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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 7

Effects of miR-487b on growth and metastatic potential of lung cancer cells in vivo.

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Effects of miR-487b on growth and metastatic potential of lung cancer ce...
(A) Growth of Calu-6, H841, and H358 subcutaneous xenografts in nude mice. Volumes of xenografts derived from Calu-6, H841, or H358 cells overexpressing miR-487b were significantly smaller than control xenografts. (B) Tumor masses from Calu-6, H841, and H358 xenografts. miR-487b overexpression significantly decreased average mass of tumor xenografts. (C) Quantitation of macroscopic pulmonary nodules derived from Calu-6 or H358 cells stably expressing miR-487b or control vectors. (D) Quantitation of total microscopic pulmonary tumors following orthotopic injection of Calu-6 or H358 cells stably expressing miR-487b or control vectors. (E) Representative microscopic images (H&E staining) of intrapulmonary tumors from Calu-6 or H358 cells stably expressing miR-487b or control vectors. Expression of miR-487b decreased invasion of lung cancer cells in vivo. Scale bars: 50 mm. Original magnification, ×100. (F) Quantitation of ipsilateral and contralateral microscopic pulmonary tumors following orthotopic injection of Calu-6 or H358 cells stably expressing miR-487b or control vectors. *P < 0.05; **P < 0.01.

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

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