microRNA-107 functions as a candidate tumor-suppressor gene in head and neck squamous cell carcinoma by downregulation of protein kinase Cε

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 C epsilon (PKC epsilon) is elevated in HNSCC and regulates the activation of Akt, Stat3 and Rho GTPases. To date, the molecular mechanism of PKC epsilon 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 PKC epsilon. An inverse relationship was revealed between miR-107 and PKCe in HNSCC cell lines. Delivery of miR-107 reduced PKCe levels in SCC15, SCC25 and CAL27, three HNSCC cell lines with high PKC epsilon and low miR-107. The activity of a luciferase reporter construct containing the 3'-UTR of PKCe 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 PKCe 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 PKCe had reduced miR-107 expression. Our results demonstrate that PKCe is directly regulated by miR-107 and, moreover, suggest that miR-107 may be a potential anti-cancer therapeutic for HNSCC. Oncogene (2012) 31, 4045-4053; doi:10.1038/onc.2011.565; published online 12 December 2011