Open Access

REVIEW

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

Chao Han, Ming Hou, Ruifeng Yang, Xiaoping Wei, Cheng Wang^*

Department of Thoracic Surgery, The Second Hospital & Second Clinical Medical College, Lanzhou University, Lanzhou, China

* Corresponding Author: Cheng Wang. Email:

Oncology Research 2026, 34(9), 8 https://doi.org/10.32604/or.2026.081222

Received 26 February 2026; Accepted 02 June 2026; Issue published 13 August 2026

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.

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