Targeting TGF-beta Signaling in Lung Cancer

人类肺癌的发生涉及基因和表观遗传改变的积累，导致 正常肺上皮的改变，原位癌，最后是浸润性和转移性癌症。这个 肿瘤中转化生长因子-FI诱导的肿瘤抑制功能的丧失被认为在其中起着关键作用。 过渡。肺癌对转化生长因子-FI的抵抗主要是通过失去转化生长因子-FI型受体而发生的 (TliRII)表达，我们的初步数据表明，77%的人TliRII表达缺失或表达减弱 人类肺癌。然而，目前尚不清楚TURN在肺肿瘤发生过程中是如何丢失的。 我们的初步实验结果表明，MAPK/ERK通路的激活 通过组蛋白去乙酰化引起TfiRII的下调，而DMA高甲基化没有 对TfiRII启动子活性的影响。此外，我们还观察到转化生长因子-1诱导的肿瘤抑制因子 通过外源TfiRII的表达或通过TfiRII的表达恢复对转化生长因子敏感的肺癌细胞的功能 组蛋白脱乙酰酶(HDAC)抑制剂(HDI)的治疗。因为大多数肺部肿瘤对 由于TliRII的缺失，我们认为转化生长因子-FI途径可能成为人类免疫缺陷病毒的潜在靶点。 化疗干预。我们提出了以下假设：1)TfiRII表达缺失 在肺癌中大多是由于表观遗传学的改变，组蛋白去乙酰化，并促进 对转化生长因子-FI诱导的肿瘤抑制作用无反应。2)在癌前阶段， 转化生长因子-FI的自分泌抗增殖作用占优势。然而，在肿瘤过程中，平衡发生了变化。 在晚期，转化生长因子-FI的促进生长作用更加明显。3) 目前处于临床试验中的抗癌药物MS-275通过HDI恢复转化生长因子-FI信号，可能是一种 肺癌治疗干预的潜在替代方案。这些假设将由 目的：1)确定肺组织中TfiRII表达下调的分子机制 癌症以及如何通过HDAC抑制剂进行靶向治疗。2)确定生物后果 人肺癌细胞系中转化生长因子-FI的高表达及信号的恢复。《长河》 本研究的长期目标是在分子水平上确定肺癌的发病机制。 对转化生长因子-FI的肿瘤抑制功能产生抵抗，并通过以下方式为其机制提供新的见解 哪些HDI针对肺癌中的转化生长因子-FI途径。加深对这些机制的理解 应该有助于改善肺癌的药物开发和治疗。

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.