Analyses of malignant mechanisms via abnormality of novel multifunctional tricellular junction molecules in cancer cells

• Project/Area Number: 19K07464
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Kojima Takashi 札幌医科大学, 医学部, 教授 (30260764)
• Co-Investigator(Kenkyū-buntansha): 幸野 貴之 札幌医科大学, 医学部, 講師 (10374563)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ３細胞間タイト結合分子 / Angulin-1/LSR / claudin-2 / EGFシグナル / TGF-betaシグナル / HDACシグナル / 癌悪性化 / HDAC阻害剤 / angulin-1/LSR / 肺腺癌 / 悪性化 / ASPP2 / 細胞分裂 / YAPシグナル / 子宮内膜癌 / JNK/cofilin/acti / 膵癌 / 診断 / 治療

Outline of Research at the Start

多機能新規３細胞間タイト結合分子LSRは、正常細胞の上皮バリアの維持だけでなく、細胞集団の安定化に重要な役割を持つと考えられている。さらにLSRは、３細胞間において様々な機能分子と相互作用をしている。そこで今回我々は、我々が確立したヒト正常上皮細胞およびLSRを高発現している癌細胞株を用いて、LSR/ASPP2/PAR3/YAP蛋白複合体の正常および癌細胞における役割および発現調節メカニズム（図1）を多面的に解析する。最終的には３細胞間局在分子の正常および癌細胞における詳細な役割を解明し、癌を含めた様々なヒト疾患における新規病態メカニズムを解明し治療につなげる。

Outline of Final Research Achievements

Multifunctional tricellular junction molecule angulin-1/LSR maintains the epithelial barrier and induces stability of the collecting cells. Its expression contributes to the malignancy of cancer cells via the binding effects with various functional molecules at tricellular contacts. We performed a multilateral analysis for the regulatory mechanisms and the roles LSR/ASPP2/PAR3/YAP complex proteins in normal human cells and cancer. As result, in various cancer cells, angulin-1/LSR is regulated via multiple intercellular signaling and prevents the malignancy.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、多機能新規３細胞間タイト結合分子angulin-1/LSRの癌細胞における発現調節機構および役割が解明できただけでなく、COVID-19感染を始めとして炎症などの重症化疾患における役割の解明さらに、治療効果のある既存および新規物質のスクリーニングにも役に立つと考えられた。

Research Products

• [Journal Article] FOXO3/TGF-β signal-dependent ciliogenesis and cell functions during differentiation of temperature-sensitive mouse cochlear precursor hair cells (2022)
  • Author(s): Kakuki T, Kohno T, Nishida S, Konno T, Kikuchi S, Ohwada K, Nakano M, Tezuka M, Takano K, Kojima T.
  • Journal Title: Histochem Cell Biol. Volume: 157(4) Issue: 4 Pages: 415-426
  • DOI: 10.1007/s00418-021-02068-8
  • Peer Reviewed / Open Access
• [Journal Article] HDAC inhibitors suppress proliferation, migration and invasion of human head and neck squamous cell carcinoma cells via p63-mediated tight junction molecules and p21-mediated growth arrest. (2021)
  • Author(s): Kakiuchi A, Kakuki T, Ohwada K, Kurose M, Kondoh A, Obata K, Nomura K, Miyata R, Kaneko Y, Konno T, Kohno T, Himi T, Takano K, Kojima T.
  • Journal Title: Oncology Rep. Volume: 45 Issue: 4 Pages: 46-46
  • DOI: 10.3892/or.2021.7997
  • Peer Reviewed / Open Access
• [Journal Article] Pyk2 inhibitor prevents epithelial hyperpermeability induced by HMGB1 and inflammatory cytokines in Caco-2 cells. (2021)
  • Author(s): Konno T, Kohno T, Miyakawa M, Tanaka H, Kojima T.
  • Journal Title: Tissue Barriers. Volume: 9(2) Issue: 2 Pages: 1890526-1890526
  • DOI: 10.1080/21688370.2021.1890526
  • Peer Reviewed / Open Access
• [Journal Article] Effects of histone deacetylase inhibitors Tricostatin A and Quisinostat on tight junction proteins of human lung adenocarcinoma A549 cells and normal lung epithelial cells (2021)
  • Author(s): Yuma Shindo
  • Journal Title: Histochem Cell Biol Volume: - Issue: 6 Pages: 637-653
  • DOI: 10.1007/s00418-021-01966-1
  • Peer Reviewed / Open Access
• [Journal Article] MCL1 inhibition enhances the efficacy of docetaxel against airway-derived squamous cell carcinoma cells. (2021)
  • Author(s): Sakuma Y, Hirai S, Sumi T, Tada M, Kojima T, Niki T, Yamaguchi M
  • Journal Title: Exp Cell Res Volume: 406 Issue: 2 Pages: 112763-112763
  • DOI: 10.1016/j.yexcr.2021.112763
  • Peer Reviewed / Open Access
• [Journal Article] Translocation of LSR from tricellular corners causes macropinocytosis at cell?cell interface as a trigger for breaking out of contact inhibition (2021)
  • Author(s): Kohno Takayuki、Konno Takumi、Kikuchi Shin、Kondoh Masuo、Kojima Takashi
  • Journal Title: The FASEB Journal Volume: 35 Issue: 9
  • DOI: 10.1096/fj.202100299r
  • Peer Reviewed / Open Access
• [Journal Article] Effects of HMGB1 on Tricellular Tight Junctions via TGF-β Signaling in Human Nasal Epithelial Cells (2021)
  • Author(s): Ohwada K, Konno T, Kohno T, Nakano M, Ohkuni T, Miyata R, Kakuki T, Kondoh M, Takano K, Kojima T.
  • Journal Title: Int J Mol Sci. Volume: 22 Issue: 16 Pages: 8390-8390
  • DOI: 10.3390/ijms22168390
  • Peer Reviewed / Open Access
• [Journal Article] Role of tight junctions in the epithelial-to-mesenchymal transition of cancer cells (2021)
  • Author(s): Kyuno Daisuke、Takasawa Akira、Kikuchi Shin、Takemasa Ichiro、Osanai Makoto、Kojima Takashi
  • Journal Title: Biochimica et Biophysica Acta (BBA) - Biomembranes Volume: 1863 Issue: 3 Pages: 183503-183503
  • DOI: 10.1016/j.bbamem.2020.183503
  • Peer Reviewed / Open Access
• [Journal Article] Dysfunction of epithelial permeability barrier induced by HMGB1 in 2.5D cultures of human epithelial cells. (2021)
  • Author(s): Kojima T, Shindo Y, Konno T, Kodera Y, Arai W, Miyakawa M, Ohwada K, Tanaka H, Tsujiwaki M, Sakuma Y, Kikuchi S, Ohkuni T, Takano K, Watanabe A, Kohno T.
  • Journal Title: Tissue Barriers. Volume: Sep 18 Issue: 2 Pages: 1972760-1972760
  • DOI: 10.1080/21688370.2021.1972760
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Roles of Tricellular Tight Junction Protein Angulin-1/Lipolysis-Stimulated Lipoprotein Receptor (LSR) in Endometriosis and Endometrioid-Endometrial Carcinoma. (2021)
  • Author(s): Shimada H, Kohno T, Konno T, Okada T, Saito K, Shindo Y, Kikuchi S, Tsujiwaki M, Ogawa M, Matsuura M, Saito T, Kojima T.
  • Journal Title: Cancers Volume: 13 Issue: 24 Pages: 6341-6341
  • DOI: 10.3390/cancers13246341
  • Peer Reviewed / Open Access
• [Journal Article] Tricellular tight junction protein LSR/angulin-1 contributes to the epithelial barrier and malignancy in human pancreatic cancer cell line (2020)
  • Author(s): Kyuno T, Kyuno D, Kohno T, Konno T, Kikuchi S, Arimoto C, Yamaguchi H, Imamura M, Kimura Y, Kondoh M, Takemasa I, Kojima T
  • Journal Title: Histochemistry and Cell Biology Volume: 153 Issue: 1 Pages: 5-16
  • DOI: 10.1007/s00418-019-01821-4
  • Peer Reviewed / Open Access
• [Journal Article] Glucose-dependent FOXM1 promotes EMT via cellular metabolism and targeting snail in human pancreatic cancer (2020)
  • Author(s): Kyuno T, Kohno T, Konno T, Yamaguchi H, Kyuno D, Imamura M, Kimura Y, Kojima T and Takemasa I
  • Journal Title: Pancreas Volume: 49 Issue: 2 Pages: 273-280
  • DOI: 10.1097/mpa.0000000000001485
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ASPP2 suppression promotes malignancy via LSR and YAP in human endometrial cancer. (2020)
  • Author(s): Konno T, Kohno T, Okada T, Shimada H, Satohisa S, Kikuchi S, Saito T, Kojima T.
  • Journal Title: Histochem Cell Biol. Volume: 154(2) Issue: 2 Pages: 197-213
  • DOI: 10.1007/s00418-020-01876-8
  • Peer Reviewed
• [Journal Article] HMGB1-downregulated angulin-1/LSR induces epithelial barrier disruption via claudin-2 and cellular metabolism via AMPK in airway epithelial Calu-3 cells. (2020)
  • Author(s): Kodera Y, Chiba H, Konno T, Kohno T, Takahashi H, Kojima T
  • Journal Title: Biochem Biophys Res Commun. Volume: 527 Issue: 2 Pages: 553-560
  • DOI: 10.1016/j.bbrc.2020.04.113
  • Peer Reviewed / Open Access
• [Journal Article] Possibility of targeting claudin-2 in therapy for human endometrioid endometrial carcinoma. (2020)
  • Author(s): Okada T, Konno T, Kohno T, Shimada H, Saito K, Satohisa S, Saito T, Kojima T.
  • Journal Title: Reprod. Sci. Volume: 27 Issue: 11 Pages: 2092-2103
  • DOI: 10.1007/s43032-020-00230-6
  • Peer Reviewed / Open Access
• [Journal Article] HMGB1 enhances epithelial permeability via p63/TGF-β signaling in lung and terminal bronchial epithelial cells. (2020)
  • Author(s): Kodera Y, Kohno T, Konno T, Arai W, Tsujiwaki M, Shindo Y, Chiba H, Miyakawa M, Tanaka H, Sakuma Y, Watanabe A, Takahashi H, Kojima T.
  • Journal Title: Tissue Barriers. Volume: 8 Issue: 4 Pages: 1805997-1805997
  • DOI: 10.1080/21688370.2020.1805997
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Downregulation of angulin-1/LSR induces malignancy via upregulation of EGF-dependent claudin-2 and TGF-β-dependent cell metabolism in human lung adenocarcinoma A549 cells. (2020)
  • Author(s): Arai W, Konno T, Kohno T, Kodera Y, Tsujiwaki M, Shindo Y, Chiba H, Miyajima M, Sakuma Y, Watanabe A, Kojima T.
  • Journal Title: Oncotarget. Volume: -
  • Peer Reviewed
• [Journal Article] A Resourceful Alteration of Tricellular Tight Junction Proteins: Roles in Endometrial Cancer Progression. Tight Junctions: Classification, Structure and Functions. (2020)
  • Author(s): Kohno T, Konno T, Kojima T.
  • Journal Title: Nova Science Publishers Volume: -
  • Peer Reviewed
• [Journal Article] HDAC inhibitors suppress proliferation, migration and invasion of human head and neck squamous cell carcinoma cells via p63-mediated tight junction molecules and p21-mediated growth arrest. (2020)
  • Author(s): Kakiuchi A, Kakuki T, Ohwada K, Kurose M, Kondoh A, Obata K, Nomura K, Miyata R, Kaneko Y, Konno T, Kohno T, Himi T, Takano K, Kojima T.
  • Journal Title: Oncology Rep. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Localization of Tricellular Tight Junction Molecule LSR at Midbody and Centrosome During Cytokinesis in Human Epithelial Cells (2019)
  • Author(s): Konno Takumi、Kohno Takayuki、Kikuchi Shin、Shimada Hiroshi、Satohisa Seiro、Takano Kenichi、Saito Tsuyoshi、Kojima Takashi
  • Journal Title: Journal of Histochemistry & Cytochemistry Volume: 68 Issue: 1 Pages: 59-72
  • DOI: 10.1369/0022155419886263
  • Peer Reviewed / Open Access
• [Journal Article] Induction of airway progenitor cells via p63 and KLF11 by Rho-kinase inhibitor Y27632 in hTERT-human nasal epithelial cells. (2019)
  • Author(s): Kaneko Y, Konno T, Kohno T, Kakuki T, Miyata R, Ohkuni T, Kakiuchi A, Yajima R, Ohwada K, Kurose M, Himi T, Takano K, Kojima T.
  • Journal Title: Am J Transl Res. Volume: 11 Pages: 599-611
  • Peer Reviewed
• [Journal Article] Rho-kinase and PKCα Inhibition Induces Primary Cilia Elongation and Alters the Behavior of Undifferentiated and Differentiated Temperature-sensitive Mouse Cochlear Cells. (2019)
  • Author(s): Kakiuchi A, Kohno T, Kakuki T, Kaneko Y, Konno T, Hosaka Y, Hata T, Kikuchi S, Ninomiya T, Himi T, Takano K, Kojima T.
  • Journal Title: J Histochem Cytochem. Volume: in press Issue: 7 Pages: 523-535
  • DOI: 10.1369/0022155419841013
  • Peer Reviewed / Open Access
• [Journal Article] Epithelial barrier dysfunction and cell migration induction via JNK/cofilin/actin by angubindin-1 (2019)
  • Author(s): Konno Takumi、Kohno Takayuki、Kikuchi Shin、Shimada Hiroshi、Satohisa Seiro、Saito Tsuyoshi、Kondoh Masuo、Kojima Takashi
  • Journal Title: Tissue Barriers Volume: 8 Issue: 1 Pages: 1695475-1695475
  • DOI: 10.1080/21688370.2019.1695475
  • Peer Reviewed / Open Access
• [Journal Article] Role of Tricellular Tight Junction Protein Lipolysis-Stimulated Lipoprotein Receptor (LSR) in Cancer Cells (2019)
  • Author(s): Takayuki Kohno, Takumi Konno, Takashi Kojima
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 14 Pages: 3555-3555
  • DOI: 10.3390/ijms20143555
  • Peer Reviewed / Open Access
• [Journal Article] Guanylate Binding Protein-1-Mediated Epithelial Barrier via Tight Junctions. (2019)
  • Author(s): Konno T, Kohno T, Takano K, Miyata R, Miyakawa M, Tanaka H, Kojima T.
  • Journal Title: Advances in Medicine and Biology. Volume: 146
  • Peer Reviewed
• [Presentation] 子宮内膜癌の悪性化におけるASPP2の役割 (2019)
  • Author(s): 嶋田浩志、郷久晴朗、金野匠、幸野貴之、小島隆、齋藤豪
  • Organizer: 第71回日本産婦人科学会
• [Presentation] Loss of ASPP2 promotes cell invasion and migration via LSR and YAP in human endometrial cancer. (2019)
  • Author(s): Konno T, Kohno T, Shimada H, Satohisa S, Kikuchi S, Saito T, Kojima T.
  • Organizer: 第71回日本細胞生物学会
• [Presentation] Loss of ASPP2 promotes cell invasion and migration via LSR and YAP in human endometrial cancer. (2019)
  • Author(s): Konno T, Kohno T, Shimada H, Satohisa S, Kikuchi S, Saito T, Kojima T.
  • Organizer: 第38回札幌国際がんシンポジウム
• [Presentation] Loss of ASPP2 promotes cell invasion and migration via LSR and YAP in human endometrial cancer. (2019)
  • Author(s): Konno T, Kohno T, Shimada H, Satohisa S, Kikuchi S, Saito T, Kojima T.
  • Organizer: 第51回日本臨床分子形態学会総会
• [Presentation] The role of tight junction molecule claudin-2 in malignancy of human endometrial cancer (endometrioid). (2019)
  • Author(s): 岡田匡氷、金野匠、嶋田浩志、郷久晴朗、幸野貴之、齋藤豪、小島隆
  • Organizer: 第42回日本分子生物学会
• [Presentation] Loss of ASPP2 promotes cell invasion and migration via LSR and YAP in human endometrial cancer. (2019)
  • Author(s): Konno T, Kohno T, Shimada H, Satohisa S, Kikuchi S, Saito T, Kojima T.
  • Organizer: ASCB
  • Int'l Joint Research
• [Presentation] Bicellular and tricellular tight junction molecules localize to midbody and centrosome during cytokinesis in human endometrial carcinoma cell line. (2019)
  • Author(s): Kojima T., Konno T, Kohno T, Kikuchi S, Shimada H, Satohisa S, Saito T.
  • Organizer: ASCB
  • Int'l Joint Research