Use of HOXC6 Gene to Develop Novel Lung Chemopreventives

描述（由申请人提供）： 肺癌是癌症相关死亡的主要原因，超过了接下来的四种主要癌症的总和，同时保持了几乎相当的发病率。吸烟占所有肺癌的近90%，但只有一小部分吸烟者患肺癌。HOX基因长期以来被认为是胚胎发育的“主调节器”。HOXC 6在胚胎形成过程中在肺中表达，并在成人肺中转录静止，这种状态可能通过主动抑制机制维持。在肿瘤发生过程中，HOXC 6是最常被重新激活和高度转录的HOX基因之一。与邻近正常组织相比，HOXC 6蛋白的显著上调发生在75%的肺鳞状细胞癌和腺癌中。HOX基因，包括HOXC 6，也被认为是类维生素A信号传导、ras诱导的致癌作用和c-Neu诱导的乳腺癌发生的介质。我们推测HOXC 6通过调节细胞生长和形态发生在肺癌发生中起重要作用。这一假设将由SAI检验：以确定肺的化学致癌物是否激活HOXC 6表达。将使用小鼠原代气管和肺上皮细胞测试候选化学致癌物在体外激活HOXC 6表达的能力。SA 2：确定HOXC 6是否调节肺的化学致癌作用。将使用SAI中优化的条件在野生型、HOX 6无效和HOXC 6过表达原代细胞中比较细胞转化表型。本研究的主要目的是：1）阐明HOXC 6和其他HOX基因在肺癌发生中的功能意义; 2）了解化学致癌的分子机制; 3）验证HOXC 6可以作为替代物来鉴定新的化学预防剂（SA 2系统）。这些研究的应用可能包括早期检测和患者分层的诊断和新的HOX相关的化学预防剂的发展。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer-related deaths, surpassing the sum total of the next 4 leading cancers while maintaining almost a comparable incidence rate. Cigarette smoking accounts for nearly 90% of all lung cancers, yet only a fraction of smokers develop lung cancer. HOX genes have long been known to act as "master regulators" of embryonic patterning. HOXC6 is expressed in the lung during embryonic patterning and becomes transcriptionally quiescent in the adult lung, a state that is likely to be maintained via a mechanism of active repression. During carcinogenesis, HOXC6 is among the most often reactivated and highly transcribed HOX genes. Dramatic upregulation of HOXC6 protein occurs in 75% of lung squamous cell carcinomas and adenocarcinomas compared to adjacent normal tissues. HOX genes, including HOXC6, also have been implicated as mediators of retinoid signaling, ras-induced carcinogenesis and c-Neu-induced breast carcinogenesis. We hypothesize that HOXC6 plays an important role in lung carcinogenesis via modulation of cellular growth and morphogenesis. This hypothesis will be tested by SAI: To determine if chemical carcinogens of the lung activate HOXC6 expression. Candidate chemical carcinogens will be tested for their ability to activate HOXC6 expression in vitro using mouse primary tracheal and lung epithelial cells. SA2: To determine if HOXC6 modulates chemical carcinogenesis of the lung. Cellular transformation phenotypes will be compared in wild type, HOX6 null, and HOXC6 overexpressor primary cells using conditions optimized in SAI. The main goals of this study are to 1) elucidate the functional significance of HOXC6 and other HOX genes in lung carcinogenesis, 2) understand the molecular mechanisms of chemical carcinogenesis in the lung and 3) validate that HOXC6 can be used as a surrogate to identify novel chemopreventive agents (SA2 system). Applications of these studies may include the development of diagnostics for early detection and patient stratification and novel HOX-associated chemopreventive agents.