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

Protein kinase Cα (PKCα) has been implicated in cancer, but the mechanism is largely unknown. Here, we show that PKCα promotes head and neck squamous cell carcinoma (SCCHN) by a feed-forward network leading to cell cycle deregulation. PKCα inhibitors decrease proliferation in SCCHN cell lines and xenografted tumors. PKCα inhibition or depletion in tumor cells decreases DNA synthesis by suppressing extracellular signal-regulated kinase phosphorylation and cyclin E synthesis. Additionally, PKCα down-regulates miR-15a, a microRNA that directly inhibits protein synthesis of cyclin E, as well as other cell cycle regulators. Furthermore, both PKCα and cyclin E protein expression are increased in primary tumors, and PKCα inversely correlates with miR-15a expression in primary tumors. Finally, PKCα is associated with poor prognosis in SCCHN. These results identify PKCα 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]