Heterogeneous Nuclear Ribonucleoprotein A/B Drives Gastric Cancer and EMT via Akt-GSK3β-Wnt Pathway

Gastric cancer (GC) is a leading cause of cancer-related deaths globally, with metastasis critically impacting prognosis. Splicing factors are key regulators of tumorigenesis, particularly in metastasis. In this exploratory study, we investigated the role and mechanism of heterogeneous nuclear ribonucleoprotein A/B (HNRNPAB) in GC cell invasion and migration. We detected a 3.45-fold increase in HNRNPAB protein levels in highly metastatic MKN45 cells compared with low metastatic MKN7 cells (P < .01) and marked upregulation in human GC tissues (n = 408) versus normal tissues (n = 211, P < .05, predicted by gene expression profiling interactive analysis). HNRNPAB overexpression in MKN45 and MKN7 cells substantially enhanced proliferation by 50% (P < .001, 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2-H-tetrazolium bromide assay), migration by 60% (P < .001, wound healing assay), and invasion by 70% (P < .001, Transwell assay), whereas knockdown reduced these by similar magnitudes. Mechanistically, HNRNPAB decreased E-cadherin (0.5 ± 0.1-fold, P < .001) and increased N-cadherin (1.8 ± 0.2-fold), Vimentin (2.0 ± 0.2-fold), and Snail levels (1.7 ± 0.2-fold, P < .001), promoting epithelial-mesenchymal transition, which was associated with Akt-GSK3β-Wnt pathway modulation by elevating phosphorylated Akt (Ser473, 2.0 ± 0.2-fold) and phosphorylated glycogen synthase kinase 3β (Ser9, 1.8 ± 0.2-fold, P < .001). These findings suggest that HNRNPAB is a potential diagnostic and therapeutic target for GC. SIGNIFICANCE STATEMENT: This exploratory study reveals that heterogeneous nuclear ribonucleoprotein A/B is associated with gastric cancer progression and epithelial-mesenchymal transition through its potential modulation of the Akt-GSK3β-Wnt signaling pathway. Targeting heterogeneous nuclear ribonucleoprotein A/B could offer novel therapeutic approaches for improving treatment outcomes in gastric cancer, highlighting its potential as a biomarker for disease prognosis.