Zhang CY, Zhang R, Zhang L, Wang ZM, Sun HZ, Cui ZG, Zheng HC. Regenerating gene 4 promotes chemoresistance of colorectal cancer by affecting lipid droplet synthesis and assembly. World J Gastroenterol 2023; 29(35): 5104-5124 [PMID: 37744296 DOI: 10.3748/wjg.v29.i35.5104]
Corresponding Author of This Article
Hua-Chuan Zheng, MD, PhD, Professor, Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, No. 2 Fifth Duan, Renmin Street, Guta District, Jinzhou 121001, Liaoning Province, China. zheng_huachuan@hotmail.com
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/
Cong-Yu Zhang, Zi-Mo Wang, Hong-Zhi Sun, Hua-Chuan Zheng, Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
Rui Zhang, Department of Colorectal Surgery, Liaoning Cancer Hospital, Shenyang 110042, Liaoning Province, China
Li Zhang, Department of Oncology, The Affiliated Hospital of Chengde Medical University, Chengde 067000, Hebei Province, China
Zheng-Guo Cui, Department of Environmental Health, University of Fukui School of Medical Sciences, Fukui 910-1193, Japan
Author contributions: Zhang CY and Zheng HC designed the study; Zhang CY participated in data collection; Zheng HC wrote the paper; Zhang R, Zhang L, Wang ZM, Sun HZ and Cui ZG were responsible for revising the manuscript; All the listed authors have contributed and approved the final manuscript.
Supported byNatural Science Foundation of Hebei Province, No. 21377772D; No. H2022406034; National Natural Scientific Foundation of China, No. 81672700.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board at the First Affiliated Hospital of Jinzhou Medical University.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Hua-Chuan Zheng, MD, PhD, Professor, Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, No. 2 Fifth Duan, Renmin Street, Guta District, Jinzhou 121001, Liaoning Province, China. zheng_huachuan@hotmail.com
Received: June 25, 2023 Peer-review started: June 25, 2023 First decision: August 8, 2023 Revised: August 10, 2023 Accepted: August 25, 2023 Article in press: August 25, 2023 Published online: September 21, 2023 Processing time: 81 Days and 9 Hours
ARTICLE HIGHLIGHTS
Research background
Regulating gene 4 (REG4) has been proved to be carcinogenic in some cancers, but its manifestation and possible carcinogenic mechanism in colorectal cancer (CRC) have not yet been elucidated. Our previous study found that the drug resistance characteristics of CRC cells may be related to their fat metabolism.
Research motivation
With the aging of the world population, the incidence of CRC is increasing. For the treatment of CRC, chemoresistance has always been an urgent problem to be solved.
Research objectives
This study aimed to explore the role of REG4 in CRC and its association with lipid droplet formation, and the molecular mechanisms involved.
Research methods
We conducted a meta-analysis and bioinformatics and pathological analysis of REG4 expression in CRC. The effects of REG4 on the phenotypes and related proteins were also investigated in CRC cells.
Research results
Compared to normal mucosa, REG4 mRNA expression was high in CRC, but protein expression was opposite. REG4-related genes included epigenetic regulation, transcription repression, sugar metabolism and transfer. REG4 exposure or overexpression promoted proliferation, antiapoptosis, migration and invasion of DLD-1 cells in an autocrine or paracrine manner by activating the epidermal growth factor receptor-phosphoinositide 3-kinase-Akt-nuclear factor-κB pathway. REG4 was involved in chemoresistance not through de novo lipogenesis, but lipid droplet assembly, which was strengthened by high glucose treatment. REG4 inhibited the transcription of acetyl-coA carboxylase 1 (ACC1) and ATP-citrate lyase (ACLY) by disassociating the complex formation of anti–acetyl (AC)-acetyl-histone 3-AC-histone 4-inhibitor of growth protein-5-si histone deacetylase-sterol-regulatory element binding protein 1 in their promoters and induced proteasomal degradation of ACC1 or ACLY.
Research conclusions
REG4 may be an indicator of drug resistance and metabolism of tumor cells. REG4 might be a useful marker for colorectal carcinogenesis, as well as a potential gene therapy target.
Research perspectives
This study provides new insights into a better understanding of the pathogenesis of CRC. REG4 may be used as a novel therapeutic target. However, the regulatory mechanism needs to be further explored.
