A novel tricellular tight junction molecule LSR in diagnosis and therapy for cancer

• Project/Area Number: 15K08350
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Sapporo Medical University
• Principal Investigator: Takashi Kojima 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)
• Co-Investigator(Renkei-kenkyūsha): KONDOH MASAO 大阪大学, 薬学部, 准教授 (50309697) ; SAWADA NORIMASA 札幌医科大学, 医学部, 教授 (30154149)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 子宮内膜癌 / 膵臓癌 / LSR / 悪性化 / Hippo pathway / TEAD1/AREG / claudin-1 / Angubindin-1 / ASPP2 / 膵癌 / 頭頚部扁平上皮癌 / adipokines

Outline of Final Research Achievements

In the present study, to apply a novel tricellular tight junction molecule LSR to diagnosis and therapy for cancer, we investigated the roles and the regulated mechanisms of LSR during malignancy of endometrial cancer and pancreatic cancer by using cancer cell lines and normal human epithelial cells. Knockdown of LSR by the siRNA in cancer cell lines promoted the migration and the invasion of cancer cells via transcriptional factor TEAD1/growth factor AREG. The mechanisms in migration and invasion of cancer cells by loss of LSR, are 1) the Hippo pathway (YAP/AMOT/merin) and 2) the pathway of the increase of MMP1 via induction of tight junction molecule claudin-1. In normal human epithelial cells, knockdown of LSR induced claudin-1 expression. Taken together, loss of LSR may contribute to the malignancy of cancer via the complex mechanisms.

Research Products

• [Journal Article] Regulation of claudin-4 via p63 in human epithelial cells. (2017)
  • Author(s): Kojima T, Kohno T, Kubo T, Kaneko Y, Kakuki T, Kakiuchi A, Kurose M, Takano KI, Ogasawara N, Obata K, Nomura K, Miyata R, Konno T, Ichimiya S, Himi T.
  • Journal Title: Ann N Y Acad Sci. Volume: 1405 Issue: 1 Pages: 25-31
  • DOI: 10.1111/nyas.13456
  • Peer Reviewed / Open Access
• [Journal Article] Loss of tricellular tight junction protein LSR promotes cell invasion and migration via upregulation of TEAD1/AREG in human endometrial cancer. (2017)
  • Author(s): Shimada H, Abe S, Kohno K, Satohisa S, Konno T, Takahashi S, Hatakeyama T, Arimoto C, Kakuki T, Kaneko Y, Takano K, Saito T, Kojima T
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 10935-10935
  • DOI: 10.1038/srep37049
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Histone deacetylase inhibition prevents cell death induced by loss of tricellular tight junction proteins in temperature-sensitive mouse cochlear cells (2017)
  • Author(s): Takano Kenichi、Kakuki Takuya、Kaneko Yakuto、Kohno Takayuki、Kikuchi Shin、Himi Tetsuo、Kojima Takashi
  • Journal Title: PLoS One Volume: 12 Issue: 8 Pages: e0182291-e0182291
  • DOI: 10.1371/journal.pone.0182291
  • Peer Reviewed / Open Access
• [Journal Article] The bicellular tensile force sorts the localization of LSRs in bicellular and tricellular junctions (2017)
  • Author(s): Kohno Takayuki、Kikuchi Shin、Ninomiya Takafumi、Kojima Takashi
  • Journal Title: Ann N Y Acad Sci Volume: 1397 Issue: 1 Pages: 185-194
  • DOI: 10.1111/nyas.13362
  • Peer Reviewed / Open Access
• [Journal Article] The role of transcriptional factor p63 in regulation of epithelial barrier and ciliogenesis of human nasal epithelial cells (2017)
  • Author(s): Kaneko Yakuto、Kohno Takayuki、Kakuki Takuya、Takano Ken-ichi、Ogasawara Noriko、Miyata Ryo、Kikuchi Shin、Konno Takumi、Ohkuni Tsuyoshi、Yajima Ryoto、Kakiuchi Akito、Yokota Shin-ichi、Himi Tetsuo、Kojima Takashi
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 10935-10935
  • DOI: 10.1038/s41598-017-11481-w
  • Peer Reviewed / Open Access
• [Journal Article] Downregulation of LSR promotes cell invasion via claudin-1-mediated MMPs in human endometrial cancer. (2017)
  • Author(s): Shimada H, Satohisa S, Kohno T, Konno T, Takano K, Takahashi S, Hatakeyama T, Arimoto C, Saito T, Kojima T
  • Journal Title: Oncology Letters Volume: 14 Pages: 6776-6782
  • DOI: 10.3892/ol.2017.7038
  • Peer Reviewed / Open Access
• [Journal Article] The behavior and role of lipolysis-stimulated lipoprotein receptor, a component of tricellular tight junctions, in head and neck squamous cell carcinomas. (2016)
  • Author(s): Takano K, Kakuki T, Obata K, Nomura K, Miyata R, Kondo A, Kurose M, Kakiuch A, Kaneko Y, Kohno T, Himi T, Kojima T.
  • Journal Title: Anticancer Research Volume: 36 Pages: 5895-5904
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Behavior of Primary Cilia and Tricellular Tight Junction Proteins during Differentiation in Temperature-Sensitive Mouse Cochlear Precursor Hair Cells. (2016)
  • Author(s): Kakuki T, Kaneko Y, Takano K, Ninomiya T, Kohno T, Kojima T, Himi T.
  • Journal Title: Adv. Otorhinolaryngol. Volume: 77 Pages: 27-32
  • DOI: 10.1159/000441867
  • ISBN: 9783318056501, 9783318056518
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Junctional Adhesion Molecule-A in Head and Neck Squamous Cell Carcinoma. (2016)
  • Author(s): Kurose M, Kakuki T, Takano K, Kondo A, Obata K, Nomura K, Miyata R, Kaneko Y, Konno T, Kohno T, Kojima T, Himi T.
  • Journal Title: Adv. Otorhinolaryngol. Volume: 77 Pages: 92-97
  • DOI: 10.1159/000441881
  • ISBN: 9783318056501, 9783318056518
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Clarithromycin prevents human respiratory syncytial virus-induced airway epithelial responses by modulating activation of interferon regulatory factor-3. (2016)
  • Author(s): Yamamoto K, Yamamoto S, Ogasawara N, Takano K, Shiraishi T, Sato T, Miyata R, Kakuki T, Kamekura R, Kojima T, Tsutsumi H, Himi T, Yokota S.
  • Journal Title: Pharmacol Res Volume: 111 Pages: 804-814
  • DOI: 10.1016/j.phrs.2016.07.033
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Mumps Virus Induces Protein-Kinase-R-Dependent Stress Granules, Partly Suppressing Type III Interferon Production. (2016)
  • Author(s): Hashimoto S, Yamamoto S, Ogasawara N, Sato T, Yamamoto K, Katoh H, Kubota T, Shiraishi T, Kojima T, Himi T, Tsutsumi H, Yokota S
  • Journal Title: PLoS One. Volume: Aug 4;3: Issue: 8 Pages: 16023-16023
  • DOI: 10.1371/journal.pone.0161793
  • Peer Reviewed / Open Access
• [Journal Article] Nuclear localization of tricellulin promotes the oncogenic property of pancreatic cancer (2016)
  • Author(s): Akira Takasawa, Masaki Murata, Kumi Takasawa, Yusuke Ono, Makoto Osanai, Satoshi Tanaka, Masanori Nojima, Tsuyoshi Kono, Koichi Hirata, Takashi Kojima, Norimasa Sawada
  • Journal Title: Scientific Reports Volume: - Issue: 1
  • DOI: 10.1038/srep33582
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Prolyl isomerase Pin1 promotes survival in EGFR-mutant lung adenocarcinoma cells with an epithelial-mesenchymal transition phenotype. (2016)
  • Author(s): Sakuma Y, Nishikiori H, Hirai S, Yamaguchi M, Yamada G, Watanabe A, Hasegawa T, Kojima T, Niki T, Takahashi H.
  • Journal Title: Lab Invest. Volume: 96 Issue: 4 Pages: 391-398
  • DOI: 10.1038/labinvest.2015.155
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The roles of tricellular tight junction protein lipolysis-stimulated lipoprotein receptor in malignancy of human endometrial cancer cells. (2016)
  • Author(s): Shimada H, Satohisa S, Kohno T, Takahashi S, Hatakeyama T, Konno T, Tsujiwaki M, Saito T, Kojima T.
  • Journal Title: Oncotarget Volume: 7 Issue: 19 Pages: 27735-27752
  • DOI: 10.18632/oncotarget.8408
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dysregulation of junctional adhesion molecule-A via p63/GATA-3 in head and neck squamous cell carcinoma. (2016)
  • Author(s): Kakuki T, Kurose M, TakanoK, Kondoh A, Obata K, Nomura K, Miyata R, Kaneko Y, Konno T, Takahashi S, Hatakeyama T, Kohno T, Himi T, Kojima T.
  • Journal Title: Oncotarget Volume: 7 Pages: 33887-33900
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Interferon-gamma increased epithelial barrier function via upregulating claudin-7 expression in human submandibular gland duct epithelium. (2016)
  • Author(s): Abe A, Takano K, Kojima T, Nomura K, Kakuki T, Kaneko Y, Yamamoto M, Takahashi H, Himi T
  • Journal Title: J Mol Histol Volume: 未定 Issue: 3 Pages: 353-363
  • DOI: 10.1007/s10735-016-9667-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Downregulation of LSR promotes cell invasion via claudin-1-mediated MMPs in human endometrial cancer. (2016)
  • Author(s): Shimada H, Satohisa S, Kohno T, Konno T, Takano K, Takahashi S, Hatakeyama T, Arimoto C, Saito T, Kojima T.
  • Journal Title: Oncology Letters Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Claudin-4 binder C-CPE 194 enhances effects of anticancer agents on pancreatic cancer cell lines via a MAPK pathway. (2015)
  • Author(s): Kono T, Kondoh M, Kyuno D, Ito T, Kimura Y, Imamura M, Kohno T, Konno T, Furuhata T, Sawada N, Hirata K, Kojima T.
  • Journal Title: Pharmacl Res Perspect. Volume: 3 Issue: 6
  • DOI: 10.1002/prp2.196
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Claudin-binder C-CPE mutants enhance permeability of insulin across human nasal epithelial cells. (2015)
  • Author(s): Kojima T, Kondoh M, Keira T, Takano KI, Kakuki T, Kaneko Y, Miyata R, Nomura K, Obata K, Kohno T, Konno T, Sawada N, Himi T.
  • Journal Title: Drug Deliv. Volume: 3 Pages: 1-8
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Poly(I:C) induced microRNA-146a regulates epithelial barrier and secretion of proinflammatory cytokines in human nasal epithelial cells. (2015)
  • Author(s): Miyata R, Kakuki T, Nomura K, Ohkuni T, Ogasawara N, Takano K, Konno T, Kohno T, Sawada N, Himi T, Kojima T.
  • Journal Title: Eur J Pharmacol. Volume: 761 Pages: 375-382
  • DOI: 10.1016/j.ejphar.2015.04.031
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Staurosporine induces formation of two types of extra-long cell protrusions: actin-based filaments and microtubule-based shafts (2015)
  • Author(s): Kohno T. Ninomiya T, Kikuchi S, Konno T, Kojima T
  • Journal Title: Mol Pharmaco Volume: 87 Issue: 5 Pages: 815-824
  • DOI: 10.1124/mol.114.096982
  • Peer Reviewed / Open Access
• [Journal Article] Aberrant expression of claudin-4 and -7 in hepatocytes in the cirrhotic human liver. (2015)
  • Author(s): Tsujiwaki M, Murata M, Takasawa A, Hiratsuka Y, Fukuda R, Sugimoto K, Ono Y, Nojima M, Tanaka S, Hirata K, Kojima T, Sawada N.
  • Journal Title: Med Mol Morphol. Volume: 48(1) Issue: 1 Pages: 33-43
  • DOI: 10.1007/s00795-014-0074-z
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Isogladine maleate regulates gap junctional intercellular communication-dependent epithelial barrier in human nasal epithelial cells. (2014)
  • Author(s): Miyata R, Nomura K, Kakuki T, Takano K, Kohno T, Konno T, Sawada N, Himi T, Kojima T.
  • Journal Title: J Membr Biol. Volume: 248(2) Issue: 2 Pages: 327-336
  • DOI: 10.1007/s00232-015-9774-0
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] c-Jun N-terminal kinase inhibitor SP600125 enhances barrier function and elogation of human pancreatic cancer cell line HPAC in a Ca-switch model. (2014)
  • Author(s): Konno T, Ninomiya T, Kohno T, Kikuchi S, Sawada N, Kojima T.
  • Journal Title: Histochem Cell Biol. Volume: 143(5) Issue: 5 Pages: 471-479
  • DOI: 10.1007/s00418-014-1300-4
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] ヒト鼻粘膜上皮バリアにおける転写制御因子p63の役割 (2017)
  • Author(s): 金子躍人、角木拓也、高野賢一、小笠原徳子、横田伸一、氷見徹夫、幸野貴之、小島隆
  • Organizer: 第106回日本病理学会
• [Presentation] 膵癌の悪性化における３細胞間タイト結合分子LSRの役割 (2017)
  • Author(s): 金野匠、及能大輔、河野剛、有元千紘、畠山翔翼、高橋駿太、幸野貴之、小島隆
  • Organizer: 第106回日本病理学会
• [Presentation] 3細胞間タイト結合蛋白LSRはYAP/AMOT/merlinを介して子宮内膜癌の悪性化へ関与する (2017)
  • Author(s): 阿部秀悦、嶋田浩志、郷久晴朗、金野匠、齋藤豪、幸野貴之、小島隆
  • Organizer: 第69回日本細胞生物学会
• [Presentation] がん細胞の上皮バリアおよび悪性化における糖代謝の役割 (2017)
  • Author(s): 金野匠、幸野貴之、及能大輔、嶋田浩志、郷久晴朗、角木拓也、金子躍人、 高野賢一、齋藤豪、小島隆
  • Organizer: 第69回日本細胞生物学会
• [Presentation] 頭頸部扁平上皮癌におけるヒストン脱アセチル化酵素(HDAC)阻害剤のp63依存性タイト結合分子を介した抗腫瘍効果 (2017)
  • Author(s): 垣内晃人、角木拓也、黒瀬誠、高野賢一、近藤敦、小幡和史、野村一顕、宮田亮、金子躍人、幸野貴之、氷見徹夫、小島隆
  • Organizer: 第69回日本細胞生物学会
• [Presentation] ３細胞間タイト結合分子LSRはAMOTにより活性化されたHippo pathwayを介して子宮内膜癌の悪性化に関与する (2017)
  • Author(s): 郷久晴朗、嶋田浩志、阿部秀悦、玉手雅人、岩崎雅宏、寺田倫子、鈴木美和、寺本瑞絵、田中綾一、小島隆、齋藤豪
  • Organizer: 第59回日本婦人科腫瘍学会学術講演会
• [Presentation] 子宮内膜癌（endometrioid)におけるタイト結合分子claudin-2の役割 (2017)
  • Author(s): 嶋田浩志、金野匠、郷久晴朗、阿部秀悦、幸野貴之、齋藤豪、小島隆
  • Organizer: 第49回日本臨床分子形態学学会
• [Presentation] マウス内耳有毛前駆細胞におけるRho/ROCK阻害剤Y27632によるprimary ciliaの変化 (2017)
  • Author(s): 保坂雪野、幸野貴之、金子躍人、垣内晃人、矢島諒人、金野匠、菊池真、高野賢一、氷見徹夫、小島隆
  • Organizer: 第49回日本臨床分子形態学学会
• [Presentation] 細胞分裂における３細胞間タイト結合分子の局在変化と役割 (2017)
  • Author(s): 金野匠、幸野貴之、菊池真、嶋田浩志、郷久晴朗、齋藤豪、小島隆
  • Organizer: 第49回日本臨床分子形態学学会
• [Presentation] ヒト鼻粘膜上皮バリアにおけるp63の役割 (2017)
  • Author(s): 小島隆、金子躍人、金野匠、角木拓也、高野賢一、菊池真、矢島諒人、大国毅、 氷見徹夫、幸野貴之
  • Organizer: 2017年生命科学系学会合同年次大会
• [Presentation] ヒストン脱アセチル化酵素(HDAC)阻害による頭頸部扁平上皮癌タイト結合分子の変化と抗腫瘍効果 (2017)
  • Author(s): 垣内晃人、角木拓也、黒瀬誠、高野賢一、近藤敦、小幡和史、野村一顕、宮田遼、金子躍人、氷見徹夫、小島隆
  • Organizer: 2017年生命科学系学会合同年次大会
• [Presentation] 細胞質分裂における３細胞間タイト結合分子の局在と役割 (2017)
  • Author(s): 金野匠、幸野貴之、菊池真、嶋田浩志、郷久晴朗、齋藤豪、小島隆
  • Organizer: 2017年生命科学系学会合同年次大会
• [Presentation] LSR/YAP/AMOT/merlinによる子宮内膜癌の悪性化への関与 (2016)
  • Author(s): 嶋田浩志、郷久晴朗、金野匠、有元千尋、高橋俊太、畠山翔翼、幸野貴之、齋藤豪、小島隆
  • Organizer: 第４８回日本分子形態学学会
  • Place of Presentation: くまもと県民交流館パレア（熊本県・熊本市）
  • Year and Date: 2016-09-23
• [Presentation] Dysregulation of junctional adhesion molecule-A via p63/GATA-3 in head and neck squamous cell carcinoma (2016)
  • Author(s): Yakuto Kaneko, Takuya Kakuki, Makoto Kurose, Ken-ichi Takano, Takayuki Kohno, Tetsuo Himi, Takashi Kojima
  • Organizer: Tight junctions and their proteins
  • Place of Presentation: ベルリン （ドイツ）
  • Year and Date: 2016-09-08
  • Int'l Joint Research
• [Presentation] Claudin-4 expression via p63 in human normal epithelial cells and diseases (2016)
  • Author(s): Takashi Kojima Yakuto Kaneko, Takuya Kakuki, Terufumi Kubo, Ken-ichi Takano, Tetsuo Himi, Takayuki Kohno
  • Organizer: Tight junctions and their proteins
  • Place of Presentation: ベルリン （ドイツ）
  • Year and Date: 2016-09-08
  • Int'l Joint Research / Invited
• [Presentation] 子宮内膜癌の悪性化におけるASPP2の役割 (2016)
  • Author(s): 小島隆、嶋田浩志、郷久晴朗、金野匠、齋藤豪、幸野貴之
  • Organizer: 第１１４回北海道癌談話会
  • Place of Presentation: 札幌医科大学（北海道・札幌市）
• [Presentation] The role of lipolysis-stimulated lipoprotein receptor in malignancy of human endometrial cancer by obesity (2015)
  • Author(s): Takashi Kojima, Hiroshi Shimada, Seirou Satohisa, Takumi Konno, Syunta Takahashi, Tihiro Arimoto, Iori Nojima, Tsuyoshi Saitoh, Takayuki Kohno
  • Organizer: BMB 2015
  • Place of Presentation: 神戸ポートアイランド（神戸市中央区）
  • Year and Date: 2015-12-01
• [Presentation] 子宮内膜癌の悪性化における新規３細胞間タイト結合分子LSRの関与 (2015)
  • Author(s): 嶋田 浩志、郷久 晴朗、金野 匠、有元 千尋、高橋 俊太、畠山 翔翼、幸野 貴之、 齋藤 豪、小島 隆
  • Organizer: 第４７回日本臨床分子形態学会
  • Place of Presentation: 長崎大学医学部良順会館（長崎県長崎市）
  • Year and Date: 2015-09-18
• [Presentation] 膵癌における３細胞間タイト結合分子LSRの役割 (2015)
  • Author(s): 有元千紘、河野剛、嶋田浩志、金野匠、畠山翔翼、高橋駿太、及能大輔、幸野貴之、小島隆
  • Organizer: 第４７回日本臨床分子形態学会
  • Place of Presentation: 長崎大学医学部良順会館（長崎県長崎市）
  • Year and Date: 2015-09-18
• [Presentation] ヒト子宮内膜癌細胞の悪性化におけるlipolysis-stimulated lipoprotein receptorの役割 (2015)
  • Author(s): 嶋田浩志、郷久晴朗、金野匠、高橋俊太、畠山翔翼、齋藤豪、幸野貴之、小島隆
  • Organizer: 第６７回日本細胞生物学会
  • Place of Presentation: タワーホール船堀(東京都江戸川区)
  • Year and Date: 2015-06-30
• [Presentation] 頭頸部扁平上皮癌におけるp63/GATA-3経路を介したタイト結合分子JAM-Aの発現調節機構 (2015)
  • Author(s): 角木拓也、黒瀬誠、高野賢一、近藤敦、小幡和史、野村一顕、宮田遼、金野匠、高橋俊太、畠山翔翼、幸野貴幸、氷見徹夫、小島隆
  • Organizer: 第６７回日本細胞生物学会
  • Place of Presentation: タワーホール船堀(東京都江戸川区)
  • Year and Date: 2015-06-30