Regulation of the Wnt/β-Catenin Signaling Pathway by Non-Coding RNAs in Esophageal Squamous Cell Carcinoma: Mechanisms, Translational Relevance, and Therapeutic Implications.

Abstract

Esophageal Squamous Cell Carcinoma (ESCC) is a highly aggressive malignancy characterized by a poor long-term prognosis. Aberrant activation of the canonical Wnt/β-catenin pathway serves as a central oncogenic driver in ESCC, with large-scale genomic analyses revealing that most patients harbor alterations in pathway-associated genes. This signaling axis orchestrates a wide array of malignant phenotypes, including tumor proliferation, invasion, epithelial-mesenchymal transition (EMT), cancer stemness, and therapeutic resistance. Therefore, this review aims to provide a comprehensive synthesis of the multifaceted crosstalk between various ncRNA classes and the Wnt/β-catenin axis, highlighting their roles in ESCC progression and their potential as mechanism-based clinical tools. Emerging evidence identifies non-coding RNAs (ncRNAs)-including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs)-as key regulators of this pathway in ESCC. In this article, we systematically summarize the molecular mechanisms by which 36 unique ncRNA species (20 miRNAs, 10 lncRNAs, and 6 circRNAs) modulate Wnt signaling. Oncogenic ncRNAs promote malignant progression by suppressing negative regulators within complex competing endogenous RNA (ceRNA) networks, whereas tumor-suppressive ncRNAs inhibit pathway activation by targeting Wnt ligands, receptors, or downstream effectors. Furthermore, we discuss the translational relevance of ncRNA-based biomarkers for risk stratification and prognosis in clinical cohorts. Finally, we evaluate pharmacological strategies for ncRNA-based therapeutics while highlighting critical challenges related to delivery efficiency, specificity, molecular stability, off-target effects, tumor heterogeneity, and clinical validation. Ultimately, a clearer understanding of the ncRNA-Wnt regulatory network is essential for developing personalized, mechanism-based diagnostic and therapeutic strategies.