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 Cε (PKCε) is elevated in HNSCC and regulates the activation of Akt, Stat3, and Rho GTPases. To date, the molecular mechanism of PKCε 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 PKCε. An inverse relationship was revealed between miR-107 and PKCε in HNSCC cell lines. Delivery of miR-107 reduced PKCε levels in SCC15, SCC25, and CAL27, three HNSCC cell lines with high PKCε and low miR-107. The activity of a luciferase reporter construct containing the 3'-UTR of PKCε was down-regulated 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 PKCε 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 to CAL27/miR-control cells. Lastly, human primary HNSCC tumors with elevated PKCε had reduced miR-107 expression. Our results demonstrate that PKCε is directly regulated by miR-107 and moreover, suggest that miR-107 may be a potential anti-cancer therapeutic for HNSCC.

Depleted Tumor Suppressor miR-107 in Plasma Relates to Tumor Progression and Is a Novel Therapeutic Target in Pancreatic Cancer

“…Regarding the function of miR-107 in cancer, reduced miR-107 expression has been reported in various types of cancer [69][70][71][72][73][74][75][76][77][78] , and several recent studies have identified the tumor suppressor functions of miR-107. One crucial function of miR-107 that has been identified is the inhibition of oncogenes, such as CDK8 in breast cancer 71 , the ATR/Chk1 pathway in cervical cancer 79 , HIF-1, CCND1, and NFKB1 in colon cancer 80,81 , CDK in gastric cancer 70 , CDK6, Notch-2, and VEGF in glioma Expression profiles of miR-107 in human organs.…”

An integrated transcriptional regulatory circuit that reinforces the breast cancer stem cell state

“…In accord with the defining high tumor formation properties of CSCs, all of these miRNAs have been have generally been described as tumor suppressors (e.g., see refs. [26][27][28][29][30][31].…”

Protein Kinase C (PKC) Isozymes and Cancer

“…PKC , on the other hand, is involved in cell proliferation, DNA replication, and invasion in HNSCC cells [248,249]. These cellular functions can be blocked by miR-107, which can inhibit PKC activation [249].…”

“…These cellular functions can be blocked by miR-107, which can inhibit PKC activation [249]. PKC -mediated HNSCC cell invasion and motility can be induced through activation of RhoA and C [248].…”