The Epigenetic Mechanism of Arsenic Lung Carcinogenesis - Role of MicroRNAs

描述（由申请人提供）：饮用水中的砷（As）污染会导致皮肤癌、肺癌和膀胱癌。然而，As引起癌症的机制尚未阐明。本研究的长期目标是确定As致癌的机制，并确定治疗和预防As暴露导致的癌症的分子靶点。 越来越多的证据表明microRNA（miRNAs）在癌症进展中的关键作用。然而，尚未确定miRNAs是否因果地促成化学致癌作用。我们的初步研究表明，As处理引起miR-200 b和200 c的耗竭，并诱导人正常支气管上皮细胞转化，其中p53表达被敲低。再表达miR-200 b或200 c显著且极大地逆转了转化的表型。我们推测p53的缺失和miR-200 b和/或200 c的下调有助于砷肺癌的发生。提出了三个具体目标来检验这一假设。具体目的1：探讨miR-200 b/200 c及其靶基因ZEB 1和ZEB 2在砷诱导的细胞转化和肿瘤发生中的作用。我们推测miR-200 b/200 c的异位表达或ZEB 1/ZEB 2的缺失抑制了As引起的细胞转化。具体目的2：研究ZEB 1/ZEB 2杂合子基因敲除小鼠对砷的肺癌发生是否具有抵抗或低敏感性。我们推测，ZEB 1/ZEB 2杂合子基因敲除小鼠将耐药或敏感性较低的肺癌。具体目标3：确定As引起ZEB 1和ZEB 2表达的机制。基于我们的初步研究结果，我们假设TGF-β信号在As暴露诱导ZEB 1/ZEB 2表达中起着关键作用。我们将研究Smad介导的和非SmadTGF-β信号在As诱导的ZEB 1和ZEB 2表达中的作用。 公共卫生相关性：砷（As）是最常见的环境污染物之一，通过饮用水暴露于As是一个主要的环境健康问题，影响着美国和许多其他国家的数百万人。本研究的目的是确定的机制，其中作为曝光导致癌症和识别分子靶点的治疗和预防癌症的曝光所造成的。

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.