Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Feb 26, 2024; 16(2): 207-227
Published online Feb 26, 2024. doi: 10.4252/wjsc.v16.i2.207
VX-509 attenuates the stemness characteristics of colorectal cancer stem-like cells by regulating the epithelial-mesenchymal transition through Nodal/Smad2/3 signaling
Yun Yuan, Xu-Fan Zhang, Yu-Chen Li, Hong-Qing Chen, Tian Wen, Jia-Lian Zheng, Zi-Yi Zhao, Qiong-Ying Hu
Yun Yuan, Yu-Chen Li, Hong-Qing Chen, Tian Wen, Qiong-Ying Hu, Department of Laboratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
Xu-Fan Zhang, Department of Nuclear Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
Xu-Fan Zhang, College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Sichuan Province, China
Jia-Lian Zheng, Department of Hepatology, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110032, Liaoning Province, China
Zi-Yi Zhao, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
Zi-Yi Zhao, Traditional Chinese Medicine Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu 610072, Sichuan Province, China
Co-first authors: Yun Yuan and Xu-Fan Zhang.
Co-corresponding authors: Jia-Lian Zheng and Qiong-Ying Hu.
Author contributions: Yuan Y, Zhang XF, Li YC, Chen HQ, Wen T, Zheng JL, Zhao ZY, and Hu QY contributed to the investigation of this manuscript; Yuan Y, Li YC, Chen HQ, and Wen T were involved in the data curation; Yuan Y, Li YC, Zheng JL, and Hu QY participated in the methodology of this study; Yuan Y, Zhang XF, Zheng JL, Zhao ZY, and Hu QY took part in the conceptualization of this article; Yuan Y and Zhang XF wrote the original draft; Zhang XF, Zheng JL, and Hu QY contributed to the project administration of this manuscript; Zheng JL, Zhao ZY, and Hu QY were major in the funding acquisition and supervision of this program.
Supported by National Natural Science Foundation of China, No. 82074298; Chengdu Science and Technology Bureau Project, No. 2021-YF05-01726-SN; and “Xinglin Scholars” Research Promotion Program of Chengdu University of Traditional Chinese Medicine, No. QJRC2022007.
Institutional review board statement: The study was reviewed and approved by Related Ethical Regulations of Chengdu University of Traditional Chinese Medicine.
Institutional animal care and use committee statement: All the animal experiments were approved by the ethics committee of the Institutional Animal Care and Use Committee of Institute of Chengdu University of Traditional Chinese Medicine.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: All data during the study are available from the corresponding author by request at qiongyinghu@163.com.
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 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: Qiong-Ying Hu, PhD, Associate Professor, Department of Laboratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shierqiao Road, Jinniu District, Chengdu 610072, Sichuan Province, China. qiongyinghu@163.com
Received: October 30, 2023
Peer-review started: October 30, 2023
First decision: December 5, 2023
Revised: December 19, 2023
Accepted: January 16, 2024
Article in press: January 16, 2024
Published online: February 26, 2024
Processing time: 118 Days and 15.4 Hours
ARTICLE HIGHLIGHTS
Research background

Colorectal cancer (CRC) is a globally prevalent malignant disease with a significant increase in incidence, and CRC patients continue to face poor outcomes characterized by ineffective early-stage diagnosis, recurrence and metastasis due to incomplete tumor removal, and resistance to chemoradiotherapy.

Research motivation

Colorectal cancer stem cells (CCSCs), that possess self-renewal ability and the capacity for multidirectional differentiation, strongly support disordered tumor growth and treatment resistance. Targeting CCSCs can be an effective strategy for eradicating CRC from the source.

Research objectives

The present study aimed to investigate the effect of VX-509 on CCSCs and elucidate the underlying mechanism.

Research methods

CCSCs were enriched from CRC cell lines and were verified the cancer stem-like phenotypic characteristics. The anticancer efficacy of VX-509 was assessed in HCT116 CCSCs and HT29 CCSCs by performing cell viability analysis, colony formation, sphere formation, flow cytometry, and western blotting assessments in vitro and tumor growth, immunohistochemistry and immunofluorescence assessments in vivo.

Research results

HCT116 CCSCs and HT29 CCSCs were enriched successfully and possessed CCSC characteristics. VX-509 inhibited the tumor malignant biological behaviors and the CSC characteristics of CCSCs. Besides, VX-509 suppressed the progression of epithelial-mesenchymal transition (EMT) signaling and downregulated the expression of Nodal and its downstream phosphorylated Smad2/3.

Research conclusions

This study demonstrated that VX-509 prevents the EMT process in CCSCs by inhibiting the transcription and protein expression of Nodal, and inhibits the dedifferentiated self-renewal of CCSCs.

Research perspectives

VX-509 inhibited the continuous self-renewal and reduced the generation of CCSCs by regulating the transcription and protein expression of Nodal to inhibit the EMT process, suggesting its potential clinical application in treating CRC.