Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Cancer Gene Ther. 2023 Feb;30(2):313-323. doi: 10.1038/s41417-022-00547-1. Epub 2022 Oct 18.
Dysregulated G protein-coupled receptor signaling is involved in the formation and progression of human cancers. The heterotrimeric G protein Gα is highly expressed in various cancers and regulates diverse cancer-related transcriptional networks and cellular functions by activating Rho. Herein, we demonstrate that increased expression of Gα promotes cell proliferation through activation of Rho and the transcription factor AP-1 in human endometrial cancer. Of interest, the RhoGTPase activating protein (RhoGAP), ARHGAP35 is frequently mutated in human endometrial cancers. Among the 509 endometrial cancer samples in The Cancer Genome Atlas database, 108 harbor 152 mutations at 126 different positions within ARHGAP35, representing a somatic mutation frequency of 20.2%. We evaluated the effect of 124 tumor-derived ARHGAP35 mutations on Gα-mediated Rho and AP-1 activation. The RhoGAP activity of ARHGAP35 was impaired by 55 of 124 tumor-derived mutations, comprised of 23 nonsense, 15 frame-shift, 15 missense mutations, and two in-frame deletions. Considering that ARHGAP35 is mutated in >2% of all tumors, it ranks among the top 30 most significantly mutated genes in human cancer. Our data suggest potential roles of ARHGAP35 as an oncogenic driver gene, providing novel therapeutic opportunities for endometrial cancer.
G 蛋白偶联受体信号失调参与了人类癌症的形成和发展。异三聚体 G 蛋白 Gα 在各种癌症中高度表达，通过激活 Rho 调节多种与癌症相关的转录网络和细胞功能。在此，我们证明 Gα 的表达增加通过激活 Rho 和转录因子 AP-1 促进人子宫内膜癌细胞的增殖。有趣的是，RhoGTP 酶激活蛋白（RhoGAP）ARHGAP35 在人类子宫内膜癌中经常发生突变。在癌症基因组图谱数据库中的 509 个子宫内膜癌样本中，有 108 个样本在 ARHGAP35 内的 126 个不同位置携带 152 个突变，代表体细胞突变频率为 20.2%。我们评估了 124 个肿瘤衍生的 ARHGAP35 突变对 Gα 介导的 Rho 和 AP-1 激活的影响。ARHGAP35 的 RhoGAP 活性被 124 个肿瘤衍生突变中的 55 个所损害，其中包括 23 个无义突变、15 个移码突变、15 个错义突变和两个框内缺失。考虑到 ARHGAP35 在超过 2%的所有肿瘤中发生突变，它在人类癌症中排名前 30 个突变最显著的基因之一。我们的数据表明 ARHGAP35 作为致癌驱动基因的潜在作用，为子宫内膜癌提供了新的治疗机会。
