SNHG5 enhances colorectal cancer metastasis through RNA-protein interaction with GNB2 and activation of canonical Wnt signaling.

Background and purpose: Colorectal cancer (CRC) is one of the most prevalent and lethal malignancies worldwide, with distant metastasis-particularly to the liver-representing the primary cause of poor prognosis. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of CRC progression, yet the mechanisms by which they modulate G protein signaling during hepatic metastasis remain unclear. This study aimed to determine the role of the lncRNA SNHG5 in CRC liver metastasis and to explore whether G protein-related mechanisms are involved in this process. Methods: We established murine MC38 CRC sublines with distinct metastatic capacities (F0 and F3) and performed RNA sequencing to identify key lncRNAs. Biotin-labeled RNA pull-down coupled with mass spectrometry was used to identify SNHG5-interacting proteins. The SNHG5-GNB2 interaction was validated using RIP, RNA-FISH, and Western blot analyses. Functional rescue assays, in vivo liver metastasis models, and Wnt pathway activity measurements were conducted to delineate downstream effects. Public transcriptomic datasets from GEO and TCGA were used to assess the expression patterns and prognostic relevance of SNHG5 and GNB2 in CRC and metastatic lesions. Results: SNHG5 was significantly upregulated in the highly metastatic F3 subline and predominantly localized in the cytoplasm. Pull-down and proteomic analysis identified GNB2, a classical G protein β-subunit, as a direct binding partner of SNHG5. Functionally, SNHG5 promoted cell proliferation, migration, epithelial-mesenchymal transition (EMT), and suppressed apoptosis, while GNB2 overexpression partially rescued the tumor-suppressive phenotypes induced by SNHG5 silencing. Mechanistically, the SNHG5-GNB2 axis enhanced Wnt/β-catenin signaling via increased p-GSK3β and β-catenin levels, thereby driving EMT. Transcriptomic analyses further revealed that GNB2 is upregulated in CRC and liver metastases and is associated with poor prognosis. Multi-omics data suggested additional roles for this axis in immune evasion, metabolic reprogramming, and remodeling of the metastatic microenvironment. Conclusion: This study provides the first evidence that SNHG5 promotes CRC liver metastasis through direct interaction with GNB2 and subsequent activation of the Wnt/β-catenin pathway. The SNHG5-GNB2 axis orchestrates a multilayered regulatory network that integrates EMT induction, immune suppression, and metabolic adaptation, highlighting its potential as a mechanistic driver and therapeutic target in metastatic CRC.