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Mol Cancer Res. 2014 May;12(5):765-74. doi: 10.1158/1541-7786.MCR-13-0377. Epub 2014 Jan 27.

PGE2-driven expression of c-Myc and oncomiR-17-92 contributes to apoptosis resistance in NSCLC.

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Authors' Affiliations: Departments of Medicine, 2Pathology and Laboratory Medicine, 3Molecular and Medical Pharmacology, 4Anesthesiology, and 5Medicine Statistics Core, David Geffen School of Medicine, University of California, Los Angeles; 6UCLA Jonsson Comprehensive Cancer Center; 7West Los Angeles VA Healthcare System, Los Angeles; 8City of Hope Comprehensive Cancer Center, Duarte, California; and 9Boston University, Boston, Massachusetts.


Aberrant expression of microRNAs (miRNA) with oncogenic capacities (oncomiRs) has been described for several different malignancies. The first identified oncomiR, miR-17-92, is frequently overexpressed in a variety of cancers and its targets include the tumor suppressor PTEN. The transcription factor c-Myc (MYC) plays a central role in proliferative control and is rapidly upregulated upon mitogenic stimulation. Expression of c-Myc is frequently deregulated in tumors, facilitating proliferation and inhibiting terminal differentiation. The c-Myc-regulated network comprises a large number of transcripts, including those encoding miRNAs. Here, prostaglandin E2 (PGE2) exposure rapidly upregulates the expression of the MYC gene followed by the elevation of miR-17-92 levels, which in turn suppresses PTEN expression, thus enhancing apoptosis resistance in non-small cell lung cancer (NSCLC) cells. Knockdown of MYC expression or the miR-17-92 cluster effectively reverses this outcome. Similarly, miR-17-92 levels are significantly elevated in NSCLC cells ectopically expressing COX-2. Importantly, circulating miR-17-92 was elevated in the blood of patients with lung cancer as compared with subjects at risk for developing lung cancer. Furthermore, in patients treated with celecoxib, miR-17-92 levels were significantly reduced. These data demonstrate that PGE2, abundantly produced by NSCLC and inflammatory cells in the tumor microenvironment, is able to stimulate cell proliferation and promote resistance to pharmacologically induced apoptosis in a c-Myc and miR-17-92-dependent manner.


This study describes a novel mechanism, involving c-Myc and miR-17-92, which integrates cell proliferation and apoptosis resistance.

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