Role of TGFB Receptor Alterations in Pancreatic Cancer

TGFB 受体改变在胰腺癌中的作用

• 批准号: 6784589
• 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/6784589
• 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）：我们确定TBETARII表达的丧失会导致胰腺导管腺癌细胞（PDAC）的群体缺乏对TGFBETA的反应，否则这些胰腺癌细胞（PDAC）否则具有完整的SMAD途径。 Tbetarii表达的丧失通常是由转录抑制引起的，该抑制涉及致癌性RAS信号，甲基化和HDAC，而不是由RII基因的突变引起的。有趣的是，我们发现TGFBETA信号传导的丧失导致在PDAC中发现的IGF-1R表达的放松管制。 PDAC中TGFBETA反应性丧失的生物学后果包括通过调节BCL家庭成员来放松生长控制和对凋亡的抗性。我们建议测试以下假设：（1）致癌性RAS信号传导与表观遗传机制之间存在收敛，导致T？RII基因的转录抑制。为了解决这一假设，我们将确定RAS信号传导，甲基化和HDAC调节TBETARII表达的机制，并确定这些过程之间是否存在分子链接。为了实现这一目标，我们建议（a）阐明受RAS信号传导，甲基化和HDAC影响的T？RII基因的转录成分，以及（b）确定RAS之间是否存在分子链接，甲基化和HDAC在导致转录抑制作用的转录抑制t？rii基因。 （2）TGFBETA信号传导的丧失有利于生长因子独立性和对凋亡的抗性，部分原因是促进LGF-1R表达的放松管制。为了解决这一假设，我们将确定TGFBETA介导的PDAC中IGF-1R信号传导的生物学后果。为了实现这一目标，我们建议（a）确定自分泌TGFBETA信号的损失是否代表了PDAC中IGF-1R表达放松调节的常见机制，（b）（b）确定TGFBETA信号是否调节IGF-IR通过C-MYC和（C）调节IGF-IR表达。确定IGF-IR和TGFBETA途径相互作用在细胞周期调节和致瘤性中的生物学意义。制定克服TBETARII转录抑制的策略可能会提供一种新的治疗方法，并提高PDAC对化学疗法或放射线的敏感性。