Mosca Nicola, Pezzullo Mariaceleste, De Leo Ilenia, Truda Anna, Marchese Giovanna, Russo Aniello, Potenza Nicoletta
Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", 81100 Caserta, Italy.
Genomix 4Life S.r.l., 84081 Baronissi, Italy.
Cells. 2025 May 23;14(11):773. doi: 10.3390/cells14110773.
Lung cancer is the most diagnosed cancer and the primary cause of cancer-related mortality worldwide, with lung adenocarcinoma (LUAD) becoming the prevalent histological subtype. Rac GTPase activating protein 1 (RacGAP1) has been found to be upregulated in several cancers, where it acts as an oncogene; nevertheless, its role in lung adenocarcinoma is largely unknown. The present study investigated the clinical relevance, the oncogenic function and the underlying molecular mechanisms of RacGAP1 in LUAD. Analyses of five patient cohorts' datasets revealed that RacGAP1 was upregulated in adenocarcinoma tissues compared to normal lung tissues, and its overexpression was associated with unfavorable prognostic factors and poor survival; intriguingly, RacGAP1 expression was related to tobacco smoke, a well-known risk factor for LUAD. Then, experimental analyses demonstrated that RacGAP1 knockdown inhibited cell proliferation, migration and invasion, thus highlighting its role in promoting LUAD. Finally, the finding of significant correlations between RacGAP1 and Wnt-altered status or β-catenin in patients led to experiments demonstrating that silencing of RacGAP1 reduced β-catenin transcriptional activity, thereby downregulating the expression of Wnt-related genes, i.e., LGR5, Wnt2B and Wnt5A. Overall, our findings indicate that RacGAP1 plays an oncogenic role in adenocarcinoma, contributing to the abnormal activation of the Wnt/β-catenin signaling pathway. These findings may pave the way for innovative therapeutic strategies and the development of advanced diagnostic panels.
肺癌是全球诊断率最高的癌症，也是癌症相关死亡的主要原因，其中肺腺癌（LUAD）成为主要的组织学亚型。已发现Rac GTP酶激活蛋白1（RacGAP1）在几种癌症中上调，在这些癌症中它作为一种癌基因发挥作用；然而，其在肺腺癌中的作用在很大程度上尚不清楚。本研究调查了RacGAP1在LUAD中的临床相关性、致癌功能及潜在分子机制。对五个患者队列数据集的分析显示，与正常肺组织相比，RacGAP1在腺癌组织中上调，其过表达与不良预后因素及较差的生存率相关；有趣的是，RacGAP1表达与烟草烟雾有关，烟草烟雾是LUAD的一个众所周知的危险因素。然后，实验分析表明，敲低RacGAP1可抑制细胞增殖、迁移和侵袭，从而突出了其在促进LUAD中的作用。最后，在患者中发现RacGAP1与Wnt改变状态或β-连环蛋白之间存在显著相关性，这导致实验表明，沉默RacGAP1可降低β-连环蛋白转录活性，从而下调Wnt相关基因即LGR5、Wnt2B和Wnt5A的表达。总体而言，我们的研究结果表明，RacGAP1在腺癌中发挥致癌作用，导致Wnt/β-连环蛋白信号通路的异常激活。这些发现可能为创新治疗策略和先进诊断方法的开发铺平道路。
