P53/miR-34a/SIRT1 positive feedback loop regulates the termination of liver regeneration

作者全名："Gong, Junhua; Cong, Minghua; Wu, Hao; Wang, Menghao; Bai, He; Wang, Jingyuan; Que, Keting; Zheng, Kaiwen; Zhang, Wenfeng; Yang, Xiaoli; Gong, Jianping; Shi, Hanping; Miao, Mingyong; Yuan, Fangchao"

作者地址："[Gong, Junhua; Wu, Hao; Wang, Menghao; Que, Keting; Zheng, Kaiwen; Zhang, Wenfeng; Gong, Jianping; Yuan, Fangchao] Chongqing Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp 2, Chongqing 400000, Peoples R China; [Cong, Minghua] Chinese Acad Med Sci & Peking Union Med Coll, Comprehens Oncol Dept, Natl Canc Ctr Canc, Natl Clin Res Ctr,Canc Hosp, Beijing 100021, Peoples R China; [Bai, He] Xian Med Univ, Dept Gen Surg, Affiliated Hosp 1, Xian 710000, Shaanxi, Peoples R China; [Wang, Jingyuan] Dianjiang Peoples Hosp Chongqing, Dept Orthopaet, Chongqing 408300, Chongqing, Peoples R China; [Yang, Xiaoli] Southwest Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp, Luzhou 646000, Sichuan, Peoples R China; [Shi, Hanping] Capital Med Univ, Beijing Shijitan Hosp, Dept Gastrointestinal Surg, Clin Nutr, Beijing 100038, Peoples R China; [Miao, Mingyong] Liaocheng Univ, Inst BioPharmaceut Res, Liaocheng 252059, Shandong, Peoples R China"

通信作者："Yuan, FC (通讯作者)，Chongqing Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp 2, Chongqing 400000, Peoples R China.; Shi, HP (通讯作者)，Capital Med Univ, Beijing Shijitan Hosp, Dept Gastrointestinal Surg, Clin Nutr, Beijing 100038, Peoples R China.; Miao, MY (通讯作者)，Liaocheng Univ, Inst BioPharmaceut Res, Liaocheng 252059, Shandong, Peoples R China."

来源：AGING-US

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001032428800013

JCR分区：Q2

影响因子：3.9

年份：2023

卷号：15

期号：6

开始页：1859

结束页：1877

文献类型：Article

关键词：liver regeneration; HCC; P53; miR-34a; SIRT1

摘要："Background: The capacity of the liver to restore its architecture and function assures good prognoses of patients who suffer serious hepatic injury, cancer resection, or living donor liver transplantation. Only a few studies have shed light on the mechanisms involved in the termination stage of LR. Here, we attempt to further verify the role of the p53/miR-34a/SIRT1 positive feedback loop in the termination of liver regeneration and its possible relationship with liver cancer. Method: We performed partial hepatectomy (PH) in mice transfected with adenovirus (Ade) overexpressing P53 and adenovirus-associated virus (AAV) overexpressing miR-34a. LR was analyzed by liver weight/body weight, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and cell proliferation, and the related cellular signals were investigated. Bile acid (BA) levels during LR were analyzed by metabolomics of bile acids. Results: We found that the P53/miR-34a/SIRT1 positive feedback loop was activated in the late phase of LR. Overexpression of P53 or miR-34a terminated LR early and enhanced P53/miR-34a/SIRT1 positive feedback loop expression and its proapoptotic effect. T-beta-MCA increased gradually during LR and peaked at 7 days after PH. T-beta-MCA inhibited cell proliferation and promoted cell apoptosis via facilitating the P53/miR-34a/SIRT1 positive feedback loop during LR by suppressing FXR/SHP. The P53/miR-34a/SIRT1 positive feedback loop was abolished in HCC patients with P53 mutations. Conclusions: The P53/miR-34a/SIRT1 positive feedback loop plays an important role in the termination of LR. Our findings showed the molecular and metabolic mechanisms of LR termination and provide a potential therapeutic alternative for treating P53-wild-type HCC patients."

基金机构："National Natural Science Foundation of China [81570569, 81672888]"

基金资助正文："This study was supported by grants from the National Natural Science Foundation of China (NSFC: No. 81570569 awarded to MMY, and No. 81672888 awarded to HPS) administered by the National Natural Science Fund Committee."