Background: While miRNAs are increasingly recognized for their role in tumorigenesis, their involvement in head and neck cancer (HNC) remains insufficiently explored. Additionally, the carcinogenic mechanisms of areca nut, a major habitual carcinogen in Southeast Asia, are not well understood. Methods and results: This study adopts a systematic approach to identify miRNA profiles associated with areca nut-induced HNC. Using miRNA microarray analysis, we identified 292 miRNAs dysregulated in areca nut-treated HNC cells, with 136 upregulated and 156 downregulated. Bioinformatic analysis of the TCGA-HNSC dataset uncovered a set of 692 miRNAs relevant to HNC development, comprising 449 overexpressed and 243 underexpressed in tumor tissues. Integrating these datasets, we defined a signature of 84 miRNAs, including 39 oncogenic miRNAs (OncomiRs) and 45 tumor-suppressive miRNAs (TsmiRs), highlighting their pivotal role in areca nut-induced carcinogenesis. MultiMiR analysis identified 740 genes cross-regulated by eight hub TsmiRs, significantly impacting key cancer-related pathways (p53, PI3K-AKT, MAPK, and Ras) and critical oncogenic processes. Moreover, we validated miR-499a-5p as a vital regulator, demonstrating its ability to mitigate areca nut-induced cancer progression by reducing cell migration, invasion, and chemoresistance. Conclusions: Thus, this miRNA signature addresses a crucial gap in understanding the molecular underpinnings of areca nut-induced carcinogenesis and offers a promising platform for clinical applications in risk assessment, diagnosis, and prognosis of areca nut-associated malignancies.
背景：尽管微小RNA（miRNA）在肿瘤发生中的作用日益受到关注，但其在头颈癌（HNC）中的参与机制仍未得到充分探索。此外，槟榔作为东南亚地区主要习惯性致癌物，其致癌机制尚不明确。方法与结果：本研究采用系统方法识别与槟榔诱导头颈癌相关的miRNA谱。通过miRNA微阵列分析，我们在槟榔处理的头颈癌细胞中发现292个失调miRNA，其中136个上调、156个下调。对TCGA-HNSC数据库的生物信息学分析揭示了692个与头颈癌发展相关的miRNA，其中449个在肿瘤组织中过表达、243个低表达。整合两组数据后，我们确定了84个特征性miRNA（包括39个促癌miRNA和45个抑癌miRNA），凸显了它们在槟榔诱导癌变中的关键作用。MultiMiR分析发现8个核心抑癌miRNA交叉调控740个基因，显著影响关键癌症相关通路（p53、PI3K-AKT、MAPK和Ras）及重要致癌过程。此外，我们验证了miR-499a-5p作为关键调控因子，能够通过降低细胞迁移、侵袭和化疗耐药性来抑制槟榔诱导的癌症进展。结论：该miRNA特征谱填补了槟榔致癌分子机制认知的重要空白，为槟榔相关恶性肿瘤的风险评估、诊断和预后临床应用提供了前景广阔的研究平台。
MiRNA Profiling of Areca Nut-Induced Carcinogenesis in Head and Neck Cancer
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