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基因PGP9.5的转基因小鼠，该基因在肺癌中经常过度表达。我们正在与Ilona Linnoila博士的实验室合作，研究这些转基因动物的转基因表达以及潜在的肺癌发生和与其他肺肿瘤动物模型的相互作用。迄今为止，我们已经鉴定出携带肺特异性表达PGP9.5基因的创始动物。这些动物现在正在为Linnoila博士的实验室繁殖，作为一项合作，以解决肺上皮中PGP9.5过度表达对EMU诱导的肺癌发生的作用。我们的第二线研究涉及SMAD 6蛋白在肺癌进展中的作用的功能分析。使用免疫组化分析，我们发现SMAD 6在肺肿瘤中的表达与腺癌中肿瘤复发的增加相关。我们认为这是由于SMAD 6表达后TGF-β/BMP的负生长信号减少所致。我们已经使用siRNA方法来显示SMAD 6的下调导致肺肿瘤细胞中细胞生长减少，但不会最小程度地转化正常肺上皮细胞。提示SMAD 6可能作为肺癌治疗的靶点。

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 frequently 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 lung carcinogenesis and interactions with other lung tumor animal models. To date, we have identified a founder animal that carries 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 for its role in lung cancers progression. Using immunohistochemical analysis we showed that SMAD6 expression in lung tumors is associated with an increase in tumor recurrence in adenocarcinomas. We propose that this is due to reduction if negative growth signaling by TGF-beta/BMP upon SMAD6 expression. We have used siRNA approach to show that down regulation of SMAD6 lead to reduced cell growth in lung tumor cells but not minimally tranformed normal lung epithelial cells. This result suggeststs that SMAD6 might be used as a therapeutic target got lung cancer.