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

由于大多数子宫内膜癌不包含任何可检测到的ras突变，因此异常ras功能对子宫内膜癌发展的确切贡献（如果有的话）仍有待确定。由于有大量证据表明ras -转化与生长因子需求减少有关，我们比较了含有野生型（石川细胞）或突变（HHUA细胞）K-ras的子宫内膜癌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Ishikawa细胞的生长，而不是HHUA细胞。此外，EGF在Ishikawa细胞中引起Ras-GTP水平升高，而在HHUA细胞中没有。然而，将突变而非正常的K-ras引入石川细胞，使其对EGF生长刺激无反应。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抑制剂可以阻止石川细胞软琼脂集落的形成，但对HHUA或突变K-ras（12V）转染的石川细胞不起作用。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，而EGTF受体功能现在对于突变的ras阳性子宫内膜癌细胞的生长是必不可少的。

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.