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

doi:10.4251/wjgo.v16.i12.4700

Matrine promotes colorectal cancer apoptosis by downregulating shank-associated RH domain interactor expression

World J Gastrointest Oncol. 2024 Dec 15;16(12):4700-4715. doi: 10.4251/wjgo.v16.i12.4700.

Authors

Yuan-Chen Zhou¹, Qian-Qian Wang¹, Ge-Yu-Jia Zhou², Teng-Fei Yin³, Dong-Yan Zhao⁴, Xi-Zhen Sun⁵, Chang Tan¹, Lei Zhou⁶, Shu-Kun Yao^{1

7}

Affiliations

¹ Graduate School, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China.
² Department of Gastroenterology, China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Beijing 100029, China.
³ Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China.
⁴ Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China.
⁵ Department of Gastroenterology, Beijing Jishuitan Hospital, Beijing 100035, China.
⁶ Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China.
⁷ Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China. shukunyao@126.com.

Abstract

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.

Keywords: Apoptosis; Colorectal cancer; Matrine; Proteomics; Shank-associated RH domain interactor.