cGAS-STING信号通路在VHL缺失透明细胞肾癌中的功能机制研究

透明细胞肾癌(ccRCC)起源于肾小管上皮细胞，约90%的ccRCC丢失抑癌基因VHL。众多研究表明cGAS-STING先天免疫通路是有效的抗癌靶点。然而，关于cGAS-STING信号通路能否影响VHL缺失ccRCC的发展进程尚不清楚。申请人前期研究结果表明VHL过表达显著增加cGAS的蛋白表达量，并增强其对双链DNA的识别能力，进而促进cGAS-STING通路的激活，提示VHL缺失导致肾癌细胞逃避免疫监视从而促进肾癌的发展。分子机制研究发现pVHL与cGAS蛋白存在相互作用，pVHL增加cGAS蛋白稳定性，提示pVHL调控cGAS蛋白表达不依赖其E3泛素连接酶活性。申请人将进一步通过体外生化实验、细胞模型及小鼠肾癌模型深入探究cGAS-STING信号通路在VHL缺失ccRCC发生发展过程中的扮演的角色。本研究有望在先天免疫角度揭示ccRCC的发展过程，为临床治疗ccRCC提供新靶点。

Clear cell renal cell carcinoma (ccRCC) is a malignant kidney cancer derived from renal tubular epithelial cells. Loss of the von Hippel–Lindau (VHL) tumor suppressor gene occur in 90% of ccRCC. And there is mounting evidence that the cGAS-STING innate immunity pathway is a potent anti-cancer target. However, whether cGAS-STING signaling pathway involved in the development of VHL-deficient ccRCC remains unclear. Our preliminary data showed that the protein level of cGAS was dramatically increased after VHL overexpression, thus enhancing its ability to detect double-stranded DNA, and thereby promoting the activation of cGAS-STING pathway, which implied that loss of VHL-mediated ccRCC escapes immunologic surveillance then promotes the malignant progression of ccRCC. Mechanistically, our evidences indicated that pVHL interacts with cGAS, and pVHL increases the protein stability of cGAS, which suggested that pVHL-mediated cGAS protein level was independent of its E3 ubiquitin ligase. We would further decipher the roles of cGAS-STING innate immunity pathway in initiation and development of VHL-deficient ccRCC through the integrated approaches of biochemical assays and cell model in vitro, as well as mouse ccRCC model in vivo. The progression of ccRCC uncovered in the perspective of innate immunity may provide a molecular basis for developing new therapeutic targets for ccRCC.