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Cigarette smoke mediates epigenetic repression of miR-487b during pulmonary carcinogenesis
Sichuan Xi, … , Leandro Mercedes, David S. Schrump
Sichuan Xi, … , Leandro Mercedes, David S. Schrump
Published February 15, 2013
Citation Information: J Clin Invest. 2013;123(3):1241-1261. https://doi.org/10.1172/JCI61271.
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Research Article Oncology Article has an altmetric score of 22

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

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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

Sichuan Xi, Hong Xu, Jigui Shan, Yongguang Tao, Julie A. Hong, Suzanne Inchauste, Mary Zhang, Tricia F. Kunst, Leandro Mercedes, David S. Schrump

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Figure 11

CSC-induced chromatin remodeling coincides with miR-487b transcription.

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CSC-induced chromatin remodeling coincides with miR-487b transcription.
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(A) Sketch diagram for MNase protection assay. (B) Results of MNase protection assays depicting 2 upstream NFR (+50 to +350 bp and +650 to +900 bp) of miR-487b in control SAECs and 1 NFR (+50 to +350) in untreated Calu-6 cells. CSC induced de novo nucleosome occupancy of these regions. (C) Quantitative ChIP analysis depicting H2AZ levels in the first NFR of miR-487b. DAC partially attenuated CSC-mediated decreases in H2AZ levels. See text for details. (D and E) qRT-PCR analysis demonstrating that CSC induces TCF1 expression in SAECs and Calu-6 and H841 cells (D); knockdown of TCF1 inhibits basal expression of miR-487b in SAECs and Calu-6 and H841 cells and augments CSC-mediated repression of miR-487b in these cells (E). (F) Quantitative ChIP analysis demonstrating decreased occupancy of TCF1 in the first NFR of miR-487b in SAECs and Calu-6 and H841 cells following CSC exposure. DAC increased TCF1 levels in this NFR in Calu-6 and H841 cells and attenuated CSC-mediated decreases in TCF1 occupancy in this NFR in SAECs and Calu-6 and H841 cells. *P < 0.05; **P < 0.01. (G, H) Quantitative ChIP analysis demonstrating significantly lower levels of H2AZ (G) and TCF1 (H) in the first NFR of miR-487b in human lung cancers relative to paired normal lung tissues. H2AZ and TCF1 enrichment levels were lower in lung cancers from active/former smokers compared with those from never smokers. N vs. T for each patient: P < 0.01; never smoker vs. smoker for both N and T: P < 0.05.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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