How does tumor formation occur in T-cell junctions?

• Project/Area Number: 19H03453
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Teikyo University (2021-2022); Osaka University (2019-2020)
• Principal Investigator: Tamura Atsushi 帝京大学, 医学部, 准教授 (00362525)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2021: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2020: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2019: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
• Keywords: クローディン / タイトジャンクション / 胃炎 / 胃がん / 幹細胞 / invasive gland / 胃腫瘍 / 細胞組織のヘテロ性 / ピロリ菌 / 胃型クローディン18 / 胃上皮バリアと胃腫瘍 / ノックアウトマウス / 組織微小環境 / 長期観察 / 腫瘍形成 / オーガナイザー

Outline of Research at the Start

タイトジャンクション(TJ)は、上皮細胞の細胞間透過性を制御する、生体内唯一の細胞間接着装置である。しかし近年の研究成果は、TJ形成の構成単位分子であるクローディン分子(Cldn)分子が、細胞増殖や分化・極性異常・臓器組織の構造決定・がんのイニシエーションなど、多細胞生物システムを上流から操作するオーガナイザーとして働くことを示す。しかしそのメカニズムは殆ど解析されていない。本申請では、Cldnを専門に研究を重ねてきた申請者が、胃に腫瘍を形成する胃型Cldn18欠損マウスに焦点を当て、Cldn分子の腫瘍形成の直接的・間接的なオーガナイザーとしての機能と、がん抑制操作法の開拓を目指す。

Outline of Final Research Achievements

Tight junctions (TJs), built with the cell membrane protein called claudin (Cldn), are crucial barrier structures located between cells on the epithelial sheets of the stomach, preventing the leakage of gastric acid into the submucosa. In the stomach, gastric-type Cldn18.2 is major Cldn for TJ formation, and its deficiency in knockout (KO) mice leads to gastritis in young age and the development of gastric tumors with aging. Our results suggested that the decrease in Cldn18.2 and the consequent increase in stemness may be important in the process of gastric cancer development, based on the analysis of these mice. In this study, we further analyzed the barrier impairment and gastric inflammation in TJ-associated COBL mutant mice as similar findings.

Academic Significance and Societal Importance of the Research Achievements

胃がんの多くは、ヘリコバクターピロリ菌の感染と、ピロリ菌により産生されるCagA因子およびその下流シグナルによる細胞増殖や細胞極性の異常化が重要であると考えられている。クローディン欠損が、ピロリ菌感染胃炎と類似の病態を示すことから、胃がんの発生に、タイトジャンクションを介する過程が非常に重要である可能性が示唆された。今後、胃がんをはじめ、他種のがんにおいても、治療標的としてのCldnの可能性の検討が期待される。

Research Products

• [Journal Article] Phase separation of an actin nucleator by junctional microtubules regulates epithelial function (2023)
  • Author(s): Tsukita Kazuto、Kitamata Manabu、Kashihara Hiroka、Yano Tomoki、Fujiwara Ikuko、Day Timothy F.、Katsuno Tatsuya、Kim Jaewon、Takenaga Fumiko、Tanaka Hiroo、Park Sungsu、Miyata Makoto、Watanabe Hitomi、Kondoh Gen、Takahashi Ryosuke、Tamura Atsushi、Tsukita Sachiko
  • Journal Title: Science Advances Volume: 9 Issue: 7
  • DOI: 10.1126/sciadv.adf6358
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The tight junction protein occludin modulates blood brain barrier integrity and neurological function after ischemic stroke in mice (2023)
  • Author(s): Sugiyama Shintaro、Sasaki Tsutomu、Tanaka Hiroo、Yan Haomin、Ikegami Takeshi、Kanki Hideaki、Nishiyama Kumiko、Beck Goichi、Gon Yasufumi、Okazaki Shuhei、Todo Kenichi、Tamura Atsushi、Tsukita Sachiko、Mochizuki Hideki
  • Journal Title: Scientific Reports Volume: 13 Issue: 1 Pages: 2892-2892
  • DOI: 10.1038/s41598-023-29894-1
  • Peer Reviewed / Open Access
• [Journal Article] Double mutation of <i>claudin‐1</i> and <i>claudin‐3</i> causes alopecia in infant mice (2023)
  • Author(s): Suzuki Koya、Yamaga Kosuke、Tokumasu Reitaro、Katsuno Tatsuya、Tanaka Hiroo、Chiba Shuhei、Yagi Takeshi、Katayama Ichiro、Tamura Atsushi、Murota Hiroyuki、Tsukita Sachiko
  • Journal Title: Annals of the New York Academy of Sciences Volume: - Issue: 1 Pages: 51-61
  • DOI: 10.1111/nyas.14980
  • Peer Reviewed
• [Journal Article] Planar cell polarity induces local microtubule bundling for coordinated ciliary beating (2021)
  • Author(s): Nakayama Shogo、Yano Tomoki、Namba Toshinori、Konishi Satoshi、Takagishi Maki、Herawati Elisa、Nishida Tomoki、Imoto Yasuo、Ishihara Shuji、Takahashi Masahide、Furuta Ken’ya、Oiwa Kazuhiro、Tamura Atsushi、Tsukita Sachiko
  • Journal Title: Journal of Cell Biology Volume: 220 Issue: 7
  • DOI: 10.1083/jcb.202010034
  • Peer Reviewed
• [Journal Article] Daple deficiency causes hearing loss in adult mice by inducing defects in cochlear stereocilia and apical microtubules (2021)
  • Author(s): Ozono Yoshiyuki、Tamura Atsushi、Nakayama Shogo、Herawati Elisa、Hanada Yukiko、Ohata Kazuya、Takagishi Maki、Takahashi Masahide、Imai Takao、Ohta Yumi、Oshima Kazuo、Sato Takashi、Inohara Hidenori、Tsukita Sachiko
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 20224-20224
  • DOI: 10.1038/s41598-021-96232-8
  • Peer Reviewed / Open Access
• [Journal Article] Deficiency of lung-specific claudin-18 leads to aggravated infection with Cryptococcus deneoformans through dysregulation of the microenvironment in lungs (2021)
  • Author(s): Sato K, Matsumoto I, Suzuki K, Tamura A, Shiraishi A, Kiyonari H, Kasamatsu J, Yamamoto H, Miyasaka T, Tanno D, Miyahara A, Zong T, Kagesawa T, Oniyama A, Kawamura K, Kitai Y, Umeki A, Kanno E, Tanno H, Ishii K, Tsukita S, Kawakami K
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 21110-21110
  • DOI: 10.1038/s41598-021-00708-6
  • Peer Reviewed / Open Access
• [Journal Article] A microtubule‐LUZP1 association around tight junction promotes epithelial cell apical constriction (2020)
  • Author(s): Yano Tomoki、Tsukita Kazuto、Kanoh Hatsuho、Nakayama Shogo、Kashihara Hiroka、Mizuno Tomoaki、Tanaka Hiroo、Matsui Takeshi、Goto Yuhei、Komatsubara Akira、Aoki Kazuhiro、Takahashi Ryosuke、Tamura Atsushi、Tsukita Sachiko
  • Journal Title: The EMBO Journal Volume: 40 Issue: 2
  • DOI: 10.15252/embj.2020104712
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Iqgap3-Ras axis drives stem cell proliferation in the stomach corpus during homoeostasis and repair (2020)
  • Author(s): Matsuo Junichi、Douchi Daisuke、、Adachi Makoto、Tamura Atsushi、、Tsukita Sachiko、Ito Yoshiaki
  • Journal Title: Gut Volume: - Issue: 10 Pages: 1833-1846
  • DOI: 10.1136/gutjnl-2020-322779
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Reciprocal Association between the Apical Junctional Complex and AMPK: A Promising Therapeutic Target for Epithelial/Endothelial Barrier Function? (2019)
  • Author(s): Tsukita, K., Yano, T., Tamura, A., and Tsukita, S.
  • Journal Title: Int J Mol Sci. Volume: 20 Issue: 23 Pages: 6012-6012
  • DOI: 10.3390/ijms20236012
  • Peer Reviewed / Open Access
• [Journal Article] Vinculin is critical for the robustness of the epithelial cell sheet paracellular barrier for ions. (2019)
  • Author(s): Konishi S, Yano T, Tanaka H, Mizuno T, Kanoh H, Tsukita K, Namba T, Tamura A, Yonemura S, Gotoh S, Matsumoto H, Hirai T, Tsukita S.
  • Journal Title: Life Sci Alliance Volume: 2 Issue: 4 Pages: e201900414-e201900414
  • DOI: 10.26508/lsa.201900414
  • NAID: 120007144472
  • Peer Reviewed / Open Access
• [Presentation] 多繊毛協調運動の確立過程のライブイメージングによる解析 (2022)
  • Author(s): 白土玄、小西聡史、矢野智樹、柏原 宏香、中山彰吾、勝野達也、Elisa Herawati、後藤慎平、近藤玄、 渡邊仁美、田村淳、月田早智子
  • Organizer: 第74回細胞生物学会
• [Presentation] StCldn18 deficiency activates signaling cascade towards gastric tumorigenesis in mice. (2021)
  • Author(s): Tamura, A. Suzuki, K., Tanaka, H., Yano, T., Hayashi, D., Sentani, K., Oshima, M., Yasui, W., and Tsukit, S.
  • Organizer: 4th International Tight Junction Conference, Berlin (online conference)
  • Int'l Joint Research
• [Presentation] TJMAP2は微小管依存的な相分離により細胞接着部位のアクチン重合を制御する (2021)
  • Author(s): 月田和人、矢野智樹、藤原郁子、Francis Day Timothy、勝野達也、柏原宏香、竹永富妙子、田中啓雄、田村淳、月田早智子
  • Organizer: 第74回細胞生物学会
• [Presentation] タイトジャンクションの変化はマウス胃腫瘍形成へのシグナルカスケードを活性化する (2020)
  • Author(s): 田村淳，鈴木浩也，田中啓雄，矢野智樹，仙谷和弘，大島正伸，安井 弥，月田早智子
  • Organizer: 第79回日本癌学会学術総会(Web開催)
• [Presentation] Role of the arrangement of basal bodies in establishment of the coordinated ciliary beating in multi-ciliated cells. (2019)
  • Author(s): Nakayama, S., Konishi, S., Yano, T., Herawati, E., Kashihara, H., Tamura, A.,and Tsukita, S.
  • Organizer: ASCB/EMBO 2019 meeting
  • Int'l Joint Research
• [Presentation] Planar cell polarity-dependent distribution of apical microtubules in tracheal multiciliated cells. (2019)
  • Author(s): Nakayama,S., Herawati,E., Takagishi,M., Torisawa,T., Namba,T., Ishihara,S., Yano,T., Tamura,A., Furuta,K., Oiwa,K., Takahashi,M., and Tsukita, S.
  • Organizer: The 20th International Conference on Systems Biology
  • Int'l Joint Research
• [Presentation] タイトジャンクション-クローディンによる細胞間バリア制御と、その異常と病態ークローディン欠損マウス解析の視点からー (2019)
  • Author(s): 田村淳、田中啓雄、矢野智樹、鈴木浩也、月田早智子
  • Organizer: 第19回日本蛋白質科学会年会・第71回日本細胞生物学会大会 合同年次大会
• [Remarks] 帝京大学 先端総合研究機構
  • URL: https://www.teikyo-u.ac.jp/affiliate/acro
• [Remarks] 月田研究室
  • URL: https://www.fbs.osaka-u.ac.jp/labs/tsukita/
• [Remarks] 大阪大学大学院生命機能研究科 月田研究室
  • URL: https://www.fbs.osaka-u.ac.jp/labs/tsukita/