GENE DIAGNOSIS AND THERAPY OF POORLY DIFFERENTIATED THYROID CARCINOMA.

人类甲状腺癌的预后通常是好的，但在某些情况下，特别是低分化癌是胎儿癌。目前尚无良好的指标来预测甲状腺癌的预后。在本项目中，我们发现ras p21蛋白是过度暴露的分化型癌，一些癌组织存在ras癌基因突变。肝细胞生长因子(HGF)模拟p21蛋白，增加GRAB和PI3-激酶的磷酸化。在分化的甲状腺癌细胞中，仅在低密度培养中观察到HGF诱导的细胞运动。另一方面，在低分化甲状腺癌细胞中，不仅在低密度培养中观察到HGF诱导的细胞运动，而且在高密度培养中也观察到HGF诱导的细胞运动。HGF增加p125FAK的酪氨酸磷酸化，这已被证明与局灶性粘连相关。这种磷酸化被去甲氧西林A抑制，这也阻断了细胞的运动反应。提示HGF在甲状腺癌的侵袭表型中起重要作用。在原发乳头状癌复发标本中，10例HGF受体c-Met均呈强阳性表达，提示细胞凋亡在内分泌系统的生理和病理过程中起重要作用。我们发现TSH通过TSH-cAMP途径抑制甲状腺细胞的凋亡，而ECM通过整合素依赖的ICE活性调节甲状腺恶性肿瘤细胞的凋亡。C-Met可能促进细胞生长，调节甲状腺肿瘤发生的第一步。因此，我们认为c-Met是乳头状癌的一个重要预后因素。HGF相关信号转导途径可能通过诱导细胞凋亡来治疗低分化甲状腺癌。

The prognosis of human thyroid carcinoma are usually good, but in some case, especially poorly differentiated carcinoma are fetal. There is no good indicator which predicate the prognosis of thyroid carcinoma. In this project we found that the ras p21 protein are overexposed differentiated carcinoma and some cancer has the mutation of ras oncogene. Hepatocyte growth factor (HGF) simulated p21 protein and increased the phospholylated of Grab and PI3-kinase. In the case of differentiated thyroid carcinoma cells, HGF-induced cell motility was observed only in a low-density culture. On the other hand, in the case of poorly differentiated thyroid carcinoma cells, HGF-induced cell motility was observed not only in a low-density cultures but also in a high-density cultures. HGF increased the tyrosine phosphorylation of p125FAK,which has been shown to correlate with focal adhesion. This phosphorylation was inhibited by herbimycin A,which also blocked the cell motility response. These data suggest that HGF plays important role in the invasive phenotype of thyroid cancers. In cases of primary specimen of papillary carcinoma with recurrence, all 10 cases strongly expressed c-Met which is the receptor of HGF.Apoptosis appears to play important roles in physiological and pathological processes of the endocrine system. We showed that TSH has an inhibitory effect on apoptosis of thyroid cells via the TSH-cyclic AMP pathway and ECM regulates apoptotic cell death of malignant thyroid cells through an integrin-dependent regulation of ICE activity. It was possible that c-Met promoted cell growth and regulated the first step of oncogenesis of the thyroid. Therefore, we suggest that c-Met is a significant prognostic factor of papillary carcinoma. And is may be possible to treated the poorly differentiated thyroid carcinoma by inducing the apoptosis by HGF related signal transaction methods