Analysis of the molecular function of PLEKHA5 involved in the onset of scirrhous gastric carcinoma and cleft lip and palate

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06879
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Sasaki Foundation
• Principal Investigator: Yamaguchi Hideki 公益財団法人佐々木研究所, 附属研究所, 部長 (10345035)
• Co-Investigator(Kenkyū-buntansha): 大木 理恵子 国立研究開発法人国立がん研究センター, 研究所, 独立ユニット長 (70356252)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: スキルス胃がん / 口唇口蓋裂 / PLEKHA5 / E-cadherin

Outline of Final Research Achievements

Familial scirrhous gastric carcinoma arises from mutations in E-cadherin, with some mutation carriers also presenting with cleft lip and palate. In this study, we analyzed the molecular function of PLEKHA5, a causative gene product of hereditary cleft lip and palate, involved in the progression of scirrhous gastric carcinoma. PLEKHA5 localized to cell-cell adhesion sites and interacted with various cell adhesion molecules, including E-cadherin, as well as signal transduction molecules. Additionally, the PH domain of PLEKHA5 bound to phosphatidylserine, an important phospholipid for intracellular transport. Knockdown of PLEKHA5 resulted in abnormal intracellular transport in scirrhous gastric carcinoma cells. These results suggest that PLEKHA5 is involved in both cell-cell adhesion and intracellular transport.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

日本に多い難治がんであるスキルス胃癌と、最も多い先天性の形態異常である口唇口蓋裂は、どちらもE-cadherinを介した細胞間接着の異常により生じると考えられている。しかしその詳細な分子機構はほとんど分かっていない。本研究により、遺伝性口唇口蓋裂の原因遺伝子産物PLEKHA5がE-cadherinと結合し、細胞間接着や細胞内輸送に関わることが示唆された。本研究成果は、両疾患の発症機構の解明や診断・治療法の開発に寄与するものと考えられる。