The Elucidation of tumorigenesis mechanisms through signal transduction starting from tight junction.

• Project/Area Number: 18K14696
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 44010:Cell biology-related
• Research Institution: Osaka University
• Principal Investigator: Yano Tomoki 大阪大学, 医学系研究科, 助教 (20546121)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: タイトジャンクション / 細胞間接着 / 上皮細胞 / 細胞骨格 / 細胞外ストレス / cingulin / AMPK / vinculin / PTEN / YAP / p38

Outline of Final Research Achievements

Multicellular organism is surrounded by the epithelial cell sheets. Epithelial cells are adhered each other by using cell-cell adhesion complexes such as adherence junctions and tight junctions (TJ). Carcinogenesis mostly arises from epithelial cells, however, it is remained unclear how TJ involved in epithelial carcinogenesis. Here we showed that AMPK, which participates in the malignancy of tumor, regulates the barrier function of TJ by which AMPK phosphorylates cingulin and changes the cingulin’s binding cytoskeleton. Moreover, we showed that vinculin, localized at the focal adhesion which participates in the invasion of carcinoma and at the cell-cell contact regulates TJ robustness to create appropriate homeostasis for epithelial cells. These results suggest that TJ involved in epithelial carcinogenesis.

Academic Significance and Societal Importance of the Research Achievements

今日まで上皮細胞接着とがん化のメカニズムの知見の多くはアドへレンスジャンクションの研究が多くを占めており、タイトジャンクションとがん化のメカニズムについての知見はほとんどなかった。本研究においてタイトジャンクションとがん化のメカニズムが密接に関与していることが示唆されたことは、今後のがん研究に新たな知見を加えることが期待できるだけでなく、細胞間接着の研究分野の発展にも貢献できるものと考える。

Research Products

• [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
• [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] AMPK-dependent phosphorylation of cingulin reversibly regulates its binding to actin filaments and microtubules (2018)
  • Author(s): Tomoki Yano, Takayuki Torisawa, Kazuhiro Oiwa & Sachiko Tsukita
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 15550-15550
  • DOI: 10.1038/s41598-018-33418-7
  • Peer Reviewed / Open Access