Cigarette smoke mediates epigenetic repression of miR-487b during pulmonary carcinogenesis
Cigarette smoke mediates epigenetic repression of miR-487b during pulmonary carcinogenesis
复制标题
香烟烟雾介导肺癌发生过程中 miR-487b 的表观遗传抑制
DOI：
10.1172/jci61271
复制
发表时间：
2013-03-01
影响因子：
15.9
通讯作者：
Schrump, David S.
中科院分区：
文献类型：
--
作者：
Xi, Sichuan;Xu, Hong;Schrump, David S.
microRNA是干细胞多能性、分化和恶性肿瘤的关键介质。关于促进人类肺癌发生和发展的microRNA改变的信息有限。在这项研究中，阵列技术被用来评估microRNA表达在正常人呼吸道上皮细胞和肺癌细胞培养的香烟烟雾冷凝物（CSC）的存在或不存在。在相关暴露条件下，CSC显著抑制miR-487 b。随后的实验表明，miR-487 b直接靶向SUZ 12、BMI 1、WNT 5A、MYC和KRAS。miR-487 b的抑制与原发性肺癌中这些靶点的过表达相关，并与DNA甲基化、从头核小体占据以及miR-487 b基因组位点内H2 AZ和TCF 1水平降低相一致。脱氧氮杂胞苷去阻遏miR-487 b并减弱CSC介导的miR-487 b沉默。miR-487 b的组成型表达消除了Wnt信号传导，抑制了CSC或miR-487 b靶点过表达介导的肺癌细胞的体外增殖和侵袭，并降低了肺癌细胞在体内的生长和转移潜力。总的来说，这些发现表明，miR-487 b是一种肿瘤抑制microRNA在烟草诱导的肺癌发生过程中被表观遗传机制沉默，并表明DNA去甲基化剂可能有助于激活miR-487 b用于肺癌治疗。
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. Deoxyazacytidine 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.