Clear cell renal cell carcinoma (ccRCC) is one of the most common and lethal human urological malignancies in the world. One of the pathological drivers for ccRCC is the Ras family of small GTPases that function as “molecular switches” in many diseases including ccRCC. Among the GTPases in the Di-Ras family, DIRAS2 gene encodes a GTPase that shares 60% homology to Ras and Rap and has a higher expression level in ccRCC compared to a normal kidney. Meanwhile, von Hippel Lindau (VHL)，a frequently lost or mutated gene in ccRCC, is one of the most important genes in ccRCC formation and development.

Wei-Qiang Gao, Li Li’s team from School of Biomedical Engineering, Shanghai Jiaotong University, published their research findings online “Di-Ras2 promotions renal cell carcinoma formation by activating the mitten activated protein kinase pathway in the ability of von Hippel-Lindau protein" in Oncogene, a nature oncogene journal, on February 25, 2020. They were also invited to write a comment on "Behind the paper: Di-Ras2, a potential oncogene associated with the crosstalk between VHL-mediated ubiquitination and the MAPK pathway in ccRCC" for Nature Research Cancer Community site.

The study continued to explore the molecular mechanism of Di-Ras2, a potential oncogene product, promoting ccRCC progression. It was found that Di-Ras2 was upregulated in ccRCC, and promoted the proliferation, migration and invasion of human ccRCC cells in the absence of von Hippel–Lindau protein (pVHL). Further research suggested that Di-Ras2 induced and regulated ccRCC formation by modulating phosphorylation of the downstream effectors and activating the Ras/MAPK signaling pathway. Based on Di-Ras2 and pVHL interaction, the team reported E3 ubiquitin ligase pVHL can facilitate the ubiquitination and degradation of Di-Ras2, thus inhibit its tumor-promting function. These results showed that Di-Ras2 can promote ccRCC oncogenesis in the absence of VHL, which provides a new perspective of the relationship between pVHL and the MAPK pathway in ccRCC tumorigenesis. Di-Ras2 may also become a new diagnostic marker and target for renal cancer.

The first authors of the paper are Hanyu Rao, a doctoral student, and Xuefeng Li, PhD, Professor Gao and Associate Researcher Li as the corresponding authors. The research was funded by the National Key R&D Program from the Ministry of Science and Technology, the National Natural Science Foundation Committee, Shanghai Science and Technology Committee and K.C. WONG Foundation. The research was also supported by the Shanghai Education Commission's Peak Plateau Discipline Construction Project.

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