Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 21, 2019; 25(7): 824-836
Published online Feb 21, 2019. doi: 10.3748/wjg.v25.i7.824
Ubiquitin-specific protease 22 enhances intestinal cell proliferation and tissue regeneration after intestinal ischemia reperfusion injury
An-Long Ji, Tong Li, Guo Zu, Dong-Cheng Feng, Yang Li, Guang-Zhi Wang, Ji-Hong Yao, Xiao-Feng Tian
An-Long Ji, Tong Li, Guo Zu, Dong-Cheng Feng, Yang Li, Guang-Zhi Wang, Xiao-Feng Tian, Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
Ji-Hong Yao, Department of Pharmacology, Dalian Medical University, Dalian 116044, Liaoning Province, China
Author contributions: Ji AL and Li T contributed equally to the present study; Ji AL, Zu G, Li T, Feng DC, Li Y, and Wang GZ performed the experiments and analysed the data; Li T and Ji AL wrote the article; Yao JH and Tian XF designed the experiments, revised the article, and obtained research funding; all authors have read and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 81679154.
Institutional review board statement: The study was reviewed and approved by the Dalian Medical University Institutional Review Board.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Dalian Medical University.
Conflict-of-interest statement: All the authors have no conflict of interest related to the manuscript.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: 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/
Corresponding author: Xiao-Feng Tian, MD, PhD, Director, Professor, Surgeon, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, 467 Zhongshan Road, Shahekou District, Dalian 116023, Liaoning Province, China. txfdl@dmu.edu.cn
Telephone: +86-411-86110010 Fax: +86-411-86110010
Received: November 6, 2018
Peer-review started: November 12, 2018
First decision: November 29, 2018
Revised: January 10, 2019
Accepted: January 18, 2019
Article in press: January 18, 2019
Published online: February 21, 2019
Abstract
BACKGROUND

Intestinal ischemia reperfusion (I/R) injury is a serious but common pathophysiological process of many diseases, resulting in a high mortality rate in clinical practice. Ubiquitin-specific protease 22 (USP22) acts as regulator of cell cycle progression, proliferation, and tumor invasion. Depleted USP22 expression has been reported to contribute to arrested cell cycle and disrupted generation of differentiated cell types in crypts and villi. However, the role of USP22 in intestinal damage recovery has not been investigated. Therefore, elucidation of the underlying mechanism of USP22 in intestinal I/R injury may help to improve the tissue repair and patient prognosis in clinical practice.

AIM

To investigate the role of USP22 in intestinal cell proliferation and regeneration after intestinal I/R injury.

METHODS

An animal model of intestinal I/R injury was generated in male Sprague-Dawley rats by occlusion of the superior mesenteric artery followed by reperfusion. Chiu’s scoring system was used to grade the damage to the intestinal mucosa. An in vitro model was developed by incubating rat intestinal epithelial IEC-6 cells in hypoxia/reoxygenation conditions in order to simulate I/R in vivo. siRNA and overexpression plasmid were used to regulate the expression of USP22. USP22, Cyclin D1, and proliferating cell nuclear antigen (PCNA) expression levels were measured by Western blot analysis and immunohistochemistry staining. Cell survival (viability) and cell cycle were evaluated using the Cell Counting Kit-8 and flow cytometry, respectively.

RESULTS

USP22 expression was positively correlated with the expression levels of PCNA and Cyclin D1 both in vivo and in vitro, which confirmed that USP22 was involved in cell proliferation and intestinal regeneration after intestinal I/R injury. Decreased levels of Cyclin D1 and cell cycle arrest were observed in the USP22 knockdown group (P < 0.05), while opposite results were observed in the USP22 overexpression group (P < 0.05). In addition, increased expression of USP22 was related to improved intestinal pathology or IEC-6 cell viability after I/R or hypoxia/reoxygenation. These results suggested that USP22 may exert a protective effect on intestinal I/R injury by regulating cell proliferation and facilitating tissue regeneration.

CONCLUSION

USP22 is correlated with promoting intestinal cell proliferation and accelerating intestinal tissue regeneration after intestinal I/R injury and may serve as a potential target for therapeutic development for tissue repair during intestinal I/R injury.

Keywords: Ubiquitin-specific protease 22, Proliferation, Regeneration, Repair, Intestinal ischemia-reperfusion

Core tip: Ubiquitin-specific protease 22 (USP22) belongs to the USPs family, which regulates cell cycle progression, proliferation, and tumor invasion. Depleted expression of USP22 has been linked to arrested cell cycle and disrupted distribution and generation of differentiated cell types in crypts and villi. However, its regulatory mechanism remains unclear. By generating models of ischemia reperfusion (I/R) injury and regulating USP22 expression levels, this study reveals that USP22 is correlated with promoting intestinal cell proliferation and accelerating intestinal tissue regeneration after intestinal I/R injury. USP22 might serve as a potential target for therapeutic development for tissue repair during intestinal I/R injury.