title: Role of Host miRNA Hsa-miR-139-3p in HPV-16-Induced Carcinomas.
abstract: 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:Usingin silicotools, 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.
authors.affiliation: Department of Otolaryngology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
authors.forename: M K
authors.initials: MK
authors.lastname: Sannigrahi
authors.affiliation: Department of Experimental Medicine and Biotechnology, PGIMER, Chandigarh, India.
authors.forename: Rajni
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Department of Otolaryngology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
authors.forename: Varinder
authors.initials: V
authors.lastname: Singh
authors.affiliation: Department of Otolaryngology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
authors.forename: Naresh K
authors.initials: NK
authors.lastname: Panda
authors.affiliation: Unit of Oral Health Sciences, PGIMER, Chandigarh, India.
authors.forename: Vidya
authors.initials: V
authors.lastname: Rattan
authors.affiliation: Department of Experimental Medicine and Biotechnology, PGIMER, Chandigarh, India. khullar.madhu@pgimer.edu.
authors.forename: Madhu
authors.initials: M
authors.lastname: Khullar
mesh_terms: D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000821:virology; D049109:Cell Proliferation / Q000235:genetics; D002945:Cisplatin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000821:virology; D054884:Host-Pathogen Interactions / Q000235:genetics*; D052162:Human papillomavirus 16 / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009856:Oncogene Proteins, Viral / Q000235:genetics; D050725:Papillomavirus E7 Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: C068651:E6 protein, Human papillomavirus type 16; C555098:MIRN139 microRNA, human; D035683:MicroRNAs; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D002945:Cisplatin; D005472:Fluorouracil