2021/10/25 更新

写真a

イイオカ ヒデカズ
飯岡 英和
IIOKA Hidekazu
所属
教育研究院 医歯学系 医学系列 助教
医歯学総合研究科 分子細胞医学専攻 細胞機能 助教
職名
助教
外部リンク

学位

  • 博士(理学) ( 2005年3月   総合研究大学院大学 )

研究分野

  • ライフサイエンス / 実験病理学

  • ライフサイエンス / 腫瘍生物学

経歴(researchmap)

  • 愛知医科大学   医学部   助教

    2012年5月 - 2015年3月

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    国名:日本国

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  • 独立行政法人日本学術振興会   特別研究員PD

    2009年4月 - 2010年9月

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    国名:日本国

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  • バージニア大学   医学部   リサーチアソシエート

    2009年2月 - 2012年4月

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    国名:アメリカ合衆国

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  • ケースウェスタンリザーブ大学   医学部   リサーチスカラー

    2007年5月 - 2009年1月

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    国名:アメリカ合衆国

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  • 基礎生物学研究所   研究員

    2005年4月 - 2007年4月

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    国名:日本国

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経歴

  • 新潟大学   医歯学総合研究科 分子細胞医学専攻 細胞機能   助教

    2015年4月 - 現在

学歴

  • 総合研究大学院大学   生命科学研究科   分子生物機構論専攻

    2002年4月 - 2005年3月

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    国名: 日本国

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  • 岐阜大学   大学院農学研究科   生物資源利用学科

    2000年4月 - 2002年3月

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    国名: 日本国

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  • 近畿大学   農学部   農芸化学科

    1996年4月 - 2000年3月

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    国名: 日本国

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留学歴

  • バージニア大学   リサーチアソシエート

    2009年2月 - 2012年4月

  • ケースウェスタンリザーブ大学   リサーチスカラー

    2007年4月 - 2009年1月

 

論文

  • Tumor-homing peptide and its utility for advanced cancer medicine. 国際誌

    Eisaku Kondo, Hidekazu Iioka, Ken Saito

    Cancer science   112 ( 6 )   2118 - 2125   2021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)  

    Cell-penetrating peptides, such as antibodies, have gained great attention as tools for the development of specific delivery systems for payloads, which might be applied as non-invasive carriers in vivo. Among these, tumor-homing peptides recently have been studied for use in tumor medicine. Tumor-homing peptides are oligopeptides, usually consisting of 30 or fewer amino acids that are efficiently and specifically incorporated into tumor cells, suggesting their potential use in establishing novel non-invasive tumor imaging systems for diagnostic and therapeutic applications. Here, we briefly introduce the biological characteristics of our tumor-homing peptides, focusing especially on those developed using a random peptide library constructed using mRNA display technology. The advantage of the tumor-homing peptides is their biological safety, given that these molecules do not show significant cytotoxicity against non-neoplastic cells; lack serious antigenicity, which alternatively might evoke unfavorable immune responses and inflammation in vivo; and are rapidly incorporated into target cells/tissues, with rates exceeding those seen for antibodies. Given their small size, tumor-homing peptides also are easy to modify and redesign. Based on these merits, tumor-homing peptides are expected to find wide application in various aspects of tumor medicine, including imaging diagnostics (eg, with dye-conjugated probes for direct visualization of invasive/metastatic tumor lesions in vivo) and therapeutics (eg, using peptide-drug conjugates [PDCs] for tumor targeting). Although further evidence will be required to demonstrate their practical utility, tumor-homing peptides are expected to show great potential as a next-generation bio-tool contributing to precision medicine for cancer patients.

    DOI: 10.1111/cas.14909

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  • PLOD2 Is Essential to Functional Activation of Integrin β1 for Invasion/Metastasis in Head and Neck Squamous Cell Carcinomas. 査読 国際誌

    Yushi Ueki, Ken Saito, Hidekazu Iioka, Izumi Sakamoto, Yasuhiro Kanda, Masakiyo Sakaguchi, Arata Horii, Eisaku Kondo

    iScience   23 ( 2 )   100850 - 100850   2020年2月

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    記述言語:英語  

    Identifying the specific functional regulator of integrin family molecules in cancer cells is critical because they are directly involved in tumor invasion and metastasis. Here we report high expression of PLOD2 in oropharyngeal squamous cell carcinomas (SCCs) and its critical role as a stabilizer of integrin β1, enabling integrin β1 to initiate tumor invasion/metastasis. Integrin β1 stabilized by PLOD2-mediated hydroxylation was recruited to the plasma membrane, its functional site, and accelerated tumor cell motility, leading to tumor metastasis in vivo, whereas loss of PLOD2 expression abrogated it. In accordance with molecular analysis, examination of oropharyngeal SCC tissues from patients corroborated PLOD2 expression associated with integrin β1 at the invasive front of tumor nests. PLOD2 is thus implicated as the key regulator of integrin β1 that prominently regulates tumor invasion and metastasis, and it provides important clues engendering novel therapeutics for these intractable cancers.

    DOI: 10.1016/j.isci.2020.100850

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  • PODXL1 promotes metastasis of the pancreatic ductal adenocarcinoma by activating the C5aR/C5a axis from the tumor microenvironment. 査読 国際誌

    Ken Saito, Hidekazu Iioka, Satoshi Maruyama, I Wayan Sumardika, Masakiyo Sakaguchi, Eisaku Kondo

    Neoplasia (New York, N.Y.)   21 ( 12 )   1121 - 1132   2019年12月

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    記述言語:英語  

    Pancreatic invasive ductal adenocarcinoma (PDAC) is a representative intractable malignancy under the current cancer therapies, and is considered a scirrhous carcinoma because it develops dense stroma. Both PODXL1, a member of CD34 family molecules, and C5aR, a critical cell motility inducer, have gained recent attention, as their expression was reported to correlate with poor prognosis for patients with diverse origins including PDAC; however, previous studies reported independently on their respective biological significance. Here we demonstrate that PODXL1 is essential for metastasis of PDAC cells through its specific interaction with C5aR. In vitro assay demonstrated that PODXL1 bound to C5aR, which stabilized C5aR protein and recruited it to cancer cell plasma membranes to receive C5a, an inflammatory chemoattractant factor. PODXL1 knockout in PDAC cells abrogated their metastatic property in vivo, emulating the liver metastatic mouse model treated with anti-C5a neutralizing antibody. In molecular studies, PODXL1 triggered EMT on PDAC cells in response to stimulation by C5a, corroborating PODXL1 involvement in PDAC cellular invasive properties via specific interaction with the C5aR/C5a axis. Confirming the molecular assays, histological examination showed coexpression of PODXL1 and C5aR at the invasive front of primary cancer nests as well as in liver metastatic foci of PDAC both in the mouse metastasis model and patient tissues. Hence, the novel direct interaction between PODXL1 and the C5aR/C5a axis may provide a better integrated understanding of PDAC biological characteristics including its tumor microenvironment factors.

    DOI: 10.1016/j.neo.2019.09.003

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  • Crumbs3 is a critical factor that regulates invasion and metastasis of colon adenocarcinoma via the specific interaction with FGFR1. 査読 国際誌

    Hidekazu Iioka, Ken Saito, Masakiyo Sakaguchi, Taro Tachibana, Keiichi Homma, Eisaku Kondo

    International journal of cancer   145 ( 10 )   2740 - 2753   2019年11月

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    記述言語:英語  

    Epithelial cell polarity regulator Crumbs3 (Crb3), a mammalian homolog within the Drosophila Crb gene family, was initially identified as an essential embryonic development factor. It is recently implicated in tumor suppression, though its specific functions are controversial. We here demonstrate that Crb3 strongly promotes tumor invasion and metastasis of human colon adenocarcinoma cells. Crb3 centrality to tumor migration was supported by strong expression at invasive front and metastatic foci of colonic adenocarcinoma of the patient tissues. Accordingly, two different Crb3-knockout (KO) lines, Crb3-KO (Crb3 -/-) DLD-1 and Crb3-KO WiDr from human colonic adenocarcinomas, were generated by the CRISPR-Cas9 system. Crb3-KO DLD-1 cells exhibited loss of cellular mobility in vitro and dramatic suppression of liver metastases in vivo in contrast to the wild type of DLD-1. Unlike DLD-1, Crb3-KO WiDr mobility and metastasis were unaffected, which were similar to wild-type WiDr. Proteome analysis of Crb3-coimmunopreciptated proteins identified different respective fibroblast growth factor receptor (FGFR) isotypes specifically bound to Crb3 isoform a through their intracellular domain. In DLD-1, Crb3 showed membranous localization of FGFR1 leading to its functional activation, whereas Crb3 bound to cytoplasmic FGFR4 in WiDr without FGFR1 expression, leading to cellular growth. Correlative expression between Crb3 and FGFR1 was consistently detected in primary and metastatic colorectal cancer patient tissues. Taking these together, Crb3 critically accelerates cell migration, namely invasion and metastasis of human colon cancers, through specific interaction to FGFR1 on colon cancer cells.

    DOI: 10.1002/ijc.32336

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  • Crumbs3 regulates the expression of glycosphingolipids on the plasma membrane to promote colon cancer cell migration. 査読 国際誌

    Hidekazu Iioka, Ken Saito, Eisaku Kondo

    Biochemical and biophysical research communications   519 ( 2 )   287 - 293   2019年11月

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    記述言語:英語  

    The cell polarity regulator Crumbs3 (Crb3) promotes colon cancer cell migration and metastasis. However, the underlying mechanism of cancer cell migration regulated by Crb3 has not been fully elucidated. Here, we demonstrated that Crb3 is associated with cell migration by regulating glycosphingolipid (GSL) expression in human colon cancer cells. Crb3-knockout (KO) cells showed a remarkable increase in ganglioside GM3 (GM3) on the cell surface. Reduced migration by Crb3-KO cells was restored by forced expression of both Crb3 and Neuraminidase3 (Neu3). Immunofluorescent staining revealed that most Crb3 is colocalized with the recycling endosome marker Rab11. These findings show that Crb3 may promote colon cancer cell migration by regulating the expression of GSLs on the cell surface.

    DOI: 10.1016/j.bbrc.2019.08.161

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  • Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts. 査読 国際誌

    Yosuke Mitsui, Nahoko Tomonobu, Masami Watanabe, Rie Kinoshita, I Wayan Sumardika, Chen Youyi, Hitoshi Murata, Ken-Ichi Yamamoto, Takuya Sadahira, Acosta Gonzalez Herik Rodrigo, Hitoshi Takamatsu, Kota Araki, Akira Yamauchi, Masahiro Yamamura, Hideyo Fujiwara, Yusuke Inoue, Junichiro Futami, Ken Saito, Hidekazu Iioka, Eisaku Kondo, Masahiro Nishibori, Shinichi Toyooka, Yasuhiko Yamamoto, Yasutomo Nasu, Masakiyo Sakaguchi

    Oncology research   27 ( 8 )   945 - 956   2019年8月

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    記述言語:英語  

    S100A11, a member of the S100 family of proteins, is actively secreted from pancreatic ductal adenocarcinoma (PDAC) cells. However, the role of the extracellular S100A11 in PDAC progression remains unclear. In the present study, we investigated the extracellular role of S100A11 in crosstalking between PDAC cells and surrounding fibroblasts in PDAC progression. An abundant S100A11 secreted from pancreatic cancer cells stimulated neighboring fibroblasts through receptor for advanced glycation end products (RAGE) upon S100A11 binding and was followed by not only an enhanced cancer cell motility in vitro but also an increased number of the PDAC-derived circulating tumor cells (CTCs) in vivo. Mechanistic investigation of RAGE downstream in fibroblasts revealed a novel contribution of a mitogen-activated protein kinase kinase kinase (MAPKKK), tumor progression locus 2 (TPL2), which is required for positive regulation of PDAC cell motility through induction of cyclooxygenase 2 (COX2) and its catalyzed production of prostaglandin E2 (PGE2), a strong chemoattractive fatty acid. The extracellularly released PGE2 from fibroblasts was required for the rise in cellular migration as well as infiltration of their adjacent PDAC cells in a coculture setting. Taken together, our data reveal a novel role of the secretory S100A11 in PDAC disseminative progression through activation of surrounding fibroblasts triggered by the S100A11-RAGE-TPL2-COX2 pathway. The findings of this study will contribute to the establishment of a novel therapeutic antidote to PDACs that are difficult to treat by regulating cancer-associated fibroblasts (CAFs) through targeting the identified pathway.

    DOI: 10.3727/096504019X15555408784978

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  • Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness. 査読 国際誌

    Youyi Chen, I Wayan Sumardika, Nahoko Tomonobu, Rie Kinoshita, Yusuke Inoue, Hidekazu Iioka, Yosuke Mitsui, Ken Saito, I Made Winarsa Ruma, Hiroki Sato, Akira Yamauchi, Hitoshi Murata, Ken-Ichi Yamamoto, Shuta Tomida, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Junichiro Futami, Miyoko Kubo, Endy Widya Putranto, Takashi Murakami, Ming Liu, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka, Masakiyo Sakaguchi

    Neoplasia (New York, N.Y.)   21 ( 7 )   627 - 640   2019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)  

    Metastatic breast cancer is the leading cause of cancer-associated death in women. The progression of this fatal disease is associated with inflammatory responses that promote cancer cell growth and dissemination, eventually leading to a reduction of overall survival. However, the mechanism(s) of the inflammation-boosted cancer progression remains unclear. In this study, we found for the first time that an extracellular cytokine, S100A8/A9, accelerates breast cancer growth and metastasis upon binding to a cell surface receptor, melanoma cell adhesion molecule (MCAM). Our molecular analyses revealed an important role of ETS translocation variant 4 (ETV4), which is significantly activated in the region downstream of MCAM upon S100A8/A9 stimulation, in breast cancer progression in vitro as well as in vivo. The MCAM-mediated activation of ETV4 induced a mobile phenotype called epithelial-mesenchymal transition (EMT) in cells, since we found that ETV4 transcriptionally upregulates ZEB1, a strong EMT inducer, at a very high level. In contrast, downregulation of either MCAM or ETV4 repressed EMT, resulting in greatly weakened tumor growth and lung metastasis. Overall, our results revealed that ETV4 is a novel transcription factor regulated by the S100A8/A9-MCAM axis, which leads to EMT through ZEB1 and thereby to metastasis in breast cancer cells. Thus, therapeutic strategies based on our findings might improve patient outcomes.

    DOI: 10.1016/j.neo.2019.04.006

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  • Extracellular S100A11 Plays a Critical Role in Spread of the Fibroblast Population in Pancreatic Cancers. 査読 国際誌

    Hitoshi Takamatsu, Ken-Ichi Yamamoto, Nahoko Tomonobu, Hitoshi Murata, Yusuke Inoue, Akira Yamauchi, I Wayan Sumardika, Youyi Chen, Rie Kinoshita, Masahiro Yamamura, Hideyo Fujiwara, Yosuke Mitsui, Kota Araki, Junichiro Futami, Ken Saito, Hidekazu Iioka, I Made Winarsa Ruma, Endy Widya Putranto, Masahiro Nishibori, Eisaku Kondo, Yasuhiko Yamamoto, Shinichi Toyooka, Masakiyo Sakaguchi

    Oncology research   27 ( 6 )   713 - 727   2019年6月

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    記述言語:英語  

    The fertile stroma in pancreatic ductal adenocarcinomas (PDACs) has been suspected to greatly contribute to PDAC progression. Since the main cell constituents of the stroma are fibroblasts, there is crosstalking(s) between PDAC cells and surrounding fibroblasts in the stroma, which induces a fibroblast proliferation burst. We have reported that several malignant cancer cells including PDAC cells secrete a pronounced level of S100A11, which in turn stimulates proliferation of cancer cells via the receptor for advanced glycation end products (RAGE) in an autocrine manner. Owing to the RAGE+ expression in fibroblasts, the extracellular abundant S100A11 will affect adjacent fibroblasts. In this study, we investigated the significance of the paracrine axis of S100A11-RAGE in fibroblasts for their proliferation activity. In in vitro settings, extracellular S100A11 induced upregulation of fibroblast proliferation. Our mechanistic studies revealed that the induction is through RAGE-MyD88-mTOR-p70 S6 kinase upon S100A11 stimulation. The paracrine effect on fibroblasts is linked mainly to triggering growth but not cellular motility. Thus, the identified pathway might become a potential therapeutic target to suppress PDAC progression through preventing PDAC-associated fibroblast proliferation.

    DOI: 10.3727/096504018X15433161908259

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  • Identification of TRA-1-60-positive cells as a potent refractory population in follicular lymphomas. 査読 国際誌

    Katsuyoshi Takata, Ken Saito, Satoshi Maruyama, Tomoko Miyata-Takata, Hidekazu Iioka, Shujiro Okuda, Yiwei Ling, Kennosuke Karube, Yukari Miki, Yoshinobu Maeda, Tadashi Yoshino, Christian Steidl, Eisaku Kondo

    Cancer science   110 ( 1 )   443 - 457   2019年1月

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    記述言語:英語  

    Despite receiving rituximab-combined chemotherapy, follicular lymphoma (FL) patients often suffer tumor recurrence and understand that the cause of relapse in FL would thus significantly ameliorate the tumor therapeutics. In the present study, we show that TRA-1-60-expressing cells are a unique population in FL, converge to the conventional stem cell marker Oct3/4 and ALDH1-positive population, and resist current B-lymphoma agents. TRA-1-60 expression was observed in scattered lymphoma cells in FL tissues only as well as in resting B-lymphocytes inside germinal centers. Retrospective comparison between recurrent and cognate primary tissues showed that the number of TRA-1-60-positive cells from rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP)-treated FL had increased relative to primary tissue, a finding corroborated by assays on different rituximab-treated FL cell lines, FL-18 and DOHH2, wherein TRA-positive cell numbers increased over 10-fold compared to the untreated sample. Concordantly, scanty TRA-1-60-positive FL-18 cells implanted s.c. into mice evinced potent tumor-initiating capacity in vivo, where tumors were 12-fold larger in volume (P = 0.0021 < 0.005) and 13-fold heavier in weight (P = 0.0015 < 0.005) compared to those xenografted from TRA-negative cells. To explain these results, gene expression profiling and qPCR analysis indicated that TRA-1-60-positive cells defined a distinct population from that of TRA-negative cells, with upregulation of multiple drug transporters and therapeutic resistance genes. Hence, TRA-1-60-expressing cells in FL are considered to be vigorously intractable against conventional therapeutic agents, which may explain its refractory recurrence.

    DOI: 10.1111/cas.13870

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  • Visualizing the Rapid and Dynamic Elimination of Allogeneic T Cells in Secondary Lymphoid Organs. 査読 国際誌

    Kanda Y, Takeuchi A, Ozawa M, Kurosawa Y, Kawamura T, Bogdanova D, Iioka H, Kondo E, Kitazawa Y, Ueta H, Matsuno K, Kinashi T, Katakai T

    Journal of immunology (Baltimore, Md. : 1950)   201 ( 3 )   1062 - 1072   2018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)  

    DOI: 10.4049/jimmunol.1700219

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  • Stromal mesenchymal stem cells facilitate pancreatic cancer progression by regulating specific secretory molecules through mutual cellular interaction. 査読 国際誌

    Ken Saito, Masakiyo Sakaguchi, Satoshi Maruyama, Hidekazu Iioka, Endy Widya Putranto, I Wayan Sumardika, Nahoko Tomonobu, Takashi Kawasaki, Keiichi Homma, Eisaku Kondo

    Journal of Cancer   9 ( 16 )   2916 - 2929   2018年

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    記述言語:英語  

    Pancreatic ductal adenocarcinoma (PDAC) is currently one of the most intractable malignancies with a typical scirrhous pattern in histology. Due to its abundant tumor stroma and scant vascularization, chemotherapeutic agents are considered inefficiently permeable to cancer nests, making it highly difficult to cure the patients with PDAC. However, PDAC is also considered to owe its intractability to other critical factors such as cellular interaction between tumor cells and tumor microenvironment as well as architectural barriers, which increases in therapeutic resistance. Here, we report a specific cellular interaction between PDAC cells and mesenchymal stem cells (MSCs) intermingled in PDAC stroma, which facilitates cancer invasion. Secretory phenotype profiling revealed that production of Amphiregulin (AREG) and MMP-3 were specifically upregulated under the coexistence of BxPC3 cells with human MSCs (approximately four to ten folds in AREG, and twenty to sixty-folds in MMP-3 compared to that of BxPC3 cells alone), whereas MMP-9 expression was decreased (less than one-tenth comparing with that of BxPC3 cells alone). Blockage of AREG production by its specific siRNA removed MSC-mediated driving force of BxPC3 invasiveness. Immunohistochemical analysis of tissue samples obtained both from PDAC patients and PDAC imitating mouse xenografted models revealed that significant coexpression of AREG and its receptor EGFR were detected on the cancer cells at invasive front. These results strongly suggested that cellular interaction between cancer cells and MSCs in the PDAC stroma might be critical to cancer progression, especially in the process of local invasion and the early stage development of metastasis.

    DOI: 10.7150/jca.24415

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  • Active Secretion of Dimerized S100A11 Induced by the Peroxisome in Mesothelioma Cells. 査読 国際誌

    Satomi Saho, Hiroki Satoh, Eisaku Kondo, Yusuke Inoue, Akira Yamauchi, Hitoshi Murata, Rie Kinoshita, Ken-Ichi Yamamoto, Junichiro Futami, Endy Widya Putranto, I Made Winarsa Ruma, I Wayan Sumardika, Chen Youyi, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Shuta Tomida, Yoshihiko Sakaguchi, Ken Saito, Hidekazu Iioka, Nam-Ho Huh, Shinichi Toyooka, Masakiyo Sakaguchi

    Cancer microenvironment : official journal of the International Cancer Microenvironment Society   9 ( 2-3 )   93 - 105   2016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)  

    S100A11, a small Ca2+ binding protein, acts extracellularly as a mediator of cancer progression. That raises the question of how a protein that lacks the classical secretory signal is able to be secreted outside cells without being damaged. Some insights into this question have been obtained, and there has been accumulating evidence indicating a pivotal role of a non-classical vesicle-mediated pathway using lysosomes or peroxisomes for the protein secretion. To obtain a more precise insight into the secretory mechanism of S100A11, we first screened representative cancer cells exhibiting significantly active secretion of S100A11. From the results of profiling, we turned our attention to aggressive cancer mesothelioma cells. In mesothelioma cells, we found that abundant dimeric S100A11 was produced selectively in the peroxisome after transportation of monomeric S100A11 through an interaction with PEX14, a peroxisome membrane protein, resulting in peroxisomal secretion of dimerized S100A11. In an extracellular environment in vitro, dimerized S100A11 promoted mesothelial cell invasion indirectly with the help of fibroblast cells. Overall, the results indicate that the peroxisome functions as an essential vesicle for the production of dimerized S100A11 and the subsequent secretion of the protein from mesothelioma cells and that peroxisome-mediated secretion of dimerized S100A11 might play a critical role in mesothelioma progression in a tumor microenvironment.

    DOI: 10.1007/s12307-016-0185-2

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  • Peptide-based tumor inhibitor encoding mitochondrial p14(ARF) is highly efficacious to diverse tumors 査読

    Ken Saito, Hidekazu Iioka, Chie Kojima, Mikako Ogawa, Eisaku Kondo

    CANCER SCIENCE   107 ( 9 )   1290 - 1301   2016年9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:WILEY-BLACKWELL  

    p14(ARF) is one of the major tumor suppressors conventionally identified both as the mdm2-binding molecule restoring p53 function in the nucleus, and as a nucleophosmin-binding partner inside the nucleolous to stabilize ribosomal RNA. However, its recently reported mitochondrial localization has pointed to novel properties as a tumor suppressor. At the same time, functional peptides are gaining much attention in nanomedicine for their in vivo utility as non-invasive biologics. We previously reported the p14(ARF)-specific peptide that restored the sensitivity to gefitinib on the gefitinib-resistant lung cancer cells. Based on the information of this prototype peptide, here we generated the more powerful anti-tumor peptide "r9-CatB-p14 MIS," which comprises the minimal inhibitory sequence of the mitochondrial targeting p14(ARF) protein in combination with the proteolytic cleavage site for cathepsin B, which is activated in various tumor cells, fused with the nine-polyarginine-domain for cell penetration, and demonstrated its novel action of regulating mitochondrial function in accordance with localization of endogenous p14(ARF). The p14 MIS peptide showed a potent tumor inhibiton in vitro and in vivo against not only lung cancer cells but also tumor cells of diverse lineages, via modulating mitochondrial membrane potential, with minimal cytotoxicity to non-neoplastic cells and tissues. Hence, this mitochondrially targeted p14 peptide agent provides a novel basis for non-invasive peptide-based antitumor therapeutics.

    DOI: 10.1111/cas.12991

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  • Detection of RNA-Protein Interactions Using Tethered RNA Affinity Capture. 査読

    Iioka H, Macara IG

    Methods in molecular biology (Clifton, N.J.)   1316   67 - 73   2015年

  • Coxsackie and adenovirus receptor is a critical regulator for the survival and growth of oral squamous carcinoma cells 査読

    K. Saito, M. Sakaguchi, H. Iioka, M. Matsui, H. Nakanishi, N. H. Huh, E. Kondo

    ONCOGENE   33 ( 10 )   1274 - 1286   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)   出版者・発行元:NATURE PUBLISHING GROUP  

    Coxsackie and adenovirus receptor (CAR) is essential for adenovirus infection to target cells, and its constitutive expression in various cancerous and normal tissues has been reported. Recently, the biological role of CAR in human cancers of several different origins has been investigated with respect to tumor progression, metastasis and tumorigenesis. However, its biological function in tumor cells remains controversial. Here we report the critical role of CAR in growth regulation of oral squamous cell carcinomas (SCCs) in vitro and in vivo via the specific interaction with Rho-associated protein kinase (ROCK). Loss of endogenous CAR expression by knockdown using specific small interfering RNA (siRNA) against CAR facilitates growth suppression of SCC cells due to cell dissociation, followed by apoptosis. The consequent morphological reaction was reminiscent of anoikis, rather than epithelial-mesenchymal transition, and the dissociation of oral SCC cells was triggered not by lack of contact with extracellular matrix, but by loss of cell-to-cell contact caused by abnormal translocation of E-cadherin from surface membrane to cytoplasm. Immunoprecipitation assays of the CAR-transfected oral SCC cell line, HSC-2, with or without ROCK inhibitor (Y-27632) revealed that CAR directly associates with ROCK! and ROCKII, which results in inhibition of ROCK activity and contributes to maintenance of cell-to-cell adhesion for their growth and survival. Based on these findings, in vivo behavior of CAR-downregulated HSC-2 cells from siRNA knockdown was compared with that of normally CAR-expressing cells in intraperitoneally xenografted mouse models. The mice engrafted with CAR siRNA-pretreated HSC-2 cells showed poor formation of metastatic foci in contrast to those implanted with the control siRNA-pretreated cells. Thus, CAR substantially has an impact on growth and survival of oral SCC cells as a negative regulator of ROCK in vitro and in vivo.

    DOI: 10.1038/onc.2013.66

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  • Antitumor impact of p14ARF on gefitinib-resistant non-small cell lung cancers. 査読 国際誌

    Ken Saito, Nagio Takigawa, Naoko Ohtani, Hidekazu Iioka, Yuki Tomita, Ryuzo Ueda, Junya Fukuoka, Kazuhiko Kuwahara, Eiki Ichihara, Katsuyuki Kiura, Eisaku Kondo

    Molecular cancer therapeutics   12 ( 8 )   1616 - 28   2013年8月

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    記述言語:英語   出版者・発行元:8  

    Activation of the epidermal growth factor receptor (EGFR) has been observed in many malignant tumors and its constitutive signal transduction facilitates the proliferation of tumors. EGFR-tyrosine kinase inhibitors, such as gefitinib, are widely used as a molecular-targeting agent for the inactivation of EGFR signaling and show considerable therapeutic effect in non-small cell lung cancers harboring activating EGFR mutations. However, prolonged treatment inevitably produces tumors with additional gefitinib-resistant mutations in EGFR, which is a critical issue for current therapeutics. We aimed to characterize the distinct molecular response to gefitinib between the drug-resistant and drug-sensitive lung adenocarcinoma cells in order to learn about therapeutics based on the molecular information. From the quantitative PCR analysis, we found a specific increase in p14(ARF) expression in gefitinib-sensitive lung adenocarcinoma clones, which was absent in gefitinib-resistant clones. Moreover, mitochondria-targeted p14(ARF) triggered the most augmented apoptosis in both clones. We identified the amino acid residues spanning from 38 to 65 as a functional core of mitochondrial p14(ARF) (p14 38-65 a.a.), which reduced the mitochondrial membrane potential and caused caspase-9 activation. The synthesized peptide covering the p14 38-65 a.a. induced growth suppression of the gefitinib-resistant clones without affecting nonneoplastic cells. Notably, transduction of the minimized dose of the p14 38-65 peptide restored the response to gefitinib like that in the sensitive clones. These findings suggest that the region of p14(ARF) 38-65 a.a. is critical in the pharmacologic action of gefitinib against EGFR-mutated lung adenocarcinoma cells and has potential utility in the therapeutics of gefitinib-resistant cancers.

    DOI: 10.1158/1535-7163.MCT-12-1239

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  • Efficient detection of RNA-protein interactions using tethered RNAs 査読

    Hidekazu Iioka, David Loiselle, Timothy A. Haystead, Ian G. Macara

    NUCLEIC ACIDS RESEARCH   39 ( 8 )   e53   2011年4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:OXFORD UNIV PRESS  

    The diverse localization of transcripts in cells suggests that there are many specific RNA-protein interactions that have yet to be identified. Progress has been limited, however, by the lack of a robust method to detect and isolate the RNA-binding proteins. Here we describe the use of an RNA aptamer, scaffolded to a tRNA, to create an affinity matrix that efficiently pulls down transcript-specific RNA-binding proteins from cell lysates. The addition of the tRNA scaffold to a Streptavidin aptamer (tRSA) increased binding efficiency by similar to 10-fold. The tRSA system with an attached G-quartet sequence also could efficiently and specifically capture endogenous Fragile X Mental Retardation Protein (FMRP), which recognizes this RNA sequence. An alternative method, using biotinylated RNA, captured FMRP less efficiently than did our tRSA method. Finally we demonstrate the identification of novel RNA-binding proteins that interact with intron2 or 3&apos;-UTR of the polarity protein Crumbs3 transcript. Proteins captured by these RNA sequences attached to the tRNA scaffold were identified by mass spectrometry. GFP-tagged versions of these proteins also showed specific interaction with either the Crb3 intron2 or 3&apos;-UTR. Our tRSA technique should find wide application in mapping the RNA-protein interactome.

    DOI: 10.1093/nar/gkq1316

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  • Axon growth-stimulus package includes local translation 査読

    Ian G. Macara, Hidekazu Iioka, Stavroula Mili

    NATURE CELL BIOLOGY   11 ( 8 )   919 - 921   2009年8月

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    記述言語:英語   出版者・発行元:NATURE PUBLISHING GROUP  

    Translation of localized mRnas is an important mechanism for controlling spatially discrete cellular processes. The polarity protein Par-3 is locally translated in axons in response to factors such as NGF and netrin-1, and this increased expression is necessary for factor-stimulated axonal outgrowth.

    DOI: 10.1038/ncb0809-919

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  • Kaiso is a bimodal modulator for Wnt/beta-catenin signaling 査読

    Hidekazu Iioka, Stephanie K. Doerner, Keiko Tamai

    FEBS LETTERS   583 ( 4 )   627 - 632   2009年2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:ELSEVIER SCIENCE BV  

    The Wnt family of secreted ligands plays critical roles during embryonic development and tumorigenesis. Here we show that Kaiso, a dual specific DNA-binding protein, functions as a bimodal regulator of canonical Wnt signaling. Loss-of-function analysis of Kaiso abrogated Wnt-mediated reporter activity and axis duplication, whereas gain-of-function analysis of Kaiso dose-dependently resulted in synergistic and suppressive effects. Our analyses further suggest Kaiso can regulate TCF/LEF1-activity for these effects via modulating HDAC1 and beta-catenin-complex formation. Our studies together provide insights into why Kaiso null mice display resistance to intestinal tumors when crossed onto an Apc(Min/+) background. (C) 2009 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.febslet.2009.01.012

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  • XRab40 and XCullin5 form a ubiquitin ligase complex essential for the noncanonical Wnt pathway 査読

    Rebecca Hui Kwan Lee, Hidekazu Iioka, Masato Ohashi, Shun-ichiro Iemura, Tohru Natsume, Noriyuki Kinoshita

    EMBO JOURNAL   26 ( 15 )   3592 - 3606   2007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)   出版者・発行元:NATURE PUBLISHING GROUP  

    Rab GTPases are key regulators of intracellular membrane trafficking. We sought to elucidate the roles of Rab GTPases in Xenopus gastrulation, and found that a Xenopus homolog of Rab40 (XRab40) is required for normal gastrulation. XRab40 is localized at the Golgi apparatus and interacts with ElonginB/C and Cullin5 to form a ubiquitin ligase. XRab40/XCullin5 functions cooperatively and regulates the ubiquitination and localization of Rap2 GTPase. Furthermore, XRab40/XCullin5 regulates the membrane localization of Dishevelled (Dsh), a key signaling molecule in the Wnt pathway, through Rap2 and its effector Misshapen/Nck-interacting kinase (XMINK). XMINK interacts with Dsh, and is translocated to the plasma membrane by Wnt activation. We propose a novel signaling cascade consisting of XRab40/XCullin5, Rap2 and XMINK, which plays a crucial role in the regulation of the noncanonical Wnt pathway.

    DOI: 10.1038/sj.emboj.7601781

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  • Wnt signalling regulates paxillin ubiquitination essential for mesodermal cell motility 査読

    Hidekazu Iioka, Shun-ichiro Iemura, Tohru Natsume, Noriyuki Kinoshita

    NATURE CELL BIOLOGY   9 ( 7 )   813 - U150   2007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  

    Gastrulation movements are critical for establishing the three germ layers and the architecture of vertebrate embryos. During Xenopus laevis gastrulation, mesodermal tissue migrates on the blastocoel roof and elongates along the antero-posterior axis(1),(2). During this process, cells in the dorsal mesoderm are polarized and intercalate with each other, which is defined as convergent extension and is known to be regulated by the non-canonical Wnt pathway(3-5). Here, we show that paxillin plays an essential role in this process. Paxillin is a focal-adhesion associated protein implicated in the regulation of actin cytoskeletal organization and cell motility(6),7, but its role in Xenopus embryogenesis has not yet been clarified. We demonstrate that the Wnt pathway controls the ubiquitination and stability of paxillin, and that this regulatory mechanism is essential for convergent extension movements. We identified a RING finger protein XRNF185, which physically binds to paxillin and the proteasome. XRNF185 destabilizes paxillin at focal adhesions and promotes mesodermal cell migration during convergent extension. We propose a mechanism to regulate gastrulation movements that involves paxillin ubiquitination and stability controlled by Wnt signalling.

    DOI: 10.1038/ncb1607

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  • Essential role of MARCKS in cortical actin dynamics during gastrulation movements 査読

    H Iioka, N Ueno, N Kinoshita

    JOURNAL OF CELL BIOLOGY   164 ( 2 )   169 - 174   2004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:ROCKEFELLER UNIV PRESS  

    Myristoylated alanine-rich C kinase substrate (MARCKS) is an actin-binding, membrane-associated protein expressed during Xenopus embryogenesis. We analyzed its function in cytoskeletal regulation during gastrulation. Here, we show that blockade of its function impaired morphogenetic movements, including convergent extension. MARCKS was required for control of cell morphology, motility, adhesion, protrusive activity, and cortical actin formation in embryonic cells. We also demonstrate that the noncanonical Wnt pathway promotes the formation of lamellipodia- and filopodia-like protrusions and that MARCKS is necessary for this activity. These findings show that MARCKS regulates the cortical actin formation that is requisite for dynamic morphogenetic movements.

    DOI: 10.1083/jcb.200310027

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  • PKC delta is essential for Dishevelled function in a noncanonical Wnt pathway that regulates Xenopus convergent extension movements 査読

    N Kinoshita, H Iioka, A Miyakoshi, N Ueno

    GENES & DEVELOPMENT   17 ( 13 )   1663 - 1676   2003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:COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT  

    Protein kinase C (PKC) has been implicated in the Wnt signaling pathway; however, its molecular role is poorly understood. We identified novel genes encoding delta-type PKC in the Xenopus EST databases. Loss of PKCdelta function revealed that it was essential for convergent extension during gastrulation. We then examined the relationship between PKCdelta and the Wnt pathway. PKCdelta was translocated to the plasma membrane in response to Frizzled signaling. In addition, loss of PKCdelta function inhibited the translocation of Dishevelled and the activation of c-Jun N-terminal kinase (INK) by Frizzled. Furthermore, PKCdelta formed a complex with Dishevelled, and the activation of PKCdelta by phorbol ester was sufficient for Dishevelled translocation and INK activation. Thus, PKCdelta plays an essential role in the Wnt/JNK pathway by regulating the localization and activity of Dishevelled.

    DOI: 10.1101/gad.1101303

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MISC

共同研究・競争的資金等の研究

  • Crb3-PTPN3系を介した新規大腸腺癌転移制御機構の解析と転移阻害への応用

    研究課題/領域番号:20K07368  2020年4月 - 2023年3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)

    飯岡 英和

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

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  • ホーミングペプチドを基盤にした新規膵癌バイオマーカー及び膵癌標的化抗体医薬の開発

    研究課題/領域番号:20H03527  2020年4月 - 2023年3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)

    近藤 英作, 飯岡 英和, 阪口 政清, 齋藤 憲

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    配分額:17810000円 ( 直接経費:13700000円 、 間接経費:4110000円 )

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  • 大腸癌の進展における基質接着性スイッチ分子としてのCrumbs3の機能解析

    研究課題/領域番号:17K08737  2017年4月 - 2020年3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)

    飯岡 英和

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    配分額:4810000円 ( 直接経費:3700000円 、 間接経費:1110000円 )

    前年度までに、Crb3に結合するタンパク質の候補を免疫沈降後の沈殿タンパク質をマススペクトル解析することにより同定した。今年度は候補タンパク質の中から、線維芽細胞増殖因子受容体(FGFR)に注目し、大腸癌細胞DLD-1における解析を行った。
    まず免疫沈降の結果を確認するため、HEK293T細胞にCrb3とFGFR1を共発現させ、FGFR1に付加したHISタグによりプルダウンし、ウェスタンブロットにより確認したところ、Crb3とFGFR1の結合が確認できた。さらに細胞内欠失変異を有するFGFR1を用いた実験では結合が見られないことから、Crb3は細胞内ドメインを介してFGFR1と結合していると考えられた。さらにCrb3ノックアウト大腸癌細胞にCrb3を強制発現させた際に、FGFR1とその下流シグナル因子であるERK1/2のリン酸化が亢進する事を見出した。このことは大腸癌細胞の移動性がERKの活性化因子であるMEKの阻害剤(U0126, SL327)により、細胞移動が抑制されることとよく一致した。また、Crb3遺伝子座からは、選択的スプライシングによりCrb3aとCrb3bの2つのアイソフォームが生成することが知られている。ノックアウト細胞にレンチウィルスベクターを用いてCrb3aまたはCrb3bをそれぞれ単独で発現させたところ、どちらのアイソフォームもFGFR1を活性化し、細胞移動を促進した。以上のことからCrb3は両アイソフォームの共通配列を介した未知のメカニズムにより、FGFR1を活性化していることを明らかにした。これまでの結果をまとめ、論文を国際誌に投稿した。

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  • Crb3aの腫瘍組織における発現と機能の解析

    研究課題/領域番号:26870692  2014年4月 - 2016年3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)

    飯岡 英和

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:4030000円 ( 直接経費:3100000円 、 間接経費:930000円 )

    細胞極性制御因子Crumbs3(Crb3)の腫瘍形成における役割は十分に判明していない。ウェスタンブロット、免疫組織化学的解析から、正常組織に加え、一部の腺癌系の細胞・組織においてもCrb3が強く発現することが明らかとなった。またCRISPR/Cas9システムを用い、大腸癌由来培養細胞を使用してCrb3ノックアウト(Crb3KO)細胞を調製した。in vitroとin vivoの実験により親株とCrb3KO細胞比較したところ、Crb3KO細胞では形質膜状のガングリオシドが増加し、移動性が顕著に低下していることが判明した。

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  • 頂底極性決定因子CrumbsのmRNA局在化機構の解析

    研究課題/領域番号:09J01309  2009年 - 2010年

    日本学術振興会  科学研究費助成事業 特別研究員奨励費  特別研究員奨励費

    飯岡 英和

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    配分額:2400000円 ( 直接経費:2400000円 )

    上皮細胞に見られる頂底極性は、細胞内で局在する頂底極性決定因子群の働きによって形成される。決定因子の一つCrumbs(Crb)タンパク質は細胞の頂部膜のみに局在し、さらに他の因子との相互作用や細胞骨格の再構成を介して頂底極性の調節・決定に寄与していると考えられる。近年ショウジョウバエ胚においてCrbがmRNAレベルで上皮細胞の頂部側に局在していることが報告された。mRNAレベルのタンパク質局在制御は出芽酵母、ショウジョウバエの生殖系列、哺乳類神経細胞などにおいて、細胞の運命決定や、機能制御に貢献していることが知られているが、哺乳類上皮細胞においてはこれまで知られていなかった。本研究ではCrb mRNAに結合するタンパク質を同定し、Crbの機能、及び、頂底極性の形成における役割を明らかにすることを目的とした。昨年度までに一次スクリーニングとしてRNA結合タンパク検出法を立ち上げた。今年度は、得られた候補タンパク質に対して網羅的にshRNAによるノックダウン実験を行った。その結果、IRSp53を平面培養した上皮細胞内でノックダウンしたところ、Crb mRNAの頂部局在が抑制された。このことはIRSp53がCrb mRNAの局在制御に役割を果たしていることを示唆している。これまでにIRSp53は細胞の突起形成やアクチン細胞骨格の再編成において機能することが報告されているが、RNAの制御に関与するという報告は皆無である。今後はRNA免疫沈降・細胞極性又はシスト形成の観察など、生化学的、細胞生物学的な実験を駆使して、更に詳細な機能解析を慎重に行う予定である。また今年度中にRNA結合タンパク質検出の方法論のみを論文にまとめ、Nucleic Acids Research誌に投稿し、受理された。

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