文章：

肿瘤来源的ARHGAP35突变增强人类子宫内膜癌中的Gα13-Rho信号轴

Tumor-derived ARHGAP35 mutations enhance the Gα13-Rho signaling axis in human endometrial cancer 

原文发布日期：2022-10-18 

英文摘要：

Dysregulated G protein-coupled receptor signaling is involved in the formation and progression of human cancers. The heterotrimeric G protein Gα13 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 Gα13 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 Gα13-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. 

摘要翻译： 

G蛋白偶联受体信号传导失调参与人类癌症的形成与进展。异源三聚体G蛋白Gα13在多种癌症中高表达，并通过激活Rho调控多种癌症相关转录网络和细胞功能。本文研究发现，Gα13表达升高通过激活Rho和转录因子AP-1促进人类子宫内膜癌的细胞增殖。值得注意的是，RhoGTP酶激活蛋白（RhoGAP）ARHGAP35在人类子宫内膜癌中存在频繁突变。在癌症基因组图谱数据库的509例子宫内膜癌样本中，108例携带ARHGAP35基因126个不同位点的152种突变，体细胞突变频率达20.2%。我们评估了124种肿瘤源性ARHGAP35突变对Gα13介导的Rho和AP-1激活的影响。其中55种突变导致ARHGAP35的RhoGAP活性受损，包括23种无义突变、15种移码突变、15种错义突变以及2种框内缺失突变。鉴于ARHGAP35在所有肿瘤中的突变率超过2%，该基因位列人类癌症显著性突变基因前30位。我们的数据表明ARHGAP35可能作为致癌驱动基因，为子宫内膜癌提供了新的治疗机遇。

原文链接：

Tumor-derived ARHGAP35 mutations enhance the Gα13-Rho signaling axis in human endometrial cancer