SFRP2 Potentiates Metastasis of Colon Cancer by Enhancing Snai1 Protein Stability via USP11

Metastatic colon cancer remains a significant clinical challenge, often associated with poor patient prognosis. Recent studies have identified the secreted frizzled-related protein 2 (SFRP2) as a key player in this malignancy, showing its overexpression in metastatic cases. This research aimed to elucidate the molecular mechanisms by which SFRP2 influences colon cancer progression. We employed in vitro assays to assess the effects of SFRP2 on cell migration and invasion, revealing that SFRP2 significantly enhances these processes without affecting cell proliferation. Mechanistically, we found that SFRP2 interacts with Snai1, a transcription factor known to promote epithelial-mesenchymal transition (EMT), thereby stabilizing Snai1 protein levels. Furthermore, SFRP2 was shown to inhibit Snai1 ubiquitination through the deubiquitinase USP11, leading to increased Snai1 activity. Notably, Snai1 also positively regulates SFRP2 transcription, establishing a feedback loop that amplifies their expression. Our findings indicate that the SFRP2-Snai1 axis promotes colon cancer cell migration and invasion via the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway. In vivo experiments further confirmed that the SFRP2-Snai1 interaction significantly enhances metastatic potential. Collectively, these results suggest that targeting the SFRP2-Snai1 signalling pathway may provide a novel therapeutic strategy for metastatic colon cancer.