The Epigenetic Mechanism of Arsenic Lung Carcinogenesis - Role of MicroRNAs

描述(申请人提供)：饮用水中的砷污染会导致皮肤癌、肺癌和膀胱癌。然而，AS致癌的机制尚不清楚。这项研究的长期目标是确定砷致癌的机制，并确定治疗和预防由砷暴露引起的癌症的分子靶点。越来越多的证据表明，microRNAs(MiRNAs)在癌症进展中起着关键作用。然而，目前还没有确定miRNAs是否在化学致癌中起因果作用。我们的初步研究表明，AS治疗导致miR-200b和200C耗尽，并诱导人正常支气管上皮细胞转化，其中P53表达下调。重新表达miR-200b或200C可显著逆转转化表型。我们推测，p53的缺失和miR-200b和/或200C的下调参与了砷肺癌的发生。为了检验这一假说，本文提出了三个具体目标。具体目的1：探讨miR-200b/200C及其靶基因ZEB1和ZEB2在砷诱导的细胞转化和肿瘤发生中的作用。我们推测miR-200b/200C的异位表达或ZEB1/ZEB2的缺失抑制了AS的细胞转化。特异性目的2：探讨ZEB1/ZEB2杂合基因敲除小鼠对AS肺癌发生是否具有抵抗力或敏感性。我们假设ZEB1/ZEB2杂合基因敲除小鼠对AS肺癌发生具有抵抗力或不那么敏感。具体目的3：确定AS引起ZEB1和ZEB2表达的机制。根据我们的初步发现，我们假设转化生长因子-β信号在砷暴露诱导ZEB1/ZEB2表达中起关键作用。我们将研究Smad介导的和非Smad的转化生长因子-β信号在AS诱导的ZEB1和ZEB2表达中的作用。 与公众健康相关：砷(As)是最常见的环境污染物之一，通过饮用水接触砷是一个主要的环境健康问题，影响到美国和许多其他国家的数百万人。这项研究的目的是确定砷暴露致癌的机制，并确定治疗和预防由砷暴露引起的癌症的分子靶点。

DESCRIPTION (provided by applicant): Arsenic (As) contamination through drinking water causes skin, lung and bladder cancers. However, the mechanism by which As causes cancers has not been elucidated. The long-term goal of this study is to determine the mechanism of As carcinogenesis and identify molecular targets for the treatment and prevention of cancers resulting from As exposure. Accumulating evidence suggests a critical role of microRNAs (miRNAs) in cancer progression. Nevertheless, it has not been determined whether miRNAs causally contribute to chemical carcinogenesis. Our preliminary studies demonstrated that As treatment caused depletion of miR-200b and 200c and induced transformation of human normal bronchial epithelial cells in which p53 expression was knocked down. Re- expressing miR-200b or 200c significantly and greatly reversed transformed phenotypes. We hypothesize that loss of p53 and down-regulation of miR-200b and/or 200c contribute to arsenic lung carcinogenesis. Three specific aims are proposed to test this hypothesis. Specific Aim 1: To determine the roles of miR-200b/200c and their target genes ZEB1 and ZEB2 in As-induced cell transformation and tumorigenesis. We hypothesize that ectopic expression of miR-200b/200c or depletion of ZEB1/ZEB2 inhibits cell transformation by As. Specific Aim 2: To investigate whether whether the ZEB1/ZEB2 heterozygous knockout mice are resistant or less sensitive to As lung carcinogenesis. We hypothesize that ZEB1/ZEB2 heterozygous knockout mice will be resistant or less sensitive to As lung carcinogenesis. Specific Aim 3: To determine the mechanism by which As causes ZEB1 and ZEB2 expression. Based on our preliminary findings, we hypothesize that TGF-beta signaling plays a critical role in the induction of ZEB1/ZEB2 expression by As exposure. We will investigate the role of Smad-mediated and non-Smad TGF-beta signaling in As-induced expression of ZEB1 and ZEB2. PUBLIC HEALTH RELEVANCE: Arsenic (As) is one of the most common environmental pollutants and exposure to As through drinking water is a major environmental health concern, affectsing millions of people in the United States and many other countries. The goal of this study is to determine the mechanism by which As exposure causes cancers and identify molecular targets for the treatment and prevention of cancers resulting from As exposure.