴木 宏和, 岡田 宣宏, 三浦 大作, 奥崎 大介, 野島 博

    日本生化学会大会プログラム・講演要旨集   84回   2P - 0473   2011.9

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    J-GLOBAL

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  • Lats1とLats2キナーゼは染色体不安定性を制御する(Lats1 and Lats2 kinases regulate chromosomal instability)

    藪田 紀一, 向井 智美, 鈴木 宏和, 岡田 宣宏, 三浦 大作, 奥崎 大介, 野島 博

    日本生化学会大会プログラム・講演要旨集   84回   1S3a - 1   2011.9

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  • 新規な乳癌抑制遺伝子としてのLatsキナーゼ・ファミリーの役割

    藪田 紀一, 伊藤 彰彦, 岡田 宣宏, 奥崎 大介, 野島 博

    日本生化学会大会プログラム・講演要旨集   82回   4P - 497   2009.9

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  • Lats2が仲介する新たなシグナル伝達経路の同定と解析

    野島博, 岡田宣宏, 藪田紀一

    生化学   2009

  • Lats2を介した新規DNA損傷シグナル経路はP-body形成を制御する

    岡田宣宏, 藪田紀一, 野島博

    生化学   2009

  • Lats2はM期においてAurora-Aキナーゼによってリン酸化されて多様な局在を示す

    藪田紀一, 岡田宣宏, 野島博

    生化学   2008

  • Lats2によるDNA damage checkpoint制御

    岡田宣宏, 藪田紀一, 野島博

    生化学   2008

  • Lats1とLats2キナーゼは相互作用して機能を相補する

    佐藤愛, 岡田宣宏, 藪田紀一, 野島博

    生化学   2008

  • Lats2はM期脱出を制御する

    岡田宣宏, 藪田紀一, 伊藤彰彦, 篠山優也, 伊川正人, 岡部勝, 野島博

    生化学   78 ( 7 )   2006

  • Lats2はM期脱出および中心体成熟において機能する

    岡田宣弘, 薮田紀一, 伊藤彰彦, 野島博

    日本癌学会学術総会記事   65th   2006

  • Lats2は中心体成熟とM期脱出に必要である

    薮田紀一, 篠山優也, 岡田宣宏, 伊藤彰彦, 岡部勝, 野島博

    日本分子生物学会年会講演要旨集   28th   2005

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Awards

  • 平成30年度岡山工学振興会科学技術賞

    2018.7   岡山工学振興会  

    岡田 宣宏

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  • 平成27年度がん若手研究者ワークショップベストトーク賞

    2015.9   文部科学省科学研究費新学術領域研究「がん研究分野等の特性を踏まえた支援活動」  

    岡田 宣宏

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  • 第82回日本生化学会大会優秀プレゼンテーション賞

    2009.10   日本生化学会  

    岡田 宣宏

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Research Projects

  • 胎児期環境により決定される疾患発症リスク診断法の開発

    2021.08 - 2022.03

    岡山大学大学院ヘルスシステム統合科学研究科  統合科学プロジェクト 

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  • 胎児期における栄養環境を標的とした乳がん予防法の開発

    2021.07 - 2022.03

    岡山工学振興会  産業先行研究助成 

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  • がん特異的糖代謝バランスを標的とした新規がん治療法の開発

    2021.06 - 2022.03

    ウエスコ学術振興財団  研究活動費助成 

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  • 乳がん細胞系譜転換における脂質代謝制御機構の解明

    2021.04 - 2022.03

    金沢大学がん進展制御研究所  共同研究助成 

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  • トリプルネガティブ乳がんにおける高QOLバイオマーカー探索

    2021.01 - 2021.03

    岡山大学大学院ヘルスシステム統合科学研究科  統合科学チャレンジ 

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  • 新生児期に形成される乳房組織細菌叢が乳がん発症に与える影響の解析

    2020.06 - 2021.03

    ウエスコ学術振興財団  研究活動費助成 

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  • 乳がん細胞系譜転換における脂質代謝制御機構の解明

    2020.04 - 2021.03

    金沢大学がん進展制御研究所  共同研究助成 

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  • 乳がんの内分泌療法抵抗性獲得機構におけるNFYAの機能解明

    2020

    武田科学振興財団  医学系研究助成(がん領域(基礎)) 

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  • 乳がん治療薬抵抗性獲得機構における NFYA の機能解明

    2019.06 - 2020.03

    ウエスコ学術振興財団  研究活動費助成 

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  • 乳がんの治療薬抵抗性獲得機構におけるNFYAの機能解明

    Grant number:19K07640  2019.04 - 2022.03

    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)

    岡田 宣宏

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    Grant amount:\4420000 ( Direct expense: \3400000 、 Indirect expense:\1020000 )

    乳がんは、悪性化進展過程でLuminalからBasalへ細胞系譜を転換させることにより治療薬抵抗性を獲得し、治療を困難にしていると考えられる。しかし、乳がんが悪性化進展過程で細胞系譜転換を起こすメカニズムは明らかになっていない。我々はこれまでに、Luminal、Basal細胞系譜間でスプライシングバリアントの発現パターンをスイッチさせている遺伝子NFYAを同定している。さらに、NFYAの各バリアントがLuminalからBasalへの細胞系譜転換を段階的に制御していることを明らかにした。しかし、NFYAによる細胞系譜転換の制御メカニズムは不明である。本研究は、乳がん悪性化進展過程でのNFYAによる細胞系譜転換の制御機構を明らかにすることを目的とする。
    我々は、これまでの研究によりNFYA long-formがBasal細胞の増殖・生存において重要な機能を果たしていることを明らかにしており、本研究ではNFYA long-form特異的ノックアウトマウスを乳がんモデルマウスMMTV-PyMTマウスと交配させることで乳がん発症・悪性化におけるNFYAの機能解析を行った。その結果、NFYA long-formの欠損が乳がんの発症を遅らせることを明らかにした。さらに、NFYA long-formの欠損がホルモン受容体(エストロゲン受容体、プロゲステロン受容体)陰性細胞を減少させることも分かった。これらのことは、NFYAがホルモン受容体陽性細胞(Luminal)からホルモン受容体陰性細胞(Basal)への乳がん細胞系譜転換を促進し、治療薬抵抗性獲得を制御していることを示している。また、我々は、NFYA long-form特異的転写標的遺伝子の同定を試み、脂肪酸合成酵素FASNを同定した。今後、NFYAによるFASN制御が脂質代謝に与える影響を検討し、細胞系譜転換機構への寄与を明らかにする。

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  • 乳がん細胞系譜転換における脂質代謝制御機構の解明

    2019.04 - 2020.03

    金沢大学がん進展制御研究所  共同研究助成 

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  • 癌の不均一性形成機構の解明による先制的な乳癌治療の実現

    2018.07 - 2019.03

    岡山工学振興会  学術研究助成 

    岡田 宣宏

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    Authorship:Principal investigator  Grant type:Competitive

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  • Analysis of the function of NFYA in cancer heterogeneity formation

    Grant number:15K18407  2015.04 - 2017.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    OKADA Nobuhiro

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    Grant amount:\4290000 ( Direct expense: \3300000 、 Indirect expense:\990000 )

    Breast cancer is classified into five subtypes by gene expression profile. In case of breast cancers, cancer heterogeneity that some different subtypes cooperate to enhance malignant progression is proposed. It is suggested that cancer heterogeneity makes it difficult to develop cancer therapy. We elucidated that NFYA plays two different roles by switching the expression of splicing variants, thereby NFYA induces the switching of breast cancer subtypes and enhances the acquisition of cancer heterogeneity.

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Class subject in charge

  • Technical English for Interdisciplinary Medical Sciences and Engineering (2021academic year) Late  - その他

  • Research Works for Interdisciplinary Medical Sciences and Engineering (2021academic year) Year-round  - その他

  • Material Process Experiment 2 (2021academic year) 1st semester  - 月5,月6,月7,月8,木5,木6,木7,木8

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  • Technical English for Interdisciplinary Medical Sciences and Engineering (2020academic year) Late  - その他

  • Research Works for Interdisciplinary Medical Sciences and Engineering (2020academic year) Year-round  - その他

  • Material Process Experiment 2 (2020academic year) 1st semester  - 月4,月5,月6,月7,木4,木5,木6,木7

  • Material Process Experiment 2 (2020academic year) 1st semester  - 月4,月5,月6,月7,木4,木5,木6,木7

  • Biotechnology experiment 2 (2020academic year) 1st semester  - 月4,月5,月6,月7,木4,木5,木6,木7

  • Biotechnology experiment 3 (2020academic year) Third semester  - 火4,火5,火6,火7,金4,金5,金6,金7

  • Biotechnology experiment 2 (2020academic year) 1st semester  - 月4,月5,月6,月7,木4,木5,木6,木7

  • Biotechnology experiment 3 (2020academic year) Third semester  - 火4,火5,火6,火7,金4,金5,金6,金7

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