Transcriptomics

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


ABSTRACT: 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 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

ORGANISM(S): Homo sapiens  

SUBMITTER: Christine H. Chung  Christine H Chung   Joel S Parker    

PROVIDER: E-GEOD-10301 | ArrayExpress | 2010-10-08

SECONDARY ACCESSION(S): GSE10301PRJNA108517

REPOSITORIES: GEO, ArrayExpress

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Publications

A feed-forward loop involving protein kinase Calpha and microRNAs regulates tumor cell cycle.

Cohen Ezra E W EE   Zhu Hongyan H   Lingen Mark W MW   Martin Leslie E LE   Kuo Wen-Liang WL   Choi Eugene A EA   Kocherginsky Masha M   Parker Joel S JS   Chung Christine H CH   Rosner Marsha Rich MR  

Cancer research 20090101 1


Protein kinase Calpha (PKCalpha) has been implicated in cancer, but the mechanism is largely unknown. Here, we show that PKCalpha promotes head and neck squamous cell carcinoma (SCCHN) by a feed-forward network leading to cell cycle deregulation. PKCalpha inhibitors decrease proliferation in SCCHN cell lines and xenografted tumors. PKCalpha inhibition or depletion in tumor cells decreases DNA synthesis by suppressing extracellular signal-regulated kinase phosphorylation and cyclin E synthesis. A  ...[more]

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