The role of Ga13 in the progression of gynecologic cancer

• Project/Area Number: 17K11282
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Kyushu University
• Principal Investigator: Yagi Hiroshi 九州大学, 医学研究院, 助教 (70623552)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: GPCR / シグナル伝達 / 卵巣癌 / 上皮間葉転換 / Gタンパク / EMT / 癌 / 転移

Outline of Final Research Achievements

G-protein-coupled receptor (GPCRs) are seven transmembrane receptors, and form a largest family among cell surface molecules. GPCR signaling regulates diverse biological functions, and is involved in cancer progression. GPCRs signal through the activation of heterotrimeric G proteins. Among them, we have focused on the role of Ga13 in the progerssion of human ovarian cancer. Ga13 is highly expressed in human ovarian cancer tissues. In vitro study revealed that the activation of Ga13 induces epithelial-mesenchymal transition in ovarian cancer cells through down-regulation of LATS1, a critical component of the Hippo signalling pathway. Our findings uncover novel mechanisms through which Ga13 activation induces dysregulation of the Hippo signalling pathway, leading to aggressive cancer phenotypes, thereby identifying a potential target for preventing metastatic spread of ovarian cancer.

Academic Significance and Societal Importance of the Research Achievements

現在の治療薬の約35%がGPCRを標的としているが、それらの治療薬が標的としているのは、GPCR全体の約15%に過ぎない。また、ヒト癌組織で発現を認めるGPCRのうち140種以上についてはリガンド分子やその機能が不明であり、興味深いことにそれらの多くはGa13とcouplingすることが報告されている。シグナル選択的なGPCRアンタゴニストや、GPCRシグナルを間接的に阻害するアロステリックタンパクなど、新たなコンセプトに基づく治療薬が開発されつつある現状を考慮すると、本研究の成果が癌に対する新たな治療法の開発につながることが期待でき、社会的意義は大きいものと考えられる。

Research Products

• [Journal Article] Gα13-mediated LATS1 down-regulation contributes to epithelial-mesenchymal transition in ovarian cancer (2019)
  • Author(s): Yagi Hiroshi、Onoyama Ichiro、Asanoma Kazuo、Hori Emiko、Yasunaga Masafumi、Kodama Keisuke、Kijima Masako、Ohgami Tatsuhiro、Kaneki Eisuke、Okugawa Kaoru、Yahata Hideaki、Kato Kiyoko
  • Journal Title: The FASEB Journal Volume: 33 Issue: 12 Pages: 13683-13694
  • DOI: 10.1096/fj.201901278r
  • Peer Reviewed / Open Access
• [Presentation] Ga13-mediated LATS1 down-regulation contributes to epithelial-mesenchymal transition in ovarian cancer (2019)
  • Author(s): Hiroshi Yagi, Keisuke Kodama, Ichiro Onoyama, Kazuo Asanoma, Kiyoko Kato
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] GEP oncogene induces epithelial-mesenchymal transition in ovarian cancer through LATS1 proteolysis (2019)
  • Author(s): Hiroshi Yagi, Ichiro Onoyama, Kazuo Asanoma, Masafumi Yasunaga, Keisuke Kodama, Shusaku Inoue, Shinichiro Yamaguchi, Tatsuhiro Ohgami, Eisuke Kaneki, Kaoru Okugawa, Hideaki Yahata, Kiyoko Kato
  • Organizer: 第71回日本産科婦人科学会学術講演会
• [Presentation] GEP oncogene induces epithelial-mesenchymal transition through LATS1 degradation in ovarian cancer (2018)
  • Author(s): Hiroshi Yagi, Keisuke Kodama, Masafumi Yasunaga, Tatsuhiro Ohgami, Ichiro Onoyama, Kazuo Asanoma, Kenzo Sonoda, Kiyoko Kato
  • Organizer: 第70回日本産科婦人科学会学術講演会
• [Presentation] GEP oncogene induces epithelial-mesenchymal transition through LATS1 degradation in ovarian cancer (2018)
  • Author(s): Hiroshi Yagi, Ichiro Onoyama, Kazuo Asanoma, Keisuke Kodama, Kenzo Sonoda, Kiyoko Kato
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] The pivotal role of LATS1 in ovarian cancer progression (2017)
  • Author(s): Yagi H, Kodama K, Yasunaga M, Ohgami T, Onoyama I, Asanoma K, Sonoda K, Kato K
  • Organizer: 第69回日本産科婦人科学会学術講演会