Mechanisms of gene expression changes in lung cancer

我们继续努力开发体内和体外模型，以更好地了解肺癌中高度差异表达的基因的机制作用。我们已经产生了携带PGP9.5基因的转基因小鼠，这种基因在肺癌中经常过度表达。我们正在与伊洛娜·利诺伊拉博士的实验室合作，检查这些转基因动物的转基因表达以及潜在的肿瘤形成、寿命变化，并将它们与其他肺癌动物模型进行繁殖。我们已经鉴定了两种携带肺特异表达PGP9.5基因的创始动物。这些动物现在是为利诺伊拉博士的实验室培育的，旨在研究肺上皮细胞中PGP9.5的过度表达在EMU诱导的肺癌发生中的作用。我们的第二项研究涉及对SMAD6蛋白的功能分析，该蛋白经常显示在肺癌中表达减少。通过免疫组织化学分析，我们发现SMAD6在肺癌中的表达与腺癌肿瘤复发率的增加有关。我们认为这是由于转化生长因子-β/骨形态发生蛋白对Smad6表达的抑制。我们正在使用siRNA方法来确定SMAD6失活是否会导致细胞生长减少。我们还使用建模系统来确定SMAD6的存在是否有助于肿瘤的发生。

We have continued our efforts to develop in vivo and in vitro models to better understand the mechanistic role of genes highly differentially expressed in lung cancers. We have generated transgenic mice carrying a gene, PGP9.5, which is often over expressed in lung cancers. We are collaborating with Dr. Ilona Linnoila's laboratory to examine these transgenic animals for transgene expression as well as potential tumor formation, life span changes, and to breed them with other lung cancer animal models. We have identified two founder animals that carry lung specific expression of the PGP9.5 gene. These animals are now being bred for Dr. Linnoila's laboratory as an collaboration to address the role of PGP9.5 over expression in lung epithelium to EMU induced lung carcinogenesis. Our second line of study involving functional analysis of SMAD6 protein that often shows reduced expression in lung cancers. Using immunohistochemical analysis we showed that SMAD6 expression in lung tumors is associated with an increased rate of tumor recurrence in adenocarcinomas. We propose that this is due to reduction if negative growth signaling by TGF-beta/BMP upon SMAD6 expression. We are using siRNA approach to determine if SMAD6 inactivation would lead to reduction in cell growth. We are also using modeling systems to determine if the presence of SMAD6 contribute to tumor genesis.