TGFBETA1 IN COLON CANCER PROGRESSION

在结肠癌发生后，TGFbeta1可以增强他们的 进展到更具侵袭性的状态。我们发现结肠癌 具有高水平的TGFbeta1蛋白的可能性是18倍(p 不到0.0013)进展到转移比低转移的癌症 转化生长因子β1水平。血管内皮生长因子β1水平升高 原发灶维持在淋巴结和转移灶。 这种选择的一种机制是自分泌转化生长因子β1发挥作用 作为一种增长因素。我们将检验这一假设 TGFbeta1-侵袭性和转移性生长刺激 结肠癌细胞是由于诱导低水平的CDK所致 稳定CDK2/Cyclin E复合体的抑制剂p21cip1和 增加它们的激酶活性，并确定其机制 控制这些细胞中p21cip1的水平。TGFbeta1信号转导 随着结肠癌细胞向更大的恶性进展而发生变化。 当TGFbeta1发起信令时，RAS被瞬时激活 导致分化和生长停滞的途径，而不是何时 TGFbeta1刺激细胞生长侵袭。我们将决定 是否通过稳定的显性转染法阻断RAS 阴性的N17rasH将阻断TGFbeta1诱导的成熟和/或 生长抑制。杯状细胞产生粘蛋白，是 第二丰富的结肠上皮细胞类型。我们会 确定结肠杯状细胞不敏感的机制 转化生长因子β1是由于β-多糖形式的水平降低所致 TbetaRIII通过转染法研究。

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.