Decoding the Oncogenic Role of GNG10 in Colorectal Cancer: A Non-Canonical Wnt Pathway-Driven Mechanism.

Guanine nucleotide-binding protein gamma 10 (GNG10) is implicated in various biological processes, yet its specific oncogenic role in colorectal cancer (CRC) remains poorly defined. This study aimed to elucidate the expression patterns, biological functions, and underlying mechanisms of GNG10 in CRC progression. We integrated TCGA datasets with tissue microarray immunohistochemistry and multivariate Cox regression models to evaluate the clinical significance of GNG10. Functional impacts on CRC malignant phenotypes and cancer stemness were assessed through gain- and loss-of-function models in vitro and in vivo. Mechanistic insights were gained via GSEA, Western blotting, and dual rescue strategies employing both pharmacological inhibition (Box5) and genetic depletion (shRHOA). We found that GNG10 was markedly overexpressed in CRC tissues, correlating with advanced pathological stage and poor overall survival. Multivariate analysis indicated that the prognostic value of GNG10 is closely associated with tumour progression. Functionally, GNG10 knockdown inhibited CRC cell proliferation, migration, and stemness while promoting apoptosis. Mechanistically, GNG10 activated the non-canonical Wnt/RHOA/JNK/NFATc1 signalling axis. Crucially, manipulation of GNG10 did not affect active or total β-catenin levels, thereby excluding canonical Wnt involvement. Both pharmacological inhibition with Box5 and genetic ablation of RHOA effectively abrogated GNG10-induced oncogenic phenotypes and the upregulation of cancer stem cell markers (CD44, CD133, OCT4, Nanog, SOX2). In vivo xenograft models confirmed that GNG10 knockdown suppressed tumour growth and decreased the expression of proliferation and stemness markers. Our findings demonstrate that GNG10 promotes CRC progression and stemness via the non-canonical Wnt signalling pathway. These findings highlight GNG10 as a promising prognostic indicator and a vulnerable target in CRC.