RhoJ promotes the progression of clear cell renal cell carcinoma via the TNF-α/NF-κB axis.

IF 1.7 3区 医学 Q4 ANDROLOGY
Translational andrology and urology Pub Date : 2025-07-30 Epub Date: 2025-07-28 DOI:10.21037/tau-2025-132
Ji Feng, Bin Zheng, Jichen Wang, Qingjiang Xu, Qing Ouyang, Huaikang Li, Tongyu Jia, Yaohui Wang, Tianwei Cai, Yi Feng, Xu Zhang, Xiubin Li, Xin Ma
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引用次数: 0

Abstract

Background: Clear cell renal cell carcinoma (ccRCC) represents the predominant form of kidney cancer. The Ras homology (Rho) GTPases family plays essential roles in several tumors. However, few studies have reported the function and clinical value of the Rho GTPases family in ccRCC. Our study aimed to systematically investigate the expression profiles, functional roles, and clinical significance of Rho GTPases in ccRCC, with the goal of identifying potential biomarkers and novel therapeutic targets to improve the treatment outcomes and survival rates of this aggressive kidney cancer.

Methods: The expression level of Ras homolog family member J (RhoJ) was detected in ccRCC cells and tissues using quantitative polymerase chain reaction (qPCR), western blotting, and immunohistochemistry (IHC). The biological functions of RhoJ were evaluated via in vitro and in vivo assays. RNA sequencing was used to investigate the underlying mechanisms. Potential RhoJ inhibitors were identified using virtual screening in a Food and Drug Administration (FDA)-approved drugs repository.

Results: Our study identified RhoJ as the only Ras-homologous guanosine triphosphate (GTP)-binding protein (Rho GTPase) associated with poor prognosis in ccRCC patients. Using ccRCC cells and tumor tissues, we found that RhoJ was significantly highly expressed in ccRCC. Moreover, RhoJ apparently enhanced ccRCC cell proliferation, migration, and invasion. Further, upregulated RhoJ could accelerate cell cycle progression, inhibit apoptosis, and enhance epithelial-mesenchymal transition (EMT). Through orthotopic tumor models, we found that knocking down RhoJ inhibited tumor growth. Mechanically, RhoJ influenced ccRCC progression through the tumor necrosis factor-alpha/nuclear factor kappa B (TNF-α/NF-κB) axis. Blocking this axis could partially rescue malignant phenotypes caused by RhoJ. Finally, since there are no available drugs targeting RhoJ, the virtual screening was used to identify potential RhoJ inhibitors based on an FDA-approved drug library, which showed that ergotamine, irinotecan, ledipasvir, pazopanib, and avodart were potential RhoJ-targeting drugs.

Conclusions: Taken together, our findings provide novel insights into the role of RhoJ and identify available potential drugs for controlling ccRCC.

RhoJ通过TNF-α/NF-κB轴促进透明细胞肾细胞癌的进展。
背景:透明细胞肾细胞癌(ccRCC)是肾癌的主要形式。Ras同源(Rho) GTPases家族在多种肿瘤中起重要作用。然而,Rho GTPases家族在ccRCC中的作用和临床价值研究较少。本研究旨在系统研究Rho GTPases在ccRCC中的表达谱、功能作用和临床意义,旨在发现潜在的生物标志物和新的治疗靶点,以改善这种侵袭性肾癌的治疗效果和生存率。方法:采用定量聚合酶链式反应(qPCR)、western blotting、免疫组化(IHC)检测Ras同源家族成员J (RhoJ)在ccRCC细胞和组织中的表达水平。通过体外和体内实验评价RhoJ的生物学功能。RNA测序被用来研究潜在的机制。潜在的RhoJ抑制剂是在美国食品和药物管理局(FDA)批准的药物库中使用虚拟筛选确定的。结果:本研究发现RhoJ是唯一与ccRCC患者预后不良相关的ras同源鸟苷三磷酸(GTP)结合蛋白(Rho GTPase)。利用ccRCC细胞和肿瘤组织,我们发现RhoJ在ccRCC中显著高表达。此外,RhoJ明显增强ccRCC细胞的增殖、迁移和侵袭。此外,RhoJ上调可以加速细胞周期进程,抑制细胞凋亡,增强上皮-间质转化(EMT)。通过原位肿瘤模型,我们发现敲低RhoJ抑制肿瘤生长。机械上,RhoJ通过肿瘤坏死因子-α/核因子κB (TNF-α/NF-κB)轴影响ccRCC进展。阻断该轴可部分挽救RhoJ引起的恶性表型。最后,由于没有可用的靶向RhoJ的药物,因此基于fda批准的药物文库,使用虚拟筛选来识别潜在的RhoJ抑制剂,结果表明麦角胺、伊立替康、来地帕韦、帕唑帕尼和avodart是潜在的RhoJ靶向药物。结论:综上所述,我们的发现为RhoJ的作用提供了新的见解,并确定了控制ccRCC的可用潜在药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
4.10
自引率
5.00%
发文量
80
期刊介绍: ranslational Andrology and Urology (Print ISSN 2223-4683; Online ISSN 2223-4691; Transl Androl Urol; TAU) is an open access, peer-reviewed, bi-monthly journal (quarterly published from Mar.2012 - Dec. 2014). The main focus of the journal is to describe new findings in the field of translational research of Andrology and Urology, provides current and practical information on basic research and clinical investigations of Andrology and Urology. Specific areas of interest include, but not limited to, molecular study, pathology, biology and technical advances related to andrology and urology. Topics cover range from evaluation, prevention, diagnosis, therapy, prognosis, rehabilitation and future challenges to urology and andrology. Contributions pertinent to urology and andrology are also included from related fields such as public health, basic sciences, education, sociology, and nursing.
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