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. Yet little is known about the biological function(s) of Di-Ras2 or how its activities are regulated. In this study, we focused on Di-Ras2, and determined its functions and underlying mechanism during formation of ccRCC. We 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). Mechanistically, Di-Ras2 induces and regulates ccRCC formation by modulating phosphorylation of the downstream effectors and activating the Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Moreover, Di-Ras2 interacts with E3 ubiquitin ligase, pVHL, which facilitates the ubiquitination and degradation of Di-Ras2. Together, these results indicate a potential function of Di-Ras2 as an oncogene in ccRCC, and these data provide a new perspective of the relationship between pVHL and the MAPK pathway in ccRCC tumorigenesis.

中文翻译：

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Di-Ras2通过在不存在von Hippel-Lindau蛋白的情况下激活有丝分裂原激活的蛋白激酶途径来促进肾细胞癌的形成。

透明细胞肾细胞癌（ccRCC）是世界上最常见和致命的人类泌尿系统恶性肿瘤之一。ccRCC的病理驱动因素之一是Ras家族的小GTP酶，在包括ccRCC在内的许多疾病中起“分子开关”的作用。在Di-Ras家族的GTPases中，DIRAS2基因编码的GTPase与Ras和Rap具有60％的同源性。关于Di-Ras2的生物学功能或如何调节其活性还知之甚少。在这项研究中，我们专注于Di-Ras2，并确定其在ccRCC形成过程中的功能和潜在机制。我们发现Di-Ras2在ccRCC中上调，并在没有von Hippel-Lindau蛋白（pVHL）的情况下促进了人ccRCC细胞的增殖，迁移和侵袭。机械上，Di-Ras2通过调节下游效应子的磷酸化并激活Ras /丝裂原激活的蛋白激酶（MAPK）信号通路来诱导和调节ccRCC的形成。此外，Di-Ras2与E3泛素连接酶pVHL相互作用，从而促进Di-Ras2的泛素化和降解。在一起，这些结果表明Di-Ras2作为ccRCC中的癌基因的潜在功能，这些数据为ccRCC肿瘤发生中pVHL和MAPK途径之间的关系提供了新的视角。