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Role of Ras and Ras-relatd protein for carcinogenesis of endometrial

Ras及Ras相关蛋白在子宫内膜癌变中的作用

基本信息

批准号：
05671379
负责人：
KATO Kiyoko
金额：
$ 1.34万
依托单位：
Kyshu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1995
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05671379/
关键词：
Ras Singnal transduction EGF recepter Endmetrial carcinoma EGF・レセプター Ras蛋白点突然変異 EGF 細胞増殖

项目摘要

Since the majority of endometrial carcinomas do not contain any detectable ras mutations, the precise contribution of aberrant Ras function, if any, to endometerial carcinoma development remains to be determineed. Since there is considerable evidence that Ras-transformation is associated with a decreased requirement growth factors, we compared the growth response of endometrial carcinoma cells harboring wild type (Ishikawa cells)or mutated (HHUA cells)K-ras to epidermal growth factor (EGF). First, we determined that both tumor cells expressed comparable levels of the EGF receptor. Next, we observed that EGF could stimulate the growth of Ishikawa, but not HHUA,cells. Furthermore, EGF caused an elevation of Ras-GTP levels in Ishikawa, but not HHUA,cells. However, the introduction of mutated, but not normal, K-ras into Ishikawa cells rendered them nonresponsive to EGF growth stimulation. Thus, the presence of mutated K-ras alone, can modulate the growth response of endometrial carcinoma cells to EGF.Finally, we observed that an inhibitor of the EGF receptor tyrosine kinase activity could prevent soft agar colony formation of Ishikawa cells, but not HHUA or mutant K-ras(12V)-transfected Ishikawa cells. Taken together, these results suggest that mutated K-ras causes a loss of responsiveness to EGF stimulation and that EGTF receptor function is now dispensable for the growth of mutant Ras-positive endometrial carcinoma cells.

由于大多数子宫内膜癌不包含任何可检测到的ras突变，RAS功能异常(如果有的话)对子宫内膜癌发生的确切贡献仍有待确定。由于有大量证据表明RAS转化与需要的生长因子减少有关，我们比较了携带野生型K-ras的子宫内膜癌细胞(石川细胞)和突变的K-ras细胞(HHUA细胞)对表皮生长因子(EGF)的生长反应。首先，我们确定两种肿瘤细胞表达的EGF受体水平相当。接下来，我们观察到EGF可以刺激石川细胞的生长，但不能刺激HHUA细胞的生长。此外，EGF引起石川细胞RAS-GTP水平升高，但不影响HHUA。然而，将突变但不正常的K-ras基因导入石川细胞，使其对EGF生长刺激没有反应。因此，突变的K-ras单独存在可以调节子宫内膜癌细胞对EGF的生长反应。最后，我们观察到EGF受体酪氨酸激酶活性的抑制剂可以阻止Ishikawa细胞的软琼脂集落形成，但不能阻止HHUA或突变的K-ras(12V)转基因的Ishikawa细胞。综上所述，这些结果表明，突变的K-ras导致对EGF刺激的反应性丧失，EGTF受体功能现在对于突变的RAS阳性的子宫内膜癌细胞的生长是必不可少的。