Drug Repurposing Targeting miRNA-mRNA Networks to Mitigate Areca Nut-Induced Head and Neck Cancer.

Abstract

Background: Areca nut is a significant risk factor for head and neck cancer (HNC), yet its molecular mechanisms, particularly miRNA-mediated regulation, remain poorly understood. This study investigates the regulatory networks underlying areca nut-induced HNC and explores therapeutic strategies through computational drug repurposing.

Materials and methods: Arecoline was used to assess its effects on invasion, migration, and cisplatin resistance in HNC cells and normal keratinocytes. Differentially expressed miRNAs and mRNAs were identified using high-throughput profiling, followed by integrative network analysis using TCGA-HNSC dataset and multiMiR. OncoPredict was used for drug repurposing to identify therapeutic agents targeting dysregulated miRNA-mRNA networks.

Results: Arecoline exposure promoted invasion and cisplatin resistance, with more pronounced effects in normal keratinocytes, indicating a potential role in early tumorigenesis. Integrative transcriptomic analysis revealed a miRNA-mRNA regulatory network comprising 1,971 oncogenes, 604 tumor suppressors, 35 oncogenic miRNA (OncomiRs), and 36 tumor suppressive miRNA (TSmiRs) regulating pathways related to cell motility and stress response. A tumor-suppressive network with miR-212-3p as a central hub and an oncogenic network modulated by miR-410 and miR-1-3p as critical hubs were identified. Drug repurposing analysis identified four potential therapeutic candidates (MK-2206, BYL-719, MG-132, and FGIN-1-27), with MK-2206 emerging as the most promising. MK-2206 effectively reversed arecoline-induced miRNA-mRNA dysregulation, mitigated malignant phenotypes, and selectively targeted HNC cells while sparing normal keratinocytes.

Conclusions: This integrative approach elucidates areca nut-driven carcinogenesis through miRNA-mRNA interactions and highlights MK-2206 as a promising therapeutic strategy for areca nut-associated HNC.