Cigarette smoke mediates epigenetic repression of miR-487b during pulmonary carcinogenesis

J Clin Invest. 2013 Mar;123(3):1241-61. doi: 10.1172/JCI61271. Epub 2013 Feb 15.

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / etiology
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / secondary
  • Animals
  • Base Sequence
  • Binding Sites
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cellular Senescence
  • Chromatin Assembly and Disassembly
  • CpG Islands
  • DNA Methylation
  • Epigenesis, Genetic
  • Female
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • Hepatocyte Nuclear Factor 1-alpha / physiology
  • Histones / metabolism
  • Humans
  • Lung Neoplasms / etiology
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mice, Nude
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Middle Aged
  • Neoplasm Transplantation
  • Polycomb Repressive Complex 1 / genetics
  • Polycomb Repressive Complex 1 / metabolism
  • Polycomb Repressive Complex 2 / genetics
  • Polycomb Repressive Complex 2 / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Proto-Oncogene Proteins p21(ras)
  • RNA Interference*
  • Smoke / adverse effects*
  • Smoking / adverse effects
  • Tobacco / chemistry
  • Transforming Growth Factor beta1 / physiology
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism
  • Wnt-5a Protein
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • BMI1 protein, human
  • HNF1A protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • Histones
  • KRAS protein, human
  • MIRN487 microRNA, human
  • MYC protein, human
  • MicroRNAs
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-myc
  • SUZ12 protein, human
  • Smoke
  • Transforming Growth Factor beta1
  • WNT5A protein, human
  • Wnt Proteins
  • Wnt-5a Protein
  • histone H2A.F-Z
  • Polycomb Repressive Complex 2
  • Polycomb Repressive Complex 1
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins