Role of TGFB Receptor Alterations in Pancreatic Cancer

TGFB 受体改变在胰腺癌中的作用

• 批准号: 6579965
• 负责人: James W. Freeman
• 金额: $ 27.45万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6579965
• 关键词: apoptosis; athymic mouse; biological signal transduction; gel mobility shift assay; gene induction /repression; growth factor receptors; guanine nucleotide binding protein; methylation; mutant; neoplasm /cancer genetics; neoplastic process; nucleic acid sequence; pancreas neoplasms; polymerase chain reaction; protein structure function; receptor expression; southern blotting; tissue /cell culture; transforming growth factors; tumor suppressor genes

DESCRIPTION (provided by applicant): We established that loss of expression of TbetaRII causes a lack of response to TGFbeta in a population of pancreatic ductal adenocarcinoma cells (PDAC) that otherwise has an intact SMAD pathway. The loss of TbetaRII expression was most often caused by transcriptional repression involving oncogenic ras signaling, methylation, and HDAC and not by a mutation of the RII gene. Interestingly, we found that loss of TGFbeta signaling contributed to the deregulation of IGF-1R expression found in PDAC. The biologic consequences of loss of TGFbeta responsiveness in PDAC include a relaxation of growth controls and an increase in resistance to apoptosis through modulation of bcl-family members. We propose to test the hypotheses that: (1) there is a convergence between oncogenic ras signaling and epigenetic mechanisms leading to a transcriptional repression of the T?RII gene. To address this hypothesis we will determine the mechanism(s) by which ras signaling, methylation and HDAC regulate TbetaRII expression and determine whether there is a molecular linkage among these processes. To accomplish this we propose to (a) elucidate the transcriptional components of the T?RII gene affected by ras signaling, methylation and HDAC and (b) determine whether there is a molecular linkage among ras, methylation and HDAC in causing transcriptional repression of the T?RII gene. (2) the loss of TGFbeta signaling favors growth factor independence and resistance to apoptosis, in part, by promoting deregulation of lGF-1R expression. To address this hypothesis we will determine the biologic consequence of TGFbeta-mediated suppression of IGF-1R signaling in PDAC. To accomplish this we propose to (a) determine whether loss of autocrine TGFbeta signaling represents a common mechanism for deregulation of IGF-1R expression in PDAC, (b) determine whether TGFbeta signaling regulates IGF-IR expression through c-Myc and (c) determine the biologic significance of the interaction of IGF-IR and TGFbeta pathways in cell cycle regulation and tumorigenicity. Developing strategies to overcome transcriptional repression of TbetaRII may provide a new approach for therapy and for increasing sensitivity of PDAC to chemotherapy or radiation.

描述(由申请人提供)：我们证实TbetaRII的表达缺失导致胰腺导管腺癌细胞(PDAC)缺乏对TGFbeta的反应，否则这些细胞具有完整的SMAD途径。TbetaRII表达的丧失最常见的原因是涉及致癌ras信号、甲基化和HDAC的转录抑制，而不是RII基因的突变。有趣的是，我们发现TGFbeta信号的丢失导致了PDAC中IGF-1R表达的解除调节。PDAC中失去TGFβ反应性的生物学后果包括放松生长控制和通过调节bc1家族成员增加对凋亡的抵抗。我们建议检验以下假设：(1)致癌ras信号和导致T？RII基因转录抑制的表观遗传机制之间存在趋同。为了解决这一假设，我们将确定ras信号、甲基化和hDAC调节TbetaRII表达的机制(S)，并确定这些过程之间是否存在分子联系。为此，我们建议(A)阐明受ras信号、甲基化和HDAC影响的T？RII基因的转录成分，以及(B)确定ras、甲基化和HDAC之间是否存在导致T？RII基因转录抑制的分子连锁。(2)TGFβ信号的缺失部分通过促进LGF-1R表达的失控，有利于生长因子的非依赖性和抗凋亡作用。为了解决这一假设，我们将确定转化生长因子β介导的抑制PDAC中IGF-1R信号的生物学后果。为此，我们建议：(A)确定自分泌TGFbeta信号的缺失是否代表了PDAC中IGF-1R表达解除调控的常见机制；(B)确定TGFbeta信号是否通过c-Myc调节IGF-IR的表达；以及(C)确定IGF-IR和TGFbeta信号通路相互作用在细胞周期调控和肿瘤发生中的生物学意义。开发克服TbetaRII转录抑制的策略可能为治疗和提高PDAC对化疗或放射的敏感性提供一种新的方法。