RNF113A Promotes Colorectal Cancer Metastasis by Regulating TGF-β Pathway and EMT via Ubiquitin-Mediated Degradation of SNIP1.

BACKGROUND: RNF113A is a RING finger protein that is upregulated in colorectal cancer (CRC). Smad nuclear-interacting protein 1 (SNIP1) negatively regulates the transforming growth factor-beta (TGF-β) pathway in CRC and plays a significant role in disease progression; however, its precise regulatory mechanism remains unclear. AIMS: To investigate whether RNF113A is associated with SNIP1 protein stability and TGF-β pathway modulation in CRC and to explore the potential underlying molecular mechanisms. STUDY DESIGN: In vitro experimental study. METHODS: Immunohistochemistry and correlation analyses were performed on clinical CRC specimens to assess the expression relationships among RNF113A, SNIP1, and TGF-β1. CRC cell clonogenic capacity and migration were evaluated using colony formation, wound healing, and transwell assays. Co-immunoprecipitation was used to assess protein-protein interactions. Protein stability was examined via RNF113A overexpression and knockdown, with or without proteasome inhibition (MG132). TGF-β pathway-related protein expression and epithelial-mesenchymal transition markers were assessed by qPCR and Western blotting, using TGF-β1 (pathway activator) and SB525334 (ALK5 inhibitor) for pharmacological modulation. RESULTS: RNF113A expression was inversely correlated with SNIP1 and positively correlated with TGF-β1 in clinical specimens. Functionally, RNF113A promoted CRC cell clonogenic capacity and migration. Mechanistically, RNF113A interacted with SNIP1. RNF113A overexpression decreased SNIP1 protein levels, whereas RNF113A knockdown increased them. This effect was reversed by MG132, suggesting ubiquitin-proteasome-mediated degradation. CONCLUSION: This study suggests that RNF113A is associated with SNIP1 ubiquitination and degradation, potentially modulating TGF-β signaling and CRC cell migration. These findings reveal a potential RNF113A/SNIP1/TGF-β regulatory axis and highlight RNF113A as a potential therapeutic target in CRC, warranting further mechanistic validation.