Systems Analysis of miRNA-Mediated Host Regulatory Response in HPV-Associated Cervical Malignancy

Persistent high-risk human papillomavirus (HPV) infection, particularly types 16 and 18, is the primary driver of cervical carcinogenesis. These viruses utilize viral oncoproteins to manipulate host gene expression through multiple regulatory mechanisms. Within this landscape, microRNAs (miRNAs) emerge as critical posttranscriptional modulators that contribute to the dysregulation of pathways involved in cellular transformation and tumor progression. In this study, we investigated HPV-associated miRNA dysregulation using HPV-negative (C33A) and HPV-positive (SiHa, HeLa) cervical cancer cell lines, integrating custom microarray profiling with comprehensive systems biology and bioinformatic analyses. Our results identified 42 dysregulated miRNAs, including hsa-miR-125b-5p, hsa-miR-106b-5p, hsa-miR-23b-3p, and hsa-miR-30d-5p, which were significantly down-regulated across all experimental models. Integration of these miRNAs with cervical carcinoma transcriptomic data (GSE151666) revealed that HPV16 and HPV18 distinctly remodel host gene networks to drive malignancy. Network analysis pinpointed specific regulatory hubs, such as SOX2 and SERPINE1 for HPV16, and ERBB4 and GLI1 for HPV18, which may facilitate malignant tumor growth by disrupting metabolic, keratinization, and extracellular matrix pathways. Furthermore, drug-gene interaction mapping highlighted potential therapeutic targets including CDKN2A, CD274, and GLI1. These findings suggest that different HPV subtypes may employ unique miRNA-mediated strategies to promote cancer, offering new avenues for the development of precise diagnostic biomarkers and targeted therapies within cervical cancer research.