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。转化生长因子-β是一种多效性细胞因子，在维持上皮细胞动态平衡中起核心作用。在早期癌变过程中，转化生长因子-β通过抑制细胞增殖发挥肿瘤抑制作用。然而，在晚期，一些研究表明，原代肿瘤细胞可以通过调节或突变失活转化生长因子-β信号通路的各个组成部分，以及通过与其他致癌途径的交叉作用来重新编程对转化生长因子-β的反应。我们已经发现，Smad6基因的敲除通过细胞周期停滞和诱导肺癌细胞的凋亡来抑制细胞的存活和增殖，但不能抑制正常的支气管上皮细胞。我们检测了基因表达的变化，并观察到Smad6的敲除导致了转化生长因子-β信号的激活。我们的结果表明，SMAD6通过抑制肺癌细胞中的转化生长因子-β信号通路，在支持细胞生长和存活方面发挥关键作用。靶向失活SMAD6基因可为表达该基因的肺癌提供一种新的治疗策略。在我们的体内研究中，我们产生了携带PGP9.5基因的转基因小鼠，这种基因在肺癌中经常过度表达。我们正在与细胞和癌症生物学分部的Ilona LInnoila博士合作，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。利诺伊拉博士实验室的初步发现表明，肺上皮过表达PGP9.5的转基因动物会导致EMU诱导的肺癌发生。

We have continued our efforts to develop in vivo and in vitro models to better understand the mechanistic role of genes that are highly differentially expressed in lung cancers. TGF-beta is a pleiotropic cytokine that plays a central role in maintaining epithelial homeostasis. In early carcinogenesis, TGF-beta acts as a tumor suppressor by inhibiting cell proliferation. However, in the late stage, several studies showed that primary tumor cells could reprogram their response to TGF-beta by dysregulation or mutational inactivation of various components of the TGF-beta signaling pathway and through cross-interaction with other oncogenic pathways. We have shown knockdown of SMAD6 inhibited cell viability and proliferation through cell cycle arrest and induction of apoptosis in lung cancer cells, but not normal bronchial epithelial cells. We examined the gene expression changes and observed that knockdown of SMAD6 led to activation of TGF-beta signaling. Our results show that SMAD6 plays a critical role in supporting cell growth and survival by inhibiting the TGF-beta signaling pathway in lung cancer cells. Targeted inactivation of SMAD6 could provide a novel therapeutic strategy for lung cancers expressing this gene. In our in vivo study, we have generated transgenic mice carrying a gene, PGP9.5, which is frequently overexpressed in lung cancers. We are collaborating with Dr. Ilona Linnoila (Cell and Cancer Biology Branch, CCR) to examine these transgenic animals for transgene expression as well as potential lung carcinogenesis and interactions with other lung tumor animal models. Preliminary findings from Dr. Linnoila's laboratory have shown that transgenic animals with PGP9.5 overexpression in lung epithelium led to EMU-induced lung carcinogenesis.