Feng CZ, Zhong SQ, Ye SW, Zheng Z, Sun H, Zhou SH. Tumor-derived exosomal miR-425-5p and miR-135b-3p enhance colorectal cancer progression through immune suppression and vascular permeability promotion. World J Gastrointest Oncol 2025; 17(6): 106161 [DOI: 10.4251/wjgo.v17.i6.106161]
Corresponding Author of This Article
Shi-Hai Zhou, Associate Chief Physician, Department of Tumor Surgery, Zhongshan City People’s Hospital, No. 2 Sunwen East Road, Shiqi District, Zhongshan 528403, Guangdong Province, China. 13068120688@163.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/
Chun-Zai Feng, Si-Quan Zhong, Shao-Wei Ye, Zheng Zheng, Hao Sun, Shi-Hai Zhou, Department of Tumor Surgery, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong Province, China
Author contributions: Feng CZ, Zhong SQ, Ye SW, Zheng Z, Sun H and Zhou SH designed the study; Feng CZ performed the research; Zhong SQ and Ye SW performed validation and data curation; Zheng Z carried out data analysis; Sun H handled visualization; Feng CZ and Zhou SH wrote and reviewed the manuscript; and all authors have read and approved the final manuscript.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of Zhongshan City People’s Hospital (Approval No. 2025-002).
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 Lai’an Technology (Guangzhou) Co., LTD (IACUC protocol number: G2024123).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: Technical appendix, statistical code, and dataset are available from the corresponding author at 13068120688@163.com.
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: Shi-Hai Zhou, Associate Chief Physician, Department of Tumor Surgery, Zhongshan City People’s Hospital, No. 2 Sunwen East Road, Shiqi District, Zhongshan 528403, Guangdong Province, China. 13068120688@163.com
Received: February 19, 2025 Revised: March 24, 2025 Accepted: April 22, 2025 Published online: June 15, 2025 Processing time: 115 Days and 10 Hours
Abstract
BACKGROUND
Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality globally. Exosomal microRNAs (miRNAs) are known to modulate tumor progression by influencing immune responses and vascular dynamics. However, the roles of specific exosomal miRNAs, such as miR-425-5p and miR-135b-3p, in CRC remain unclear.
AIM
To explore the specific roles and underlying mechanisms of exosomal miR-425-5p and miR-135b-3p in CRC progression.
METHODS
Differentially expressed miRNAs were identified through microarray analysis of exosomes isolated from CRC tissues and adjacent normal mucosa. Functional roles of miR-425-5p and miR-135b-3p were evaluated in vitro using macrophage polarization, T cell differentiation, and vascular permeability assays, as well as in vivo tumor formation and metastasis experiments in nude mice. Validation experiments were performed using CRC cell lines (HCT116 and SW620).
RESULTS
Exosomal miR-425-5p and miR-135b-3p were significantly upregulated in CRC compared to normal tissues. Functional studies revealed that miR-425-5p promotes macrophage M2-like polarization and suppresses T cell proinflammatory responses, while miR-135b-3p enhances vascular permeability and angiogenesis. Inhibition of these miRNAs in CRC cell-derived exosomes significantly suppressed tumor growth and metastasis in nude mice, reprogramming the tumor microenvironment toward reduced angiogenesis and enhanced immune activation. Combined inhibition of both miRNAs resulted in the most pronounced effects.
CONCLUSION
Exosomal miR-425-5p and miR-135b-3p drive CRC progression by promoting immune suppression and vascular permeability. Their inhibition offers a promising strategy for modulating the tumor microenvironment and limiting CRC metastasis.
Core Tip: This study identifies exosomal miR-425-5p and miR-135b-3p as critical regulators of colorectal cancer (CRC) progression. These microRNAs (miRNAs) are significantly upregulated in CRC-derived exosomes and modulate the tumor microenvironment through distinct mechanisms. MiR-425-5p promotes immune suppression by inducing macrophage M2 polarization and skewing T cell differentiation toward pro-tumor subsets, while miR-135b-3p enhances vascular permeability and angiogenesis. Inhibition of these miRNAs in preclinical models significantly reduces tumor growth and metastasis, suggesting they represent promising therapeutic targets for CRC. The findings provide novel insights into exosomal miRNA-mediated immune modulation and vascular remodeling in CRC progression.
