Mechanisms of cancer progression control mediated by LPA-induced YAP activation

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07472
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Akita University
• Principal Investigator: Daisuke Yasuda 秋田大学, 医学系研究科, 講師 (70594951)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: リゾホスファチジン酸 / 血管新生 / DLL4 / YAP/TAZ / GPCR

Outline of Final Research Achievements

Lysophosphatidic acid (LPA) is a potent lipid mediator with various biological functions mediated through six G protein-coupled receptors (GPCRs), LPA1-6. We show a critical role of LPA4 and LPA6 in developmental angiogenesis. In mice, endothelial cell (EC)-specific Lpa4;Lpa6 DKO retinas had impaired sprouting angiogenesis. Mechanistically, LPA activated the transcriptional regulators YAP and TAZ through LPA4/LPA6-mediated Gα12/Gα13-Rho-ROCK signaling in ECs. YAP/TAZ knockdown increased β-catenin- and Notch intracellular domain (NICD)-mediated endothelial expression of the Notch ligand delta-like 4 (DLL4). Of note, the inhibition of Notch signaling also ameliorated impaired retinal angiogenesis in EC-specific Lpa4;Lpa6 DKO mice. Overall, these results suggest that the Gα12/Gα13-coupled receptors LPA4 and LPA6 synergistically regulate endothelial Dll4 expression through YAP/TAZ activation. Our findings provide a novel insight into the biology of GPCR-activated YAP/TAZ.

Free Research Field

分子細胞生物学

Academic Significance and Societal Importance of the Research Achievements

今回はLPA4とLPA6が協調してG12/13-Rho-Rockシグナルを惹起してYAP/TAZを活性化し、Dll4遺伝子の発現を抑制することを証明することができた。この成果は、LPAによる血管新生制御について新規分子メカニズムを解明したことになる。LPAのYAP活性化による血管新生を介したがん進展制御の関わりはまだ見出せていないが、LPA4とLPA6はリンパ管新生にも重要であることを明らかにしており、このメカニズムを基盤に病的な血管・リンパ管新生を減らすなどの戦略により、がんや加齢黄斑変性症などの「血管新生病」に対する治療法開発が進むことが期待される。