Clear cell renal cell carcinoma, as the most common type of kidney cancer, is characterized by diverse molecular features and poor prognosis. Deep exploration of the molecular pathology may help understand ccRCC biological behaviors and develop effective drugs for ccRCC. Ras homolog family member J (RhoJ), a the member of Rho GTPases family, is crucial for multiple cellular processes. Moreover, an increasing number of studies have shown that RhoJ plays a vital role in different aspects of tumor occurrence and development, such as epithelial-mesenchymal transition (EMT), angiogenesis, and DNA damage repair. However, the biological functions and underlying molecular mechanisms of RhoJ in ccRCC remain unexplored.

The expression level of RhoJ was detected in ccRCC tissues using immunohistochemistry. The biological functions of RhoJ were evaluated via in vitro and in vivo assays. RNA sequencing was used to investigate the underlying mechanisms.

Firstly, we analyzed and found that among this family of molecules, the expression level of Ras homolog family member J (RhoJ) is associated with poor overall survival (OS) in ccRCC patients, and RhoJ expression is significantly higher in ccRCC tumor tissues compared to adjacent tissues. Knocking down RhoJ significantly inhibited the proliferation, migration, and invasion of ccRCC cells, and prohibited epithelial-mesenchymal transition (EMT). RNA-seq and further experiments indicated that RhoJ regulates the proliferation, migration, and EMT of ccRCC cells through the TNF-α/NF-κB signaling pathway. Ultimately, blocking the TNF-α/NF-κB signaling pathway can inhibit the enhanced proliferation, migration, and EMT effects caused by RhoJ overexpression.

These results suggest that upregulation of RhoJ mediates the proliferation, migration, and EMT of ccRCC cells by activating the TNF-α/NF-κB signaling pathway, and RhoJ may serve as a potential biomarker and therapeutic target for ccRCC.