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

由于大多数子宫内膜癌不含任何可检测的ras突变，因此，如果存在Ras功能异常，其对子宫内膜癌发生的确切作用仍有待确定。由于有相当多的证据表明Ras转化与生长因子需求减少有关，我们比较了携带野生型（石川细胞）或突变型（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相当水平的EGF受体。接着，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引起的Ras-GTP水平的升高在石川，但不是HHUA，细胞。然而，引入突变的，但不是正常的，K-ras进入石川细胞使他们无反应的EGF生长刺激。因此，突变的K-ras的存在下，可以单独调节子宫内膜癌细胞的生长反应，EGF。最后，我们观察到，EGF受体酪氨酸激酶活性的抑制剂可以防止软琼脂集落形成的石川细胞，但没有HHUA或突变的K-ras（12 V）转染的石川细胞。两者合计，这些结果表明，突变的K-ras引起的EGF刺激的反应性的损失，EGTF受体的功能是现在的突变Ras阳性子宫内膜癌细胞的生长。

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.