Bridging Inflammation and Cigarette Smoke-associated Lung Carcinogenesis by MUC1

描述(申请人提供)：肺癌是美国癌症相关死亡的主要原因。香烟烟雾(CS)是众所周知的肺癌风险。炎症显然已成为导致肺癌和其他癌症发展的关键过程。然而，影响癌症发展的炎症调控的基因靶点和途径还没有被清楚地阐明。这一应用建立在文献和我们团队的新兴研究基础上，这些研究表明MUC1在连接炎症和癌症发生中发挥着重要作用。这一应用的中心假设是CS引起的气道炎症诱导MUC1表达，从而通过增强EGFR介导的Akt和细胞外信号调节激酶(ERK)途径而触发肺癌的发生。这一假说将在三个具体目标上得到检验：1.确定促炎细胞因子是否为肿瘤坏死因子？2.通过增强表皮生长因子受体介导的Akt和ERK信号转导通路，研究MUc1是否促进了CS诱导的支气管上皮细胞转化；3.研究MUc1在CS诱导的苯并(A)芘(BaP)和4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK)诱导的A/J肺癌模型和裸鼠人肺癌移植瘤模型中的作用。这项研究的成功完成将可能揭示CS诱导的肺癌发生的新的分子机制，涉及MUC1，并将为炎症如何影响细胞转化和肿瘤的发展提供新的见解，并可能为肺癌的预防和介入治疗寻找新的靶点。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer-related death in the United States. Cigarette smoke (CS) is a well- known risk for lung cancer. Inflammation has clearly emerged as a key process contributing to the development of lung and other cancers. However, the gene targets and pathways modulated by inflammation that impact cancer development have not been clearly elucidated. This application builds on emerging studies from the literature and by our group that implicate an important role for MUC1 in linking inflammation and carcinogenesis. The central hypothesis of this application is that airway inflammation resulting from CS induces MUC1 expression, which triggers lung cancer development through potentiation of the EGFR- mediated Akt and extracellular signal-regulated kinases (ERK) pathways. This hypothesis will be tested in the three Specific Aims: 1. To determine if the pro-inflammatory cytokine TNF? mediates CS-induced MUC1 expression in bronchial epithelial cells and if MUC1 potentiates cell transformation; 2. To determine if MUC1 facilitates CS-induced bronchial epithelial cell transformation through potentiation of the EGFR-mediated Akt and ERK pathways; 3. To investigate the role of MUC1 in CS-induced lung carcinogenesis with CS-derived carcinogen benzo(a)pyrene (BaP)- and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced A/J lung cancer models and in a xenografted human lung tumor model in nude mice. Successful completion of this study will likely reveal a new molecular mechanism of CS-induced lung carcinogenesis that involves Muc1 and will provide new insights into how inflammation influences cell transformation and tumor development and could identify novel targets for prevention and intervention therapy for lung cancer.