Analysis of signal transduction associate with carcinogenesis and progression in endometrial and ovarian carcinoma.

点击翻译按钮获取中文摘要

(1)We investigated the biological significance of estrogen receptors (ER) in NIH3T3 cell transformation by the [12Val] K-Ras mutant. This mutant enhanced the steady state level and transcriptional activity of ER.Co- expression of progesterone receptor (PR) with mutant K-Ras led to suppression of tumorigenicity and inhibition of the activation of ER.The antisense oligomers complementary to the ER suppressed proliferation and transformed phenotypes of K1 2V cells. These observations support the importance of ER in Ras-mediated cell transformation.(2)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 K-ras mutation did not significantly affect the level of the EGF receptor expressed in these carcinoma cells. Next, we observed that EGF could stimulate the growth of Ishikawa, but not HHUA cells. Furthermore, EGF caused elevation of Ras-GTP levels in Ishi … More kawa, 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 EGF receptor function is dispensable for the growth of mutant Ras-positive endometrial carcinoma cells.(3)Hepatocyte growth factor is a multifunctional growth factor which has pleiotrophic biological effects on epithelial cells such as proliferation, motogenesis, invasiveness, and morphogenesis. Peritoneal dissemination is critical for progression of ovarian cancer, and our study revealed that hepatocyte growth factor induces migration and invasion of ovarian cancer cells. We also demonstrated here thet hepatocyte growth factor stimulates autophosphorylation of its receptor which is followed by activation of the Ras-MAP kinase cascade. Moreover, infection of ovarian cancer cells with ras dominant-negative adenovirus reduced hepatocyte growth factor-induced motogenic and invasive activity. These results suggested that the Ras-MAP kinase pathway plays an important role in progression of ovarian cancer, specifically in peritoneal dissemination. Less