TGFBETA1 IN COLON CANCER PROGRESSION

TGFβ1 在结肠癌进展中的作用

• 批准号: 2700766
• 负责人: EILEEN Anne FRIEDMAN
• 金额: $ 22.79万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-16 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2700766
• 关键词: animal genetic material tag; antisense nucleic acid; athymic mouse; colon neoplasms; enzyme activity; gene induction /repression; human genetic material tag; human tissue; neoplasm /cancer genetics; neoplastic process; polymerase chain reaction; protein kinase; tissue /cell culture; transforming growth factors

After colon cancer have developed, TGFbeta1 can enhance their progression to more invasive states. We found that colon cancers with high levels of TGFbeta1 protein were 18 times more likely (p less than 0.0013) to progress to metastases than cancers with low TGFbeta 1 levels. Elevated levels of TGFbeta 1 found in the primary tumor were maintained in lymph nodes and metastases. One mechanism for this selection is that autocrine TGFbeta 1 acts as a growth factor. We will test the hypothesis that the TGFbeta1-growth stimulation seen in aggressive and metastatic colon carcinoma cells is due to induction of low levels of the CDK inhibitor p21cip1 which stabilize cdk2/cyclin E complexes and increase their kinase activity, and determine the mechanisms for controlling p21cip1 levels in these cells. TGFbeta1 signaling changes as colon carcinoma cells progress to greater malignancy. Ras is transiently activated when TGFbeta1 initiates a signaling pathway leading to differentiation and growth arrest, not when TGFbeta1 stimulates cell growth the invasion. We will determine whether blocking ras by stable transfection of the dominant negative N17rasH will block TGFbeta1-induced maturation and/or growth inhibitition. Goblet cells produce mucins and are the second most abundant colon epithelial cell-type. We will determine whether the mechanism of colon goblet cell insensitivity to TGFbeta 1 is due to reduced levels of the betaglycan form of TbetaRIII by transfection studies.

结肠癌发展后，TGFBETA1可以增强其 发展为更具侵入性状态。 我们发现结肠癌 高水平的TGFBETA1蛋白的可能性高18倍（P 小于0.0013）要比低癌 TGFBETA 1级别。 TGFBETA 1的水平升高 原发性肿瘤保持在淋巴结和转移酶中。 一种选择的机制是自分泌TGFBETA 1 ACTS 作为增长因素。 我们将检验以下假设 TGFBETA1增长刺激在侵略性和转移性中可见 结肠癌细胞是由于诱导低水平的CDK所致 稳定CDK2/细胞周期蛋白E络合物的抑制剂P21CIP1和 增加其激酶活性，并确定 控制这些细胞中的P21CIP1水平。 TGFBETA1信号传导 随着结肠癌细胞发展到更大的恶性肿瘤的变化。 当TGFBETA1启动信号传导时，RAS会瞬时激活 导致差异化和增长逮捕的途径，而不是 TGFBETA1刺激细胞生长侵袭。 我们将确定 是否通过稳定转染主导抗性阻断RAS 负N17RASH将阻止TGFBETA1诱导的成熟和/或 生长抑制。 杯状细胞产生粘蛋白，是 第二大结肠上皮细胞类型。 我们将 确定结肠杯状细胞的机制不敏感 到TGFBETA 1是由于betaglycan形式的水平降低 TBETARIII通过转染研究。