GENE DIAGNOSIS AND THERAPY OF POORLY DIFFERENTIATED THYROID CARCINOMA.

甲状腺癌预后一般较好，但在某些情况下，特别是低分化癌是胎儿癌。甲状腺癌的预后目前尚无较好的预测指标。本课题研究发现rasp 21蛋白在分化型癌中过度表达，部分癌组织中存在ras癌基因突变。肝细胞生长因子（HGF）可刺激p21蛋白表达，促进Grab和PI 3-kinase的磷酸化。在分化型甲状腺癌细胞的情况下，观察到HGF诱导的细胞运动，仅在低密度培养。另一方面，在低分化甲状腺癌细胞的情况下，HGF诱导的细胞运动性不仅在低密度培养中观察到，而且在高密度培养中也观察到。HGF增加p125 FAK的酪氨酸磷酸化，这已被证明与粘着斑相关。这种磷酸化被除草霉素A抑制，这也阻断了细胞的运动性反应。提示HGF在甲状腺癌的侵袭表型中起重要作用。10例复发性乳头状癌组织中，HGF受体c-Met均呈强阳性表达，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-环AMP途径对甲状腺细胞凋亡具有抑制作用，ECM通过ICE活性的整合素依赖性调节来调节恶性甲状腺细胞的凋亡细胞死亡。c-Met可能促进细胞生长并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。通过HGF相关信号转导途径诱导细胞凋亡治疗低分化甲状腺癌是可能的

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