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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 12

TGFB1 mediates repression of miR-487b by CSC.

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TGFB1 mediates repression of miR-487b by CSC.
(A) qRT-PCR analysis demon...
(A) qRT-PCR analysis demonstrating that CSC enhances TGFB1 expression in SAECs and Calu-6 and H841 cells. (B) qRT-PCR analysis demonstrating that knockdown of TGFB1 markedly increases miR-487b expression and abrogates CSC-mediated repression of miR-487b in SAECs and to a lesser extent in Calu-6 and H841 cells. Knockdown of TGFB1 had no effect on miR-665 expression in these cells. (C) qRT-PCR analysis demonstrating dose-dependent decreases in miR-487b (but not miR-665) in SAECs and Calu-6 and H841 cells following 48-hour exposure to recombinant TGFB1. *P < 0.05; **P < 0.01. (D) MeDIP analysis demonstrating that knockdown of TGFB1 markedly decreases DNA methylation levels in untreated SAECs and Calu-6 cells and diminishes CSC-mediated increases in DNA methylation around the miR-487b genomic locus in these cells.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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