Activation of the hepatocyte growth factor (HGF)-Met system in papillary thyroid cancer:: Biological effects of HGF in thyroid cancer cells depend on Met expression levels
Activation of the hepatocyte growth factor (HGF)-Met system in papillary thyroid cancer:: Biological effects of HGF in thyroid cancer cells depend on Met expression levels
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DOI：
10.1210/en.2003-1762
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发表时间：
2004-09-01
期刊：
影响因子：
4.8
通讯作者：
Belfiore, A
中科院分区：
文献类型：
--
作者：
Mineo, R;Costantino, A;Belfiore, A
肝细胞生长因子（HGF）的受体Met在约90%的甲状腺乳头状癌中过表达。为了研究HGF-Met系统在这些肿瘤中的作用，我们检测了各种原代培养物、正常或恶性甲状腺细胞和组织标本中的HGF和Met表达，并分析了不同的HGF效应（促进有丝分裂、分支形态发生和细胞运动和侵袭）。在癌症标本中，肿瘤间质细胞产生高水平的HGF，并且Met在恶性细胞中组成性磷酸化。在一组恶性甲状腺癌细胞中没有发现HGF产生。在具有高或低Met表达的乳头状癌细胞培养物中检查HGF的生物学效应。高Met细胞对HGF的生长效应更敏感（高或低Met细胞的ED 50分别为3-5 ng/ml和10-15 ng/ml）。此外，只有高蛋氨酸细胞进行分支形态发生响应HGF。相反，高Met细胞显示出减少的迁移。小干扰RNA下调Met导致细胞迁移增强和对HGF响应的分支形态发生的废除。相反，Met过表达损害细胞迁移，同时有利于分支形态发生和细胞粘附底物。这些数据表明，甲硫氨酸和肝细胞生长因子在甲状腺乳头状癌中过表达，甲硫氨酸在这些癌中经常被激活，可能有利于肿瘤生长，甲硫氨酸表达的丰度可能不同地调节细胞生长，形态发生和迁移，以响应肝细胞生长因子。
Met, the receptor for hepatocyte growth factor (HGF), is overexpressed in approximately 90% papillary thyroid carcinomas. To investigate the role of the HGF-Met system in these tumors, we examined HGF and Met expression in a variety of primary cultures, normal or malignant thyroid cells, and tissue specimens and analyzed the different HGF effects (promotion of mitogenesis, branching morphogenesis, and cell motility and invasion). In cancer specimens, HGF was produced at high levels by tumor stromal cells, and Met was constitutively phosphorylated in malignant cells. No HGF production was found in a panel of malignant thyroid cancer cells. Biological effects of HGF were examined in papillary cancer cell cultures with either high or low Met expression. High-Met cells were more sensitive to the growth effect of HGF (ED50 = 3-5 ng/ml and 10-15 ng/ml in high- or low-Met cells, respectively). Moreover, only high-Met cells underwent branching morphogenesis in response to HGF. In contrast, high-Met cells showed a reduced migration. Met down-regulation by small interfering RNAs resulted in enhanced cell migration and abrogation of branching morphogenesis in response to HGF. Conversely, Met overexpression impaired cell migration while favoring branching morphogenesis and cell adherence to substrate. These data suggest that both Met and HGF are overexpressed in papillary thyroid carcinomas, that Met is frequently activated in these carcinomas and may favor tumor growth, and that the abundance of Met expression may differently regulate cell growth, morphogenesis, and migration in response to HGF.