Clinical and Translational Research
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Apr 15, 2024; 16(4): 1421-1436
Published online Apr 15, 2024. doi: 10.4251/wjgo.v16.i4.1421
NOX4 promotes tumor progression through the MAPK-MEK1/2-ERK1/2 axis in colorectal cancer
Yu-Jie Xu, Ya-Chang Huo, Qi-Tai Zhao, Jin-Yan Liu, Yi-Jun Tian, Lei-Lei Yang, Yi Zhang
Yu-Jie Xu, Ya-Chang Huo, Qi-Tai Zhao, Jin-Yan Liu, Yi-Jun Tian, Lei-Lei Yang, Yi Zhang, Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
Yu-Jie Xu, Department of Oncology, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou 450003, Henan Province, China
Co-first authors: Yu-Jie Xu and Ya-Chang Huo.
Author contributions: Xu YJ and Huo YC equally contributed to this work. Xu YJ, Huo YC, and Zhao QT analyzed the data; Xu YJ performed the experiments and drafted the manuscript; Huo YC and Zhao QT prepared the figures; Liu JY and Tian YJ performed hematoxylin-eosin and immunohistochemical staining experiments; Yang LL corrected the figures; Zhang Y designed, supervised and supported the study, and edited the manuscript; and all authors have read and approve the final the manuscript.
Supported by Henan Province Medical Science and Technology Research Provincial and Ministry Co-constructed Projects, No. SBGJ202101010; Major Public Welfare Projects in Henan Province, No. 201300310400; Joint Construction Project of Henan Medical Science and Technology Research Plan, No. LHGJ20220050; and Major Science and Technology Project of Henan Province, No. 221100310100.
Institutional review board statement: Approval of the research protocol by the Committee of First Affiliated Hospital of Zhengzhou University (No. 2022-KY-0828-003).
Clinical trial registration statement: This manuscript is not a Clinical Trial. The clinical part in the manuscript is a retrospective analysis. So we don’t have a clinical trial registration statement.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: All public data can be downloaded from TCGA through online database UCSC Xena (xena.ucsc.edu) and GEO using the access number: GSE17536. Other data used in the study are available from the corresponding author upon reasonable request.
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: Yi Zhang, MD, PhD, Chief Physician, Full Professor, Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, Henan Province, China. yizhang@zzu.edu.cn
Received: December 8, 2023
Peer-review started: December 8, 2023
First decision: December 21, 2023
Revised: January 4, 2024
Accepted: February 7, 2024
Article in press: February 7, 2024
Published online: April 15, 2024
Abstract
BACKGROUND

Metabolic reprogramming plays a key role in cancer progression and clinical outcomes; however, the patterns and primary regulators of metabolic reprogramming in colorectal cancer (CRC) are not well understood.

AIM

To explore the role of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) in promoting progression of CRC.

METHODS

We evaluated the expression and function of dysregulated and survival-related metabolic genes using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Consensus clustering was used to cluster CRC based on dysregulated metabolic genes. A prediction model was constructed based on survival-related metabolic genes. Sphere formation, migration, invasion, proliferation, apoptosis and clone formation was used to evaluate the biological function of NOX4 in CRC. mRNA sequencing was utilized to explore the alterations of gene expression NOX4 over-expression tumor cells. In vivo subcutaneous and lung metastasis mouse tumor model was used to explore the effect of NOX4 on tumor growth.

RESULTS

We comprehensively analyzed 3341 metabolic genes in CRC and identified three clusters based on dysregulated metabolic genes. Among these genes, NOX4 was highly expressed in tumor tissues and correlated with worse survival. In vitro, NOX4 overexpression induced clone formation, migration, invasion, and stemness in CRC cells. Furthermore, RNA-sequencing analysis revealed that NOX4 overexpression activated the mitogen-activated protein kinase-MEK1/2-ERK1/2 signaling pathway. Trametinib, a MEK1/2 inhibitor, abolished the NOX4-mediated tumor progression. In vivo, NOX4 overexpression promoted subcutaneous tumor growth and lung metastasis, whereas trametinib treatment can reversed the metastasis.

CONCLUSION

Our study comprehensively analyzed metabolic gene expression and highlighted the importance of NOX4 in promoting CRC metastasis, suggesting that trametinib could be a potential therapeutic drugs of CRC clinical therapy targeting NOX4.

Keywords: Colorectal cancer, Metabolic reprogramming, Metastasis, Nicotinamide adenine dinucleotide phosphate oxidase 4, Mitogen-activated protein kinase signaling

Core Tip: We first identified three clusters with different survival status based on dysregulated metabolic genes in colorectal cancer (CRC). In addition, based on differentially expressed survival-related metabolic genes, we constructed and validated a prediction model using different cohorts. Among these genes, nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) overexpression activated the mitogen-activated protein kinase-MEK1/2-ERK1/2 signaling pathway to promote cancer metastasis, whereas trametinib (a MEK1/2 inhibitor) treatment reversed this effect. Our study analyzed metabolic gene expression and highlighted the importance of NOX4 in promoting CRC metastasis, suggesting that NOX4 could be a new therapeutic target and modulating the response to clinical therapy.