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Drug repurposing targeting miRNA-mRNA networks to mitigate areca nut-induced head and neck cancer
Hung-Han Huang1, Joseph T Chang2, Guo-Rung You3
1Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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 the 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 1971 oncogenes, 604 tumor suppressors, 35 oncogenic miRNA (OncomiRs), and 36 tumor suppressor 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.
Insights
Areca nut promotes head and neck cancer (HNC) via miRNA-mRNA changes. The drug MK-2206 shows promise in reversing these effects and treating HNC.
Area of Science:
- Molecular Oncology
- Cancer Genomics
- Pharmacology
Background:
- Areca nut is a major risk factor for head and neck cancer (HNC).
- Molecular mechanisms, especially miRNA regulation, in areca nut-induced HNC are not well understood.
- This study investigates regulatory networks and explores computational drug repurposing for HNC.
Purpose of the Study:
- To elucidate miRNA-mRNA regulatory networks in areca nut-induced HNC.
- To identify potential therapeutic agents for HNC through drug repurposing.
- To evaluate the efficacy of identified agents in preclinical models.
Main Methods:
- Assessed arecoline effects on HNC cells and keratinocytes (invasion, migration, cisplatin resistance).
- Performed high-throughput miRNA and mRNA profiling.
- Integrated transcriptomic data (TCGA-HNSC) and network analysis (multiMiR) to identify regulatory networks.
- Utilized OncoPredict for drug repurposing to target dysregulated networks.
Main Results:
- Arecoline promoted invasion and cisplatin resistance, particularly in normal keratinocytes.
- Identified a complex miRNA-mRNA network involving 1,971 oncogenes, 604 tumor suppressors, 35 oncogenic miRNAs, and 36 tumor suppressive miRNAs.
- Discovered key regulatory networks, including a tumor-suppressive network (miR-212-3p hub) and an oncogenic network (miR-410, miR-1-3p hubs).
- Identified four drug candidates (MK-2206, BYL-719, MG-132, FGIN-1-27), with MK-2206 showing significant promise.
- MK-2206 reversed arecoline-induced molecular changes, reduced malignant phenotypes, and selectively targeted HNC cells.
Conclusions:
- This study clarifies areca nut's role in carcinogenesis via miRNA-mRNA interactions.
- Highlights MK-2206 as a potential therapeutic strategy for areca nut-associated HNC.
- Suggests MK-2206's selective efficacy warrants further clinical investigation.
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