Copyright
©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
Matrine promotes colorectal cancer apoptosis by downregulating shank-associated RH domain interactor expression
Yuan-Chen Zhou, Qian-Qian Wang, Ge-Yu-Jia Zhou, Teng-Fei Yin, Dong-Yan Zhao, Xi-Zhen Sun, Chang Tan, Lei Zhou, Shu-Kun Yao
Yuan-Chen Zhou, Qian-Qian Wang, Chang Tan, Shu-Kun Yao, Graduate School, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
Ge-Yu-Jia Zhou, Department of Gastroenterology, China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Beijing 100029, China
Teng-Fei Yin, Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China
Dong-Yan Zhao, Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
Xi-Zhen Sun, Department of Gastroenterology, Beijing Jishuitan Hospital, Beijing 100035, China
Lei Zhou, Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China
Shu-Kun Yao, Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
Co-corresponding authors: Lei Zhou and Shu-Kun Yao.
Author contributions: Zhou YC conceived and designed the study, performed sample collection, experiments, acquired and analyzed data, and prepared the original draft; Wang QQ, Zhou GY, Zhao DY, Yin TF, Tan C, and Sun XZ participated in sample acquisition, data analysis, and manuscript revision; All authors read and approved the final manuscript. Both Yao SK and Zhou L have played important and indispensable roles in the experimental design, data interpretation and manuscript preparation as the co-corresponding authors. Yao SK applied for and obtained the funds for this research project.
Supported by National Key Development Plan for Precision Medicine Research, No. 2017YFC0910002.
Institutional review board statement: The study was reviewed and approved by the Clinical Research Ethics Committee of the China-Japan Friendship Hospital (No. 2018-116-K85).
Conflict-of-interest statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at
shukunyao@126.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: Shu-Kun Yao, MD, PhD, Chief Physician, Doctor, Professor, Graduate School, Peking University China-Japan Friendship School of Clinical Medicine, No. 2 Yinghua East Road, Chaoyang District, Beijing 100029, China.
shukunyao@126.com
Received: June 16, 2024
Revised: September 17, 2024
Accepted: October 16, 2024
Published online: December 15, 2024
Processing time: 148 Days and 22.5 Hours
BACKGROUND
The 5-year survival rate of patients with colorectal cancer (CRC) in China is only 56.9%, highlighting the need for new therapeutic drugs. Previous studies have shown that matrine exhibits antitumor effects by inducing apoptosis. However, the mechanism by which matrine regulates antiapoptotic proteins in CRC remains unclear.
AIM
To identify apoptotic proteins from proteomics and investigate the role of matrine in impeding CRC apoptosis by regulating these proteins.
METHODS
Tumor and adjacent normal tissues were collected from 52 patients with CRC who underwent surgery between January and December 2021. Data-independent acquisition quantitative proteomic analysis was performed to identify differentially expressed apoptotic proteins. The selected apoptotic proteins were identified through their association with tumor-node-metastasis (TNM) stage and prognosis, then confirmed by immunohistochemical (IHC) staining in validation cohort. In vitro, the role of matrine or apoptotic proteins on cancer cells were analyzed.
RESULTS
Compared to normal tissues, 88 anti-apoptotic proteins from proteomic results were selected. Among them, Shank-associated RH domain interactor (SHARPIN) was identified because of its relationship with TNM stage and overall survival in TCGA database. In the IHC-confirmed cohort, SHARPIN was highly expressed in CRC tissues and localized in the cytoplasm. Higher SHARPIN expression was associated with TNM stage, carbohydrate antigen 153 levels, and gross type compared to low expression. SHARPIN knockdown promoted apoptosis, significantly upregulated the expression of Bcl-2 associated agonist of cell death, Bcl-2 associated X protein, caspase 3, and caspase 8, and downregulated B-cell lymphoma-2 (P < 0.05). Importantly, matrine treatment promoted apoptosis and reversed the proliferation, invasion, and migration of CRC cells by repressing SHARPIN.
CONCLUSION
SHARPIN was identified as an upregulated anti-apoptotic protein in CRC, and matrine exhibited anticancer effects by downregulating its expression. Thus, matrine appears to be a promising drug for CRC.
Core Tip: Despite advances in therapy for colorectal cancer (CRC), the 5-year survival rate for CRC patients in China remains only 56.9%. This study explored the effects of matrine on CRC by targeting a newly identified anti-apoptotic protein, Shank-associated RH domain interactor (SHARPIN). SHARPIN was discovered through proteomic analysis and its expression was validated in both the TCGA database and our patient cohort using immunohistochemistry. Inhibiting SHARPIN expression led to increased apoptosis and reduced proliferation, invasion, and migration of CRC cells in vitro. Matrine's ability to inhibit SHARPIN and induce apoptosis highlights its potential as a promising therapeutic agent for CRC.
