Rictor mediates p53 deactivation to facilitate the malignant transformation of hepatocytes and promote hepatocarcinogenesis

作者：Chun Wang, Hui Kang, Yun Yi, Yang Ding, Fan Wang, Jie Luo, Mingliang Ye, Yinghui Hong, Chao Xia, Junwei Yan, Lan Liu, Jing Liu, Zibiao Zhong, Zhonglin Zhang, Qiu Zhao, Ying Chang · 发表于：Journal of Translational Medicine · 年份：2023 · DOI：10.1186/s12967-023-04799-9 · 被引用次数：10 · 研究领域：MicroRNA in disease regulation、Cancer-related Molecular Pathways、Cancer-related molecular mechanisms research

Abstract Background Mutations in TP53 gene is considered a main driver of hepatocellular carcinoma (HCC). While TP53 mutations are the leading cause of p53 dysfunction, their occurrence rates may drop to approximately 10% in cohorts without hepatitis B virus and aflatoxin exposure. This observation suggests that the deactivation of wild-type p53 (p53 wt ) may be a critical factor in the majority of HCC cases. However, the mechanism undermining p53 wt activity in the liver remains unclear. Methods Microarray analysis and luciferase assay were utilized to confirm target associations. Gain- and/or loss-of-function methods were employed to assess alterations in signaling pathways. Protein interactions were analyzed by molecular immunological methods and further visualized by confocal microscopy. Bioinformatic analysis was performed to analyze clinical significance. Tumor xenograft nude mice were used to validate the findings in vivo. Results Our study highlights the oncogenic role of Rictor, a key component of the mammalian target of rapamycin complex 2 (mTORC2), in hepatocytes. Rictor exerts its oncogenic function by binding to p53 wt and subsequently blocking p53 wt activity based on p53 status, requiring the involvement of mTOR. Moreover, we observed a dynamic nucleocytoplasmic distribution pattern of Rictor, characterized by its translocation from the nucleus (in precancerous lesions) to the cytoplasm (in HCCs) during malignant transformation. Notably, Rictor is directly targ...