Inhibition of the Metalloproteinase ADAMTS5 Suppresses Colorectal Cancer Metastasis via the PEDF/Wnt/β-Catenin Pathway.

At present, colorectal cancer (CRC) ranks as the third most prevalent cancer globally and is the second most common cause of mortality associated with cancer. The expression of A Disintegrin and Metalloproteinase with Thrombospondin Motifs 5 (ADAMTS5) is upregulated in CRC, and high ADAMTS5 expression strongly correlates with an unfavorable prognosis. However, the function of ADAMTS5 in CRC remains unknown. This study aimed to investigate the role of ADAMTS5 in CRC and its potential mechanisms of action. The results showed that ADAMTS5 expression was higher in CRC tissues than in paracancerous tissues. Bioinformatics analysis revealed that its expression gradually increased with tumor progression and that high expression was correlated with poor prognosis. ADAMTS5 knockdown suppressed the proliferation and migration of HCT116 and HT29 cells, and ADAMTS5 inhibition suppressed epithelial-mesenchymal transition (EMT) in HCT116, HT29, and patient-derived organoids. Mechanistic analysis using the STRING database revealed that ADAMTS5 expression was strongly correlated with the Wnt signaling pathway. Western blotting analysis confirmed that ADAMTS5 inhibition suppressed tumor cell invasion and migration and blocked EMT in vitro through the PEDF/Wnt/β-catenin pathway. Furthermore, ADAMTS5 inhibition significantly inhibited tumor proliferation and metastasis within a nude mouse CRC liver metastasis model. These findings indicated that inhibition of ADAMTS5 could suppress CRC progression and metastasis via the PEDF/Wnt/β-catenin pathway.