Moniaux N, Lacaze L, Gothland A, Deshayes A, Samuel D, Faivre J. Cyclin-dependent kinase inhibitors p21 and p27 function as critical regulators of liver regeneration following 90% hepatectomy in the rat. World J Hepatol 2020; 12(12): 1198-1210 [PMID: 33442448 DOI: 10.4254/wjh.v12.i12.1198]
Corresponding Author of This Article
Nicolas Moniaux, PhD, Academic Research, Research Scientist, Senior Scientist, INSERM, U1193, Paul-Brousse University Hospital, Hepatobiliary Centre, 12-14 Ave Paul Vaillant-Couturier, Villejuif 94800, France. nicolas.moniaux@inserm.fr
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Hepatol. Dec 27, 2020; 12(12): 1198-1210 Published online Dec 27, 2020. doi: 10.4254/wjh.v12.i12.1198
Cyclin-dependent kinase inhibitors p21 and p27 function as critical regulators of liver regeneration following 90% hepatectomy in the rat
Nicolas Moniaux, Laurence Lacaze, Adélie Gothland, Alice Deshayes, Didier Samuel, Jamila Faivre
Nicolas Moniaux, Laurence Lacaze, Adélie Gothland, Alice Deshayes, Didier Samuel, Jamila Faivre, INSERM, U1193, Paul-Brousse University Hospital, Hepatobiliary Centre, Villejuif 94800, France
Nicolas Moniaux, Laurence Lacaze, Adélie Gothland, Alice Deshayes, Didier Samuel, Jamila Faivre, Université Paris-Saclay, Faculté de Médecine Le Kremlin, Bicêtre 94270, France
Jamila Faivre, Department of Pôle de Biologie Médicale, Laboratoire d’Onco-Hématologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Paul-Brousse University Hospital, Villejuif 94800, France
Author contributions: Moniaux N, Lacaze L, and Gothland A performed most of the experiments and analyzed the data; Deshayes A helped with handling animal tissues and western blot analysis; Faivre J designed the experiments, analyzed the data, and supervised the research; Moniaux N, Faivre J, and Samuel D wrote the manuscript.
Institutional animal care and use committee statement: Animal studies were performed in compliance with the institutional and European Union guidelines for laboratory animal care and approved by the CE2A-03-CNRS-Orléans Ethics Committee (Accreditation No. 01417.01).
Conflict-of-interest statement: All authors declare that they have no conflicts of interest.
Data sharing statement: Technical appendices, statistical codes, and datasets are available from the corresponding author at nicolas.moniaux@inserm.fr. No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared in accordance with them.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Nicolas Moniaux, PhD, Academic Research, Research Scientist, Senior Scientist, INSERM, U1193, Paul-Brousse University Hospital, Hepatobiliary Centre, 12-14 Ave Paul Vaillant-Couturier, Villejuif 94800, France. nicolas.moniaux@inserm.fr
Received: June 15, 2020 Peer-review started: June 15, 2020 First decision: July 30, 2020 Revised: August 26, 2020 Accepted: October 28, 2020 Article in press: October 28, 2020 Published online: December 27, 2020 Processing time: 185 Days and 15.9 Hours
ARTICLE HIGHLIGHTS
Research background
Liver reduction is routinely performed as curative treatment of primary liver cancer and liver metastases, but its use remains limited as liver regeneration requires a minimum of 30% functional parenchyma.
Research motivation
As such, less than 30% of patients with hepatocellular carcinoma are eligible for surgery, and this is connected to the underlying chronic inflammation and the preoperative chemotherapies. Post-surgery accumulation of liver injuries, excessive portal blood inflow, and oxidative stress are the main causal factors suspected to give rise to liver failure, but the molecular mechanisms that block liver regeneration remain unclear.
Research objectives
Our objective was to monitor, step by step, the molecular events in relation to liver regeneration after extended liver resection and so to clearly delineate the blocking points that prevent liver regeneration.
Research methods
Post-operative liver failure was modelled in the rat by 90% liver resection. Animals undergoing simple laparotomy and 70% hepatectomy were used as control. All animals received glucose infusion to avoid post-operative hypoglycemia. Animals were sacrificed every 3 h for the first 24 h and every 24 h for the following 7 d. Blood and liver samples were collected at the time of sacrifice and used to investigate liver function, morphology, and regeneration by biochemical methods.
Research results
Twenty-nine percent of all deaths occurred in the first 24 h in link with massive liver injuries and impaired liver function. For all other deaths, the temporal sequence of events that prime liver regeneration after 90% liver resection occurred properly, but S phase progression and mitosis were delayed by 24 h in conjunction with the rise in p27 (Kip1) and p21 (Waf1/Cip1) cell cycle inhibitor levels.
Research conclusions
The cyclin/cyclin-dependent kinase inhibitors of the Cip/Kip family are critical regulators of the liver regeneration following extended hepatectomy.
Research perspectives
The use of extracorporeal support devices along with inhibitors of p21 and p27 should be evaluated to manage liver failure after extended hepatectomy.
