TUMOR PROMOTING EFFECTS OF TGF-BETA1

TGF-BETA1 的促肿瘤作用

• 批准号: 6210159
• 负责人: DEBABRATA SAHA
• 金额: $ 3.92万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-11-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6210159
• 关键词: biological signal transduction; carcinogenesis; cell growth regulation; cell line; cell transformation; epithelium; gene expression; gene mutation; genetically modified animals; guanine nucleotide binding protein; laboratory mouse; neoplastic process; prostaglandin endoperoxide synthase; protein protein interaction; transforming growth factors

Transforming growth factor (TGF-beta) is a multi-functional factor that induces a wide variety of cellular processes affecting growth and differentiation. In normal epithelial cells, including intestinal epithelium, TGF-beta has a potent growth inhibitory effect and serves a tumor suppressor role. On the other hand, under selected conditions TGF-beta may actually promote tumorigenesis. Mutations in the TGF-beta receptors and selected TGF-beta signal transduction proteins (Smad family of proteins) have been associated with a significant fraction of human colorectal and pancreatic cancers. Evidence suggests that several effects of TGF-beta such as increased chemotactic activity and invasiveness, increased expression of COX-2 and prostaglandin release and increased expression of RhoB cause a epithelial to mesenchymal expression of COX-2 and prostaglandin release and increased expression of RhoB cause a epithelial to mesenchymal transition (EMT). Based on recent observations, the central hypothesis of this proposal is: tumor promoting effects of TGF-beta over-ride tumor suppressor effects during of intestinal and other types of epithelial cells, due to a witch in TGF-beta signal transduction. A long term of this investigation is to identify novel therapeutic strategies that selectively target the tumor promoting effects of TGF-beta, while preserving the tumor suppressive actions.

转化生长因子（TGF-β）是一种多功能因子，其诱导影响生长和分化的多种细胞过程。在正常上皮细胞中，包括肠上皮，TGF-β具有有效的生长抑制作用，并起到肿瘤抑制作用。另一方面，在选定的条件下，TGF-β实际上可能促进肿瘤发生。TGF-β受体和选定的TGF-β信号转导蛋白（Smad蛋白家族）的突变与相当一部分人结肠直肠癌和胰腺癌相关。有证据表明，TGF-β的几种作用，如增加的趋化活性和侵袭性、增加的考克斯-2表达和前列腺素释放以及增加的RhoB表达导致上皮细胞向间充质细胞表达考克斯-2和前列腺素释放，以及增加的RhoB表达导致上皮细胞向间充质细胞转化（EMT）。基于最近的观察，该建议的中心假设是：由于TGF-β信号转导中的一个开关，在肠和其他类型的上皮细胞中，TGF-β的促肿瘤作用超过了肿瘤抑制作用。这项研究的长期目标是确定新的治疗策略，选择性地靶向TGF-β的肿瘤促进作用，同时保留肿瘤抑制作用。