title: Loss of miR125a expression in a model of K-ras-dependent pulmonary premalignancy.
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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine; Departments of Jonsson Comprehensive Cancer Center;
authors.forename: Elvira L
authors.initials: EL
authors.lastname: Liclican
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine; Departments of Jonsson Comprehensive Cancer Center;
authors.forename: Tonya C
authors.initials: TC
authors.lastname: Walser
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine; Departments of Jonsson Comprehensive Cancer Center;
authors.forename: Saswati
authors.initials: S
authors.lastname: Hazra
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine; Departments of Jonsson Comprehensive Cancer Center;
authors.forename: Kostyantyn
authors.initials: K
authors.lastname: Krysan
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine; Departments of Jonsson Comprehensive Cancer Center;
authors.forename: Stacy J
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA;
authors.forename: Paul C
authors.initials: PC
authors.lastname: Pagano
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine; Departments of Jonsson Comprehensive Cancer Center;
authors.forename: Brian K
authors.initials: BK
authors.lastname: Gardner
authors.affiliation: Departments of Medicine and Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Jill E
authors.initials: JE
authors.lastname: Larsen
authors.affiliation: Departments of Medicine and Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.affiliation: 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.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dubinett
mesh_terms: D001980:Bronchi / Q000166:cytology; D002460:Cell Line; D049109:Cell Proliferation; D054360:Chemokine CXCL1 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004848:Epithelium / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D009154:Mutation; D000077205:Pioglitazone; D017354:Point Mutation; D011230:Precancerous Conditions / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D045162:Thiazolidinediones / Q000737:chemistry; D014157:Transcription Factors / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; C000715470:MAS1 protein, human; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering; D045162:Thiazolidinediones; D014157:Transcription Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C065788:transcription factor PEA3; D018631:ras Proteins; D000077205:Pioglitazone