title: microRNA-107 functions as a candidate tumor-suppressor gene in head and neck squamous cell carcinoma by downregulation of protein kinase Cɛ.
abstract: Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with about 600 000 new cases diagnosed each year. Understanding the molecular pathways that lead to HNSCC is crucial to identify new targets for anti-cancer drug development. Protein kinase Cɛ (PKCɛ) is elevated in HNSCC and regulates the activation of Akt, Stat3 and Rho GTPases. To date, the molecular mechanism of PKCɛ dysregulation in HNSCC remains to be elucidated. In silico analysis identified three putative microRNA-107 (miR-107) binding sites in the 3'-untranslated region (UTR) of PKCɛ. An inverse relationship was revealed between miR-107 and PKCɛ in HNSCC cell lines. Delivery of miR-107 reduced PKCɛ levels in SCC15, SCC25 and CAL27, three HNSCC cell lines with high PKCɛ and low miR-107. The activity of a luciferase reporter construct containing the 3'-UTR of PKCɛ was downregulated by miR-107 and mutations in the three cognate miR-107 binding sites completely ablated the regulation by miR-107. Treatment with miR-107 significantly blocked cell proliferation, DNA replication, colony formation and invasion in SCC25 and CAL27 cells. Ectopic expression of miR-resistant PKCɛ was sufficient to partially rescue the loss-of-function phenotype in miR-107-overexpressing SCC25 cells. Tumor growth in nude mice was retarded by 93±7% in CAL27/miR-107 cells compared with CAL27/miR-control cells. Last, human primary HNSCC tumors with elevated PKCɛ had reduced miR-107 expression. Our results demonstrate that PKCɛ is directly regulated by miR-107 and, moreover, suggest that miR-107 may be a potential anti-cancer therapeutic for HNSCC.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: J
authors.initials: J
authors.lastname: Datta
authors.forename: A
authors.initials: A
authors.lastname: Smith
authors.forename: J C
authors.initials: JC
authors.lastname: Lang
authors.forename: M
authors.initials: M
authors.lastname: Islam
authors.forename: D
authors.initials: D
authors.lastname: Dutt
authors.forename: T N
authors.initials: TN
authors.lastname: Teknos
authors.forename: Q
authors.initials: Q
authors.lastname: Pan
mesh_terms: D000818:Animals; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D051744:Protein Kinase C-epsilon / Q000235:genetics* / Q000378:metabolism; D047368:Tumor Burden
chemical_list: C549045:MIRN107 microRNA, human; D035683:MicroRNAs; D051744:Protein Kinase C-epsilon