RGL2 Drives the Metastatic Progression of Colorectal Cancer via Preventing the Protein Degradation of β-catenin and KRAS

Abstract Background: Colorectal cancer (CRC) is a common cancer and results in high mortality worldwide, owing to cancer progression, e.g., metastasis. However, the molecular mechanism underlying the metastatic evolution of CRC remains largely unknown. In this study, we investigated the clinical relevance and oncogenic function of RGL2 in CRC.Methods: Cellular migration ability was assessed by transwell cultivation. The metastatic potential was estimated by lung colony-forming assay. DNA-binding activity of transcription factors was determined by luciferase-based reporter assay. RGL2 expression was analyzed by immunohistochemistry in human CRC specimens. RGL2 mRNA expression from the Cancer Genome Atlas (TCGA) CRC database was compared between the primary tumors and normal tissues.Results: The upregulation of Ral Guanine Nucleotide Dissociation Stimulator Like 2 (RGL2) was commonly detected in primary tumors compared with normal tissues and is significantly associated with a poorer prognosis in CRC patients. Moreover, RGL2 expression appeared to positively correlate with the metastatic potential of CRC cells. Whereas RGL2 knockdown dramatically suppressed the metastatic potential of CRC cells in vitro and in vivo, RGL2 overexpression in poorly metastatic CRC cells and reconstitution in RGL2-silenced CRC cells enhanced and rescued the cellular metastatic ability, respectively. Computational simulation using the Gene Set Enrichment Analysis program and cell-based assays demonstrated that RGL2 expression was causally associated with the activity of the Wnt/β-catenin signaling axis and KRAS, as well as the progression of epithelial-mesenchymal transition (EMT) in the detected CRC cells. Importantly, RGL2 upregulation was capable of preventing the protein degradation of β-catenin and KRAS in CRC cells. Conclusion: RGL2 has metastasis-promoting effects via stabilizing β-catenin and KRAS in CRC cells and prognostic significance in CRC patients. These findings suggest that RGL2 acts as a driver to promote the metastatic progression of CRC and serves as a poor prognostic biomarker in CRC patients.