Use of HOXC6 Gene to Develop Novel Lung Chemopreventives

描述(由申请人提供)： 肺癌是与癌症相关的死亡的主要原因，超过了紧随其后的4种主要癌症的总和，同时保持了几乎可比的发病率。吸烟占所有肺癌的近90%，但只有一小部分吸烟者患上肺癌。长期以来，HOX基因一直被认为是胚胎模式的“主要调节者”。HOXC6在胚胎模式形成期间在肺中表达，在成年肺中转录静止，这一状态可能通过主动抑制机制维持。在癌变过程中，HOXC6是最常被重新激活和高度转录的HOX基因之一。与邻近的正常组织相比，75%的肺鳞癌和腺癌中HOXC6蛋白表达显著上调。HOX基因，包括HOXC6，也被认为是维甲酸信号、ras诱导的癌变和c-Neu诱导的乳腺癌的媒介。我们推测HOXC6通过调节细胞生长和形态发生在肺癌发生中发挥重要作用。这一假设将由SAI进行验证：以确定肺部的化学致癌物是否会激活HOXC6的表达。候选化学致癌物将在体外使用小鼠原代气管和肺上皮细胞来测试它们激活HOXC6表达的能力。SA2：确定HOXC6是否调节肺的化学致癌作用。使用SAI中优化的条件，对野生型、HOX6缺失和HOXC6过表达的原代细胞的细胞转化表型进行比较。本研究的主要目的是：1)阐明HOXC6和其他HOX基因在肺癌发生中的功能意义；2)了解肺内化学致癌的分子机制；3)验证HOXC6可以作为新的化学预防药物(SA2系统)的替代物。这些研究的应用可能包括开发用于早期发现和患者分层的诊断学，以及新型HOX相关化学预防药物。

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.