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

Abstract

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

Integrative Analysis of Head and Neck Cancer Identifies Two Biologically Distinct HPV and Three Non-HPV Subtypes

“…S1), an Illumina cohort (Yordy and colleagues; unpublished results), and two Affymetrix cohorts (9,11). These crossplatform datasets were used as the discovery set for the classification of HNSCC samples.…”

Link Protein N-terminal Peptide Binds to Bone Morphogenetic Protein (BMP) Type II Receptor and Drives Matrix Protein Expression in Rabbit Intervertebral Disc Cells

“…Through a cell-autonomous loop BMP-4 and BMP-7 engage BMP-RI to sustain or amplify Smad signal transduction, ultimately promoting expression of SOX9 and downstream aggrecan and collagen II genes. B, in a feedforward circuit A activates B, and A and B activate C (42). C, we propose that LPP initiates a feedforward circuit in which A is represented by BMP-RII, B by BMP-RI, and C by Smad1/5.…”

MicroRNA Dysregulation in Squamous Cell Carcinoma of Head and Neck

“…Expression of miR-15a was inversely correlated with protein kinase C which was usually overexpressed in primary HNSCC (Cohen et al, 2009). It has been shown that overexpression of miR-15a suppressed cyclin E protein expression and inhibition of miR-15a enhanced cyclin E protein expression in laryngeal cancer cell line.…”

“…It has been shown that overexpression of miR-15a suppressed cyclin E protein expression and inhibition of miR-15a enhanced cyclin E protein expression in laryngeal cancer cell line. Precursor miR-15a could also affect DNA synthesis in laryngeal carcinoma cells but the related mechanisms are not yet identified (Cohen et al, 2009). These results indicated that miR-15a might function as a tumor suppressor through regulating the gene associated with the proliferation pathways of cancer cells (Cohen et al, 2009).…”