多機能新規３細胞間局在分子異常による癌の悪性化のメカニズム解明

2021 Fiscal Year Annual Research Report

• Project/Area Number: 19K07464
• Research Institution: Sapporo Medical University
• Principal Investigator: 小島 隆 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
• 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阻害剤 / 肺腺癌 / 悪性化

Outline of Annual Research Achievements

多機能新規３細胞間タイト結合分子angulin-1/LSRは、正常細胞の上皮バリアの維持だけでなく、その発現変化は様々な癌の悪性化への関与が考えられる。そこで今回我々は、我々が確立したヒト正常肺上皮細胞およびangulin-1/LSRを高発現している肺腺癌細胞株を用いて、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を多面的に解析した。本年度の研究成果としては、肺腺癌細胞株A549において、angulin-1/LSRをsiRNAを用いて発現低下により肺腺癌に高発現し悪性化に関与の知られているリーキー型タイト結合分子claudin-2をEGFシグナル依存性に誘導した。さらに癌のワールブルク効果として知られ、ミトコンドリア呼吸能で示される細胞代謝をTGF-betaシグナル依存性に亢進させた。これらの変化は抗腫瘍効果のあるヒストン脱アセチル化酵素(HDAC)阻害剤Trichostatin A (TSA) and Quisinostat (JNJ-2648158)処置により阻害されるとともに、癌の悪性化を示す細胞増殖および細胞遊走も抑制することができた。正常肺上皮細胞においては、TSAおよびQuisinostat処置によりangulin-1/LSR、claudin-2,-7の増加およびclaudin-1の低下がみられた。以上のことは、多機能新規３細胞間タイト結合分子angulin-1/LSRは、肺腺癌において、EGF, TGF-beta, HDACシグナルを介して悪性化に関与していると考えられた。

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) Pages: 415-426
  • DOI: 10.1007/s00418-021-02068-8
  • Peer Reviewed / Open Access
• [Journal Article] HDAC inhibitors suppress the proliferation, migration and invasiveness 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 Pages: 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) Pages: 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): Shindo Y, Arai W, Konno T, Kohno T, Kodera Y, Chiba H, Miyajima M, Sakuma Y, Watanabe A, Kojima T.
  • Journal Title: Histochem Cell Biol. Volume: 155(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(2) Pages: 112763
  • DOI: 10.1016/j.yexcr.2021.112763
  • Peer Reviewed / Open Access
• [Journal Article] Translocation of LSR from treicellular corners causes micropinocytosis at cell-cell interface as a trigger for breaking out of contact inhibition. (2021)
  • Author(s): Kohno T, Konno T, Kikuchi S, Kondoh M, Kojima T.
  • Journal Title: FASEB J. Volume: 35(9) Pages: e21742
  • 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 Pages: 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 D, Takasawa A, Kikuchi S, Takemasa I, Osanai M, Kojima T.
  • Journal Title: Biochim Biophys Acta Biomembr. Volume: 1863 Pages: 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 Pages: 1972760
  • DOI: 10.1080/21688370.2021.1972760
  • Peer Reviewed / Open Access
• [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 Pages: 6341
  • DOI: 10.3390/cancers13246341
  • Peer Reviewed / Open Access