miR-497~195簇靶向RTN4调控三羧酸循环代谢途径及其在肾透明细胞癌发生发展中的研究

肾透明细胞癌（ccRCC）是最常见的肾脏恶性肿瘤，目前尚无有效的治疗药物。细胞代谢重编程是ccRCC的标志性特征之一，深入研究其背后机理将有助于发掘新的治疗靶点。网状蛋白4（RTN4）是一种定位于内质网的跨膜蛋白，近年来被发现广泛参与肿瘤的疾病进程，但其在ccRCC中的功能及机制尚未得到阐明。申请者前期运用多种生物学方法发现RTN4：①是ccRCC的抑癌基因；②可能参与三羧酸循环代谢通路；③受到miR-497~195簇的靶向负调控。据此我们推测，miR-497~195簇可能通过靶向RTN4调控三羧酸循环代谢途径，最终促进ccRCC的发生发展。本项目拟采用载体构建、miRNA mimics、Luxcel细胞代谢检测、裸鼠成瘤、Co-IP等技术，明确miR-497~195簇-RTN4信号轴在ccRCC进程中的作用及机制。本项目有望揭示ccRCC新的发病机理，为其临床治疗提供理论基础和科学依据。

Clear cell renal cell carcinoma (ccRCC) is the most common malignant type of kidney cancer. However, there is currently no effective treatment. Cellular metabolic reprogramming is one of the signature features of ccRCC. Therefore, in-depth study of the underlying mechanism will help to discover new therapeutic targets for ccRCC. Reticulin 4 is a transmembrane protein localized in the endoplasmic reticulum. In recent years, it has been found to be involved in the development of a variety of tumors, but its role and mechanism in ccRCC have not been clarified. In our previous study, by employing various biological methods, we found that RTN4 was a tumor suppressor gene for ccRCC; RTN4 participated in the tricarboxylic acid cycle metabolic pathway; RTN4 was negatively regulated by the miR-497~195 cluster. Based on these preliminary results, we hypothesized that miR-497~195 cluster may regulate the tricarboxylic acid cycle metabolic pathway by targeting RTN4 and thus promoted the occurrence and development of ccRCC. This project intends to clarify the role of miR-497~195 cluster-RTN4 axis in the ccRCC development and clarify the possible mechanism by using vector construction, miRNA mimics, Luxcel cell metabolism detection, nude mice, Co-IP, etc. Moreover, this project promises to reveal the new pathogenesis of ccRCC and provide experimental basis and scientific basis for its clinical treatment.