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）：我们确定，TbetaRII 表达缺失会导致胰腺导管腺癌细胞 (PDAC) 群体缺乏对 TGFbeta 的反应，而这些细胞原本具有完整的 SMAD 途径。 TbetaRII 表达的丧失通常是由涉及致癌 ras 信号、甲基化和 HDAC 的转录抑制引起的，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 PDAC 中 IGF-1R 表达的失调。 PDAC 中 TGFbeta 反应性丧失的生物学后果包括生长控制的放松以及通过调节 bcl 家族成员来增加对细胞凋亡的抵抗力。我们建议检验以下假设：（1）致癌ras信号传导和表观遗传机制之间存在趋同性，导致T?RII基因的转录抑制。为了解决这个假设，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联系。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、甲基化和 HDAC 之间是否存在分子联系，从而导致 T?RII 基因的转录抑制。 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细胞凋亡的抵抗，部分原因是促进 lGF-1R 表达的失调。为了解决这一假设，我们将确定 PDAC 中 TGFbeta 介导的 IGF-1R 信号传导抑制的生物学后果。为了实现这一目标，我们建议（a）确定自分泌 TGFbeta 信号传导的丧失是否代表 PDAC 中 IGF-1R 表达失调的常见机制，（b）确定 TGFbeta 信号传导是否通过 c-Myc 调节 IGF-IR 表达，以及（c）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。开发克服 TbetaRII 转录抑制的策略可能为治疗和提高 PDAC 对化疗或放疗的敏感性提供新方法。