TIMP‐2 Modulates 5‐Fu Resistance in Colorectal Cancer Through Regulating JAK–STAT Signalling Pathway

• Published in: Journal of cellular and molecular medicine Vol. 29; no. 6; pp. e70470 - n/a
• Main Authors: Xu, Chuchu, Zhu, Renjun, Dai, Qingfeng, Li, Yaoqing, Hu, Gengyuan, Tao, Kelong, Xu, Yuhong, Xu, Guangen, Zhang, Guolin
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.03.2025; John Wiley and Sons Inc
• Subjects: 5-Fluorouracil; 5‐Fu; Antibodies; Cancer; Cancer therapies; Cell culture; Cell cycle; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Chemotherapy; Cholecystokinin; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Cytokines; DNA methylation; Drug delivery; drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Enzyme-linked immunosorbent assay; Enzymes; Fluorouracil - pharmacology; Gene Expression Regulation, Neoplastic - drug effects; Growth factors; Humans; JAK–STAT signalling pathway; Janus Kinases - metabolism; Kinases; Male; Medical prognosis; Medical research; Metastasis; Molecules; Original; Ovaries; Patients; Proteins; Signal transduction; Signal Transduction - drug effects; STAT Transcription Factors - metabolism; TIMP‐2; Tissue Inhibitor of Metalloproteinase-2 - blood; Tissue Inhibitor of Metalloproteinase-2 - genetics; Tissue Inhibitor of Metalloproteinase-2 - metabolism; Tissue inhibitor of metalloproteinases; Western blotting; JAK–STAT signalling pathway; TIMP‐2; 5‐Fu; colorectal cancer; drug resistance
• ISSN: 1582-1838; 1582-4934; 1582-4934
• DOI: 10.1111/jcmm.70470

ABSTRACT The main reason for the failure of chemotherapy therapies based on 5‐Fluorouracil (5‐Fu) is the development of resistance to 5‐Fu in cancer patients, particularly those with colorectal cancer. Tissue inhibitor of metalloproteinases 2 (TIMP‐2) has been shown to be associated with colorectal cancer (CRC), but its correlation with 5‐Fu resistance in colorectal cancer has not been thoroughly studied. We screen the expression of different cytokines through Cytokine array. CCK‐8 assay was conducted to evaluate the IC50 of 5‐Fu and cell proliferation. ELISA and RT‐qPCR were performed to detect TIMP‐2 expression levels in cells and patient serum. Western blotting was utilised to analyse the differences in the expression of proteins related to signalling pathways in cells. Through cytokine array screening, we found that the expression of TIMP‐2 was significantly increased in CRC drug‐resistant cell lines. In addition, the expression of TIMP‐2 in the serum of patients with CRC resistance to 5‐Fu was significantly increased. Subsequent mechanistic experiments showed that TIMP‐2 regulated the resistance of CRC cells to 5‐Futhrough the JAK–STAT signalling pathway. Moreover, anti‐TIMP‐2 antibody or small molecule drug LY2784544 targeting the JAK–STAT signalling pathway can effectively reverse the resistance of CRC cells to 5‐Fu. It is exactly TIMP‐2 that mediates the resistance of CRC to 5‐Fu through the JAK–STAT signalling pathway. Targeting drugs for TIMP‐2 or the JAK–STAT signalling pathway are expected to be opportunities to reverse 5‐Fu resistance in CRC.