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A Feed-Forward Loop Involving Protein Kinase C and MicroRNAs Regulates Tumor Cell Cycle

¹ Section of Hematology/Oncology, Department of Medicine, ² Ben May Department for Cancer Research, ³ Department of Pathology and Department of Radiation and Cellular Oncology, ⁴ Section of General Surgery, Department of Surgery, and ⁵ Department of Health Studies, University of Chicago, Chicago, Illinois; ⁶ Expression Analysis, Durham, North Carolina; and ⁷ Divison of Hematology/Oncology, Department of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee

Requests for reprints: Marsha Rosner, Ben May Department for Cancer Research, Gordon Center for Integrative Sciences, University of Chicago, 929 East 57th Street, W421C, Chicago, IL 60637. Phone: 312-702-0380; E-mail: m-rosner{at}uchicago.edu.

Key Words: cyclin E • microRNA • protein kinase C

Protein kinase C (PKC) has been implicated in cancer, but the mechanism is largely unknown. Here, we show that PKC promotes head and neck squamous cell carcinoma (SCCHN) by a feed-forward network leading to cell cycle deregulation. PKC inhibitors decrease proliferation in SCCHN cell lines and xenografted tumors. PKC inhibition or depletion in tumor cells decreases DNA synthesis by suppressing extracellular signal-regulated kinase phosphorylation and cyclin E synthesis. Additionally, PKC down-regulates miR-15a, a microRNA that directly inhibits protein synthesis of cyclin E, as well as other cell cycle regulators. Furthermore, both PKC and cyclin E protein expression are increased in primary tumors, and PKC inversely correlates with miR-15a expression in primary tumors. Finally, PKC is associated with poor prognosis in SCCHN. These results identify PKC as a key regulator of SCCHN tumor cell growth by a mechanism involving activation of mitogen-activated protein kinase, an initiator of the cell cycle, and suppression of miR-15a, an inhibitor of DNA synthesis. Although the specific components may be different, this type of feed-forward loop network, consisting of a stimulus that activates a positive signal and removes a negative brake, is likely to be a general one that enables induction of DNA synthesis by a variety of growth or oncogenic stimuli. [Cancer Res 2009;69(1):65–74]

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