Research Paper Volume 15, Issue 6 pp 1859—1877
P53/miR-34a/SIRT1 positive feedback loop regulates the termination of liver regeneration
- 1 Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400000, China
- 2 Comprehensive Oncology Department, National Cancer Center/National Clinical Research Center for Cancer/Chinese Academy of Medical Sciences and Peking Union Medical College, Cancer hospital, Beijing 100021, Beijing, China
- 3 Department of General Surgery, The First Affiliated Hospital of Xi’an Medical University, Lianhu, Xi’an 710000, Shaanxi Province, China
- 4 Department of Orthopaetics, Dianjiang People’s Hospital of Chongqing, Chongqing 408300, Chongqing, China
- 5 Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China
- 6 Department of Gastrointestinal Surgery/Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- 7 Institute of BioPharmaceutical Research, Liaocheng University, Liaocheng 252059, China
Received: July 26, 2021 Accepted: February 1, 2023 Published: March 28, 2023
https://doi.org/10.18632/aging.203920How to Cite
Copyright: © 2023 Gong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
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-β-MCA increased gradually during LR and peaked at 7 days after PH. T-β-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.
Abbreviations
ALT: alanine transaminase; AST: aspertate aminotransferase; AAV: adenovirus associated virus; Ade: adenovirus; BA: bile acid; FXR: farnesoid x receptor; GFP: green fluorescent protein; HCC: hepatocellular carcinoma; IHC: immunohistochemistry; LR: liver regeneration; MCA: muricholic acid; T-β-MCA: tauro-β-muricholic acid; PH: partial hepatectomy; RFP: red fluorescent protein; SHP: small heterodimer partner; TUNEL: TdT-mediated dUTP nick end labeling; UDCA: ursodeoxycholic acid; UHPLC: ultrahigh-performance liquid chromatography.