Zhang XF, Chen Q, Jiang Q, Hu QY. Targeting STAT3 with SH-4-54 suppresses stemness and chemoresistance in cancer stem-like cells derived from colorectal cancer. World J Clin Oncol 2025; 16(2): 97296 [DOI: 10.5306/wjco.v16.i2.97296]
Corresponding Author of This Article
Qiong-Ying Hu, MD, 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
Research Domain of This Article
Oncology
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/
World J Clin Oncol. Feb 24, 2025; 16(2): 97296 Published online Feb 24, 2025. doi: 10.5306/wjco.v16.i2.97296
Targeting STAT3 with SH-4-54 suppresses stemness and chemoresistance in cancer stem-like cells derived from colorectal cancer
Xu-Fan Zhang, Qian Chen, Qin Jiang, Qiong-Ying Hu
Xu-Fan Zhang, Qian Chen, Department of Nuclear Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 641000, Sichuan Province, China
Xu-Fan Zhang, College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
Qin Jiang, Department of Laboratory Medicine, Hospital of Mianyang Traditional Chinese Medicine, Chengdu 641000, Sichuan Province, China
Qiong-Ying Hu, Department of Laboratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
Co-first authors: Xu-Fan Zhang and Qian Chen.
Author contributions: Zhang XF and Chen Q contribute equally to this study as co-first authors; Zhang XF, Chen Q, and Hu QY designed the experiments; Zhang XF and Chen Q performed cell culture experiments; Zhang XF and Jiang Q are responsible for data collection and performed the statistical analysis; all authors read and approved the final manuscript; Zhang XF, Chen Q, Jiang Q and Hu QY confirmed the authenticity of all the raw data.
Institutional animal care and use committee statement: This study adhered to the guidelines outlined in the “Guide for the Care and Use of Laboratory Animals” published by the National Institutes of Health. The Experimental Animal Ethics Committee of the Affiliated Hospital of Chengdu University of Traditional Chinese Medicine approved the protocol (Protocol number: 2024074) at date of 03/12/2020. Strict humane endpoints were established, whereby animals experiencing > 30% body mass loss and labored breathing were euthanized. When both of these clinical signs were observed in rats, they were considered to have reached the experimental endpoint and were immediately euthanized following the protocol of the Experimental Animal Ethics Committee of the Affiliated Hospital of Chengdu University of Traditional Chinese Medicine.
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
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, MD, 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: May 27, 2024 Revised: September 26, 2024 Accepted: November 19, 2024 Published online: February 24, 2025 Processing time: 197 Days and 18.8 Hours
Abstract
BACKGROUND
Over the years, the numbers of treatment options for colorectal cancer (CRC) have increased, leading to notable improvements in the overall survival of CRC patients. Although therapy may initially yield positive results, the development of drug resistance can result in treatment failure and cancer recurrence. This resistance is often attributed to the presence of cancer stem cells (CSCs). These CSCs not only contribute to therapeutic resistance but also play crucial roles in the initiation and development of tumor metastasis.
AIM
To investigate the antitumor effects of SH-4-54, which are mediated by targeting CSCs relative to treatment outcomes.
METHODS
CSCs were enriched by culturing CRC cells in serum-free medium. Hallmarks of stemness and IL-6/JAK2/STAT3 signaling were detected by Western blotting. Indicators of CSC malignancy, including proliferation, invasion, and tumor formation, were measured.
RESULTS
In this study, we employed SH-4-54, which exhibits anticancer activity in solid tumors through targeting the SH2 domain of both the signal transducer and activator of transcription (STAT)3 and the STAT5, and evaluated its effects on stemness and chemoresistance in colorectal CSCs. As expected, SH-4-54 treatment inhibited the phosphorylation of STAT3 (p-STAT3) and decreased the percentage of ALDH1A1-positive CRC cells. The addition of SH-4-54 dissociated colorectal spheroids and decreased the expression of stemness markers, including ALDH1A1, CD44 and Nanog. SH-4-54 treatment decreased IL-6/JAK2/STAT3 signaling by inhibiting p-STAT3 and thus inhibited spheroid formation by SW480 and LoVo cells. Moreover, SH-4-54 treatment inhibited indicators of malignancy, including cell proliferation, invasion, and tumor formation, in CSCs in vitro and in vivo. Notably, SH-4-54 treatment significantly increased chemosensitivity to oxaplatin.
CONCLUSION
Taken together, these results indicate that SH-4-54 is a promising molecule that exerts antitumor effects on colorectal CSCs by inhibiting STAT3 signaling.
Core Tip: Targeting cancer stem cells (CSCs) has emerged as an appealing approach for combating colorectal cancer (CRC) and improving treatment outcomes. Specifically, the study employed a compound called SH-4-54, which targets the SH2 domain of both signal transducer and activator of transcription (STAT)3 and STAT5, thereby exhibiting anticancer activity in colorectal CSCs. Taken together, our study suggests that SH-4-54 is a promising molecule that can target and inhibit colorectal CSCs by modulating the STAT3 signaling pathway, thereby presenting a potential therapeutic approach for combating CRC.
