Published online Dec 15, 2024. doi: 10.4251/wjgo.v16.i12.4700
Revised: September 17, 2024
Accepted: October 16, 2024
Published online: December 15, 2024
Processing time: 148 Days and 22.5 Hours
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.
To identify apoptotic proteins from proteomics and investigate the role of matrine in impeding CRC apoptosis by regulating these proteins.
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.
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.
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.