Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 21, 2023; 29(35): 5104-5124
Published online Sep 21, 2023. doi: 10.3748/wjg.v29.i35.5104
Regenerating gene 4 promotes chemoresistance of colorectal cancer by affecting lipid droplet synthesis and assembly
Cong-Yu Zhang, Rui Zhang, Li Zhang, Zi-Mo Wang, Hong-Zhi Sun, Zheng-Guo Cui, Hua-Chuan Zheng
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 by Natural 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
Abstract
BACKGROUND

Regenerating gene 4 (REG4) has been proved to be carcinogenic in some cancers, but its manifestation and possible carcinogenic mechanisms in colorectal cancer (CRC) have not yet been elucidated. Our previous study found that the drug resistance of CRC cells may be closely linked to their fat metabolism.

AIM

To explore the role of REG4 in CRC and its association with lipid droplet formation and chemoresistance.

METHODS

We conducted a meta-analysis and bioinformatics and pathological analyses of REG4 expression in CRC. The effects of REG4 on the phenotypes and related protein expression were also investigated in CRC cells. We detected the impacts of REG4 on the chemoresistance and lipid droplet formation in CRC cells. Finally, we analyzed how REG4 regulated the transcription and proteasomal degradation of lipogenic enzymes in CRC cells.

RESULTS

Compared to normal mucosa, REG4 mRNA expression was high in CRC (P < 0.05) but protein expression was low. An inverse correlation existed between lymph node and distant metastases, tumor-node-metastasis staging or short overall survival and REG4 mRNA overexpression (P < 0.05), but vice versa for REG4 protein expression. REG4-related genes included: Chemokine activity; taste receptors; protein-DNA and DNA packing complexes; nucleosomes and chromatin; generation of second messenger molecules; programmed cell death signals; epigenetic regulation and DNA methylation; transcription repression and activation by DNA binding; insulin signaling pathway; sugar metabolism and transfer; and neurotransmitter receptors (P < 0.05). 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. 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.

CONCLUSION

REG4 may be involved in chemoresistance through lipid droplet assembly. REG4 reduces expression of de novo lipid synthesis key enzymes by inhibiting transcription and promoting ubiquitination-mediated proteasomal degradation.

Keywords: Colorectal cancer, Regenerating gene 4, Aggressive behavior, Prognosis, Chemoresistance, Lipid droplet formation, Epidermal growth factor receptor signal

Core Tip: The roles of regenerating gene 4 (REG4) in colorectal cancer (CRC) and the related molecular mechanisms are still unknown. REG4 may be involved in tumorigenesis and aggressiveness of CRC via the epidermal growth factor receptor-phosphoinositide 3-kinase-Akt-nuclear factor-κB pathway, and chemoresistance through lipid droplet assembly. REG4 might be used as a useful marker for colorectal carcinogenesis and subsequent progression, as well as a potential gene therapy target.