title: Cigarette smoke mediates epigenetic repression of miR-487b during pulmonary carcinogenesis.
abstract: MicroRNAs are critical mediators of stem cell pluripotency, differentiation, and malignancy. Limited information exists regarding microRNA alterations that facilitate initiation and progression of human lung cancers. In this study, array techniques were used to evaluate microRNA expression in normal human respiratory epithelia and lung cancer cells cultured in the presence or absence of cigarette smoke condensate (CSC). Under relevant exposure conditions, CSC significantly repressed miR-487b. Subsequent experiments demonstrated that miR-487b directly targeted SUZ12, BMI1, WNT5A, MYC, and KRAS. Repression of miR-487b correlated with overexpression of these targets in primary lung cancers and coincided with DNA methylation, de novo nucleosome occupancy, and decreased H2AZ and TCF1 levels within the miR-487b genomic locus. Deoxy-azacytidine derepressed miR-487b and attenuated CSC-mediated silencing of miR-487b. Constitutive expression of miR-487b abrogated Wnt signaling, inhibited in vitro proliferation and invasion of lung cancer cells mediated by CSC or overexpression of miR-487b targets, and decreased growth and metastatic potential of lung cancer cells in vivo. Collectively, these findings indicate that miR-487b is a tumor suppressor microRNA silenced by epigenetic mechanisms during tobacco-induced pulmonary carcinogenesis and suggest that DNA demethylating agents may be useful for activating miR-487b for lung cancer therapy.
authors: Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors: Sichuan
authors: S
authors: Xi
authors: Hong
authors: H
authors: Xu
authors: Jigui
authors: J
authors: Shan
authors: Yongguang
authors: Y
authors: Tao
authors: Julie A
authors: JA
authors: Hong
authors: Suzanne
authors: S
authors: Inchauste
authors: Mary
authors: M
authors: Zhang
authors: Tricia F
authors: TF
authors: Kunst
authors: Leandro
authors: L
authors: Mercedes
authors: David S
authors: DS
authors: Schrump
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D016922:Cellular Senescence; D042002:Chromatin Assembly and Disassembly; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000378:metabolism / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009363:Neoplasm Proteins; D009368:Neoplasm Transplantation; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D034622:RNA Interference; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D000071818:Wnt-5a Protein; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C069077:BMI1 protein, human; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D006657:Histones; C117307:KRAS protein, human; C568526:MIRN487 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; C430461:SUZ12 protein, human; D012906:Smoke; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C077020:histone H2A.F-Z; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins