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Cancer Prev Res (Phila). 2014 Aug;7(8):845-55. doi: 10.1158/1940-6207.CAPR-14-0063. Epub 2014 Jun 9.

Loss of miR125a expression in a model of K-ras-dependent pulmonary premalignancy.

Author information

1
Division of Pulmonary and Critical Care Medicine, Department of Medicine; Departments of Jonsson Comprehensive Cancer Center;
2
Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA;
3
Departments of Medicine and Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas.
4
Division of Pulmonary and Critical Care Medicine, Department of Medicine; Departments of Pathology and Laboratory Medicine and Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA; Jonsson Comprehensive Cancer Center; VA Greater Los Angeles Health Care Center, Los Angeles, California; and sdubinett@mednet.ucla.edu.

Abstract

Understanding the molecular pathogenesis of lung cancer is necessary to identify biomarkers/targets specific to individual airway molecular profiles and to identify options for targeted chemoprevention. Herein, we identify mechanisms by which loss of microRNA (miRNA)125a-3p (miR125a) contributes to the malignant potential of human bronchial epithelial cells (HBEC) harboring an activating point mutation of the K-ras proto-oncogene (HBEC K-ras). Among other miRNAs, we identified significant miR125a loss in HBEC K-ras lines and determined that miR125a is regulated by the PEA3 transcription factor. PEA3 is upregulated in HBEC K-ras cells, and genetic knockdown of PEA3 restores miR125a expression. From a panel of inflammatory/angiogenic factors, we identified increased CXCL1 and vascular endothelial growth factor (VEGF) production by HBEC K-ras cells and determined that miR125a overexpression significantly reduces K-ras-mediated production of these tumorigenic factors. miR125a overexpression also abrogates increased proliferation of HBEC K-ras cells and suppresses anchorage-independent growth (AIG) of HBEC K-ras/P53 cells, the latter of which is CXCL1-dependent. Finally, pioglitazone increases levels of miR125a in HBEC K-ras cells via PEA3 downregulation. In addition, pioglitazone and miR125a overexpression elicit similar phenotypic responses, including suppression of both proliferation and VEGF production. Our findings implicate miR125a loss in lung carcinogenesis and lay the groundwork for future studies to determine whether miR125a is a possible biomarker for lung carcinogenesis and/or a chemoprevention target. Moreover, our studies illustrate that pharmacologic augmentation of miR125a in K-ras-mutated pulmonary epithelium effectively abrogates several deleterious downstream events associated with the mutation.

PMID:
24913817
PMCID:
PMC4125465
DOI:
10.1158/1940-6207.CAPR-14-0063
[Indexed for MEDLINE]
Free PMC Article

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