Protein Kinase C Alpha Promotes Tumor Growth by Initiating a Feed-forward Network Involving miR-15a and Cyclin E

Protein Kinase C alpha (PKC) is associated with progression and poor prognosis in head and neck cancer. Previous studies have demonstrated that PKC sustains the proliferative signal by increasing cyclin E expression, leading to enhanced E2F target gene transcription and DNA synthesis. Here we show that PKC increases DNA synthesis through inhibition of the microRNA, miR-15a, upregulating translation of its target cyclin E. Importantly, gene expression and qRT-PCR analysis of primary squamous cell carcinoma tumors of the head and neck (SCCHN) reveals a significant negative correlation between PKC alpha and miR-15a levels. In contrast to normal cell cycle initiation, PKC decreases microRNA expression, leading first to increased cyclin E protein followed by enhanced transcription of cyclin E and other DNA synthesis mediators. These results identify a signaling network regulated by PKC whereby constitutive kinase activation switches the system to feed forward, overriding normal regulation of cell cycle progression through a post-transcriptional mechanism involving microRNAs. This reprogramming of the network is likely a more general phenomenon that can account for the oncogenic potency of established signaling pathways. Keywords: miRNA; dose response; cancer 6 treated samples across two time points hybridized to paired time 0, untreated controls