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ARAP1通过控制Rho信号通路负向调节肺腺癌中应力纤维的形成和转移。

ARAP1 negatively regulates stress fibers formation and metastasis in lung adenocarcinoma via controlling Rho signaling.

作者信息

Zhang Zhengzheng, Xie Wenran, Gong Bojiang, Liang Xue, Yu Hongjia, Yu Yanwen, Dong Zhixiong, Shao Fanggui

机构信息

Department of Laboratory Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People's Republic of China.

Department of Intensive Care Unit, the First Affiliated Hospital of Wenzhou Medical University, 2 Fuxue Lane, Wenzhou, 325000, Zhejiang, China.

出版信息

Discov Oncol. 2023 Nov 27;14(1):214. doi: 10.1007/s12672-023-00832-x.

Abstract

Small GTPases regulate multiple important cellular behaviors and their activities are strictly controlled by a mass of regulators. The dysfunction or abnormal expression of small GTPases or their regulators was frequently observed in various cancers. Here, we analyzed the expression and prognostic correlation of several GTPases and related regulators based on the TCGA database and found that Ankyrin Repeat and PH Domain 1 (ARAP1), a GTPase activating protein (GAP), is reduced in lung adenocarcinoma tissues compared to normal tissues and displays a positive correlation with overall survival (OS) and progression-free survival (PFS) of patients with lung adenocarcinoma. qPCR and western blot verified that ARAP1 is frequently downregulated in lung adenocarcinoma tumor tissues and cancer cells, and its downregulation might be mediated by epigenetic modification. Moreover, metastatic assays showed that overexpression of ARAP1 significantly inhibits metastasis of lung adenocarcinoma in vitro and in vivo. We further demonstrated that Rho signaling inhibition, mediated by RhoGAP activity of ARAP1, majorly contributes to suppressing migration and invasion of lung adenocarcinoma cancer cells via inhibiting stress fibers formation. In summary, this study indicates that ARAP1 may serve as a potential prognostic predictor and a metastatic suppressor in lung adenocarcinoma via its RhoGAP activity.

摘要

小GTP酶调节多种重要的细胞行为,其活性受到大量调节因子的严格控制。在各种癌症中经常观察到小GTP酶或其调节因子的功能障碍或异常表达。在此,我们基于TCGA数据库分析了几种GTP酶及其相关调节因子的表达和预后相关性,发现锚蛋白重复序列和PH结构域1(ARAP1),一种GTP酶激活蛋白(GAP),在肺腺癌组织中与正常组织相比表达降低,并且与肺腺癌患者的总生存期(OS)和无进展生存期(PFS)呈正相关。qPCR和蛋白质印迹验证了ARAP1在肺腺癌肿瘤组织和癌细胞中经常下调,其下调可能由表观遗传修饰介导。此外,转移实验表明,ARAP1的过表达在体外和体内均显著抑制肺腺癌的转移。我们进一步证明,由ARAP1的RhoGAP活性介导的Rho信号抑制主要通过抑制应力纤维形成来抑制肺腺癌细胞的迁移和侵袭。总之,本研究表明ARAP1可能通过其RhoGAP活性作为肺腺癌潜在的预后预测指标和转移抑制因子。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a7b6/10678915/2dca66039767/12672_2023_832_Fig1_HTML.jpg

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