Targeting the Wnt/β-catenin pathway and epithelial-mesenchymal transition in gastric cancer: mechanisms, therapeutic strategies, and clinical challenges
Ruixin Shi, Z. Alexander Cao, Jie Li, Ru Ji, Zhijuan Guo
Abstract
Gastric cancer (GC) remains the foremost contributor to global cancer mortality, largely attributable to metastatic dissemination and therapeutic refractoriness. Emerging data implicate the Wnt/β-catenin signaling cascade as a pivotal regulator of epithelial-mesenchymal plasticity, stemness acquisition, and multidrug tolerance in GC. This review delineates the molecular landscape of Wnt/β-catenin aberrations, encompassing genomic perturbations ( NAT10 , SMC4 ), non-coding RNA circuitry ( LINC00665 , circ0000670 ), and (epigenetic reprogramming (e.g., miR-33b hypermethylation). Mechanistically, these alterations cooperate with EMT drivers to potentiate metastatic outgrowth and therapeutic evasion. Of particular translational significance are emerging interventions targeting this axis: phytochemicals (Rutin, ginsenoside Rg3) with dual Wnt-CSC inhibitory activity, CRISPR-edited epigenetic modulators ( TET1 /FOXO4), and immune checkpoint blockade-Wnt inhibitor synergism. Notwithstanding preclinical success, clinical implementation faces two critical bottlenecks—pathway pleiotropy and biomarker paucity. To bridge this gap, we propose a precision oncology framework leveraging multi-omics-guided patient stratification, potentially reshaping GC therapeutic paradigms.