Tumor-derived ARHGAP35 mutations enhance the Gα13-Rho signaling axis in human endometrial cancer
Tumor-derived ARHGAP35 mutations enhance the Gα13-Rho signaling axis in human endometrial cancer
复制标题
DOI：
10.1038/s41417-022-00547-1
复制
发表时间：
2022-10-18
影响因子：
6.4
通讯作者：
Kato, Kiyoko
中科院分区：
文献类型：
--
作者：
Yagi, Hiroshi;Onoyama, Ichiro;Kato, Kiyoko
失调的 G 蛋白偶联受体信号传导参与人类癌症的形成和进展。异源三聚体 G 蛋白 G α(13) 在多种癌症中高表达，并通过激活 Rho 调节多种癌症相关转录网络和细胞功能。在此，我们证明在人子宫内膜癌中，G α(13) 表达的增加可通过激活 Rho 和转录因子 AP-1 来促进细胞增殖。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的 509 个子宫内膜癌样本中，有 108 个在 ARHGAP35 的 126 个不同位置上有 152 个突变，体细胞突变频率为 20.2%。我们评估了 124 个肿瘤源性 ARHGAP35 突变对 G α(13) 介导的 Rho 和 AP-1 激活的影响。 ARHGAP35 的 RhoGAP 活性受到 124 个肿瘤衍生突变中的 55 个的损害，其中包括 23 个无义突变、15 个移码突变、15 个错义突变和 2 个框内缺失。考虑到 ARHGAP35 在所有肿瘤中>2% 发生突变，它跻身人类癌症中突变最显着的前 30 个基因之列。我们的数据表明 ARHGAP35 作为致癌驱动基因的潜在作用，为子宫内膜癌提供新的治疗机会。
Dysregulated G protein-coupled receptor signaling is involved in the formation and progression of human cancers. The heterotrimeric G protein G alpha(13) 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 G alpha(13) 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 G alpha(13)-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.