Purpose: Human papillomavirus 16 (HPV-16) is an important risk factor in head and neck cancer (HNC). Studies suggest that miRNAs play an important role in cancer; however, their role in HPV-mediated oncogenesis remains largely unknown. We investigated the role of miRNAs with HPV-16 as putative target in HPV-16-mediated cancers.Experimental Design: Using in silico tools, we identified miRNAs with putative binding sequences on HPV-16 miRNAs. Hsa-miR-139-3p was identified as best candidate miRNA by luciferase reporter assay and was found to be significantly downregulated in HPV-16-positive tissues and cell lines. Overexpression/inhibition studies were performed to determine the role of miRNA in regulating oncogenic pathways.Results: Hsa-miR-139-3p was found to target high-risk HPV-16 oncogenic proteins and revive major tumor suppressor proteins (p53, p21, and p16). This resulted in inhibition of cell proliferation and cell migration, cell-cycle arrest at G₂-M phase and increased cell death of HPV-16-positive cells. Analysis of The Cancer Genome Atlas (TCGA) data showed decreased expression of Hsa-miR-139-3p in HPV-16-positive HNC and cervical cancer cases, and its higher expression correlated with better survival outcome in both cases. Increased DNA methylation of Hsa-miR-139-3p harboring gene PDE2A at its promoter/CpG islands was observed in HPV-16-positive tissues and cell lines, which further correlated with Hsa-miR-139-3p expression, suggesting its role in regulating Hsa-miR-139-3p expression. Furthermore, we observed an increased sensitization of Hsa-miR-139-3p overexpressed HPV-16-positive cells to chemotherapeutic drugs (cisplatin and 5-fluorouracil).Conclusions: HPV-16-mediated downregulation of Hsa-miR-139-3p may promote oncogenesis in HNC and cervical cancer. Clin Cancer Res; 23(14); 3884-95. ©2017 AACR.

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