突变 Gq/11 通过激活 YAP 促进葡萄膜黑色素瘤的发生。

Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP.

机构信息

Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.

Department of Ophthalmology and Shiley Eye Center and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Ophthalmology of the Second Xiangya Hospital, International Academy of Translational Medicine, Central South University, Changsha 410011, China; Molecular Medicine Research Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.

出版信息

Cancer Cell. 2014 Jun 16;25(6):822-30. doi: 10.1016/j.ccr.2014.04.017. Epub 2014 May 29.

DOI:10.1016/j.ccr.2014.04.017

PMID:24882516

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4075337/

Abstract

Uveal melanoma (UM) is the most common cancer in adult eyes. Approximately 80% of UMs harbor somatic activating mutations in GNAQ or GNA11 (encoding Gq or G11, respectively). Herein, we show in both cell culture and human tumors that cancer-associated Gq/11 mutants activate YAP, a major effector of the Hippo tumor suppressor pathway that is also regulated by G protein-coupled receptor signaling. YAP mediates the oncogenic activity of mutant Gq/11 in UM development, and the YAP inhibitor verteporfin blocks tumor growth of UM cells containing Gq/11 mutations. This study reveals an essential role of the Hippo-YAP pathway in Gq/11-induced tumorigenesis and suggests YAP as a potential drug target for UM patients carrying mutations in GNAQ or GNA11.

摘要

葡萄膜黑色素瘤（UM）是成人眼内最常见的癌症。大约 80%的 UMs 存在 GNAQ 或 GNA11（分别编码 Gq 或 G11）的体细胞激活突变。在此，我们在细胞培养和人类肿瘤中均表明，癌相关 Gq/11 突变体激活 YAP，YAP 是 Hippo 肿瘤抑制途径的主要效应物，也受 G 蛋白偶联受体信号的调节。YAP 介导了 UM 发育中突变 Gq/11 的致癌活性，并且包含 Gq/11 突变的 UM 细胞中的 YAP 抑制剂 verteporfin 可阻断肿瘤生长。这项研究揭示了 Hippo-YAP 途径在 Gq/11 诱导的肿瘤发生中的重要作用，并表明 YAP 可作为携带 GNAQ 或 GNA11 突变的 UM 患者的潜在药物靶标。