Targeting TGF-beta Signaling in Lung Cancer

人类的肺癌发生涉及遗传和表观遗传变化的积累， 正常肺上皮、原位癌以及最后的侵袭性和转移性癌症的改变。的 肿瘤中TGF-β 1诱导的肿瘤抑制功能的丧失被认为在这一过程中起关键作用。 过渡肺癌中对TGF-β 1的抗性主要通过TGF-β 1 II型受体的丧失而发生 我们的初步数据表明，在77%的人中，TliRII的表达缺失或减弱， 人类肺癌然而，目前尚不清楚TURN表达在肺肿瘤发生过程中如何丢失。 我们最初的实验已经得出了一个重要的观察结果，即MAPK/ERK通路的激活 通过组蛋白去乙酰化导致TfiRII下调，而DMA超甲基化对TfiRII的表达没有影响。 对TfiRII启动子活性的影响。此外，我们还观察到TGF-β 1诱导的肿瘤抑制因子 在TGF-11抗性肺癌细胞中通过外源性TfiRII表达或用TGF-11抗性肺癌细胞中的TfiRII表达恢复功能。 组蛋白脱乙酰酶（HDAC）抑制剂（HDI）治疗。由于大多数肺肿瘤对 由于TliRII的损失，我们认为TGF-f1途径可能是HDIs的潜在靶点， 化疗干预我们提出了以下假设：1）TfiRII表达缺失 在肺癌中主要是由于表观遗传变化，组蛋白脱乙酰化，并促进 对TGF-β 1诱导的肿瘤抑制作用无反应。2)在癌前阶段， TGF-β 1的自分泌抗增殖作用占主导地位。然而，在肿瘤发生期间， 随着肿瘤的进展，TGF-β 1的促生长作用在晚期变得明显。第三章 通过HDI，MS-275，一种目前在临床试验中的抗癌药物，恢复TGF-β信号传导，可能是一种新的治疗方法。 肺癌治疗干预的潜在替代方案。这些假设将由 具体目的如下：1）确定肺组织中TfiRII下调的分子机制 以及HDAC抑制剂如何靶向癌症。2)为了确定 在人肺癌细胞系中TGF-f1的过表达和TGF-f1信号传导的恢复。长 本研究的长期目标是在分子水平上确定肺肿瘤 变得对TGF-β肿瘤抑制功能具有抗性，并通过以下方式提供对该机制的新见解： 哪些HDIs靶向肺癌中的TGF-β通路。加深对这些机制的了解 应该有助于改善药物开发和肺癌治疗。

Lung carcinogenesis in humans involves an accumulation of genetic and epigenetic changes that lead to alterations in normal lung epithelium, in situ carcinoma, and finally invasive and metastatic cancers. The loss of TGF-fi-induced tumor suppressor function in tumors is believed to play a pivotal role in this transition. Resistance to TGF-fi in lung cancers occurs mostly through loss of TGF-fi type II receptor (TliRII) expression, and our preliminary data suggest that expression of TliRII is lost or weak in 77% of human lung cancers. However, it is not known how TURN expression is lost during lung tumorigenesis. Our initial experiments have resulted in an important observation that activation of the MAPK/ERK pathway causes down-regulation of TfiRII through histone deacetylation and that DMA hypermethylation has no effect on TfiRII promoter activity. In addition, we have observed that TGF-li-induced tumor suppressor function is restored in TGF-li resistant lung cancer cells via exogenous TfiRII expression or with the treatment of histone deacetylase (HDAC) inhibitor (HDI). Since the majority of lung tumors are resistant to TGF-li due to loss of TliRII, we believe that the TGF-fi pathway could be a potential target of HDIs for chemothrapeutic intervention. We have formulated the following hypotheses: 1) Loss of TfiRII expression in lung cancer is mostly due to the epigenetic change, histone deacetylation, and promotes unresponsiveness to TGF-fi-induced tumor suppressor effects. 2) In the pre-malignant phase, the autocrine anti-proliferative effects of TGF-fi predominate. However, the balance shifts during tumor progression, and growth-promoting effects of TGF-fi become pronounced in the advanced stage. 3) Restoration of TGF-fi signaling by the HDI, MS-275, an anticancer drug currently in clinical trials, may be a potential alternative for therapeutic intervention of lung cancers. These hypotheses will be tested by the following specific aims: 1) To determine the molecular mechanism of down-regulation of TfiRII in lung cancer and how that can be targeted by HDAC inhibitors. 2) To determine the biological consequences of over-expression of TGF-fi and restoration of TGF-fi signaling in human lung cancer cell lines. The long term objective of this study is to determine, at the molecular level, the mechanism by which lung tumors become resistant to TGF-fi tumor suppressor function and to provide new insights into the mechanism by which HDIs target the TGF-fi pathway in lung cancer. Increased understanding of these mechanisms should help to improve drug development and treatment of lung cancer.