title: A feed-forward loop involving protein kinase Calpha and microRNAs regulates tumor cell cycle.
abstract: 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. Additionally, PKCalpha down-regulates miR-15a, a microRNA that directly inhibits protein synthesis of cyclin E, as well as other cell cycle regulators. Furthermore, both PKCalpha and cyclin E protein expression are increased in primary tumors, and PKCalpha inversely correlates with miR-15a expression in primary tumors. Finally, PKCalpha is associated with poor prognosis in SCCHN. These results identify PKCalpha 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.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ezra E W
authors.initials: EE
authors.lastname: Cohen
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhu
authors.forename: Mark W
authors.initials: MW
authors.lastname: Lingen
authors.forename: Leslie E
authors.initials: LE
authors.lastname: Martin
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Kuo
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Choi
authors.forename: Masha
authors.initials: M
authors.lastname: Kocherginsky
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.forename: Christine H
authors.initials: CH
authors.lastname: Chung
authors.forename: Marsha Rich
authors.initials: MR
authors.lastname: Rosner
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D048708:Cell Growth Processes / Q000502:physiology; D019927:Cyclin E / Q000096:biosynthesis; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005260:Female; D015870:Gene Expression; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009061:Mouth Mucosa / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018797:Cell Cycle Proteins; D019927:Cyclin E; D004273:DNA, Neoplasm; C505361:MIRN15 microRNA, human; D035683:MicroRNAs; D051571:Protein Kinase C-alpha