Molecular mechanism of endometrial carcinoma development and their application for the new molecular target therapy

1.我们已经确定1 q42区域为子宫内膜癌抑制基因位点。在该区域有3种基因（ORF 12、HUBCEP 70和ENST 27746）参与。现在，我们正在通过转染子宫内膜癌细胞系来研究这些基因的肿瘤抑制功能。2.a.在大鼠子宫内膜细胞（RENT 4）中，K-和H-Ras均介导增殖信号。而K-Ras通过激活MAPK诱导凋亡，H-Ras则通过保护RENT 4免于凋亡。这些数据表明，每个Ras蛋白具有不同的功能。ERα在K-Ras下游发挥作用。活化的[12 Val] K-Ras的表达通过激活作为转录因子的ERα活性而导致NIH 3 T3细胞（K12 V细胞）转化。K12 V细胞中ERα的显性负表达导致细胞生长抑制和随后的细胞衰老诱导。通过DNERα-MDM 2-p53信号传导的p21上调对应于该细胞衰老诱导。结果表明，NIH 3 T3细胞中ERα的表达通过c-Jun上调MDM 2的表达，提示ERα通过p53信号通路调控NIH 3 T3细胞的衰老。在pRb蛋白完整的子宫内膜癌和卵巢癌中，NaB（丁酸钠）通过p53非依赖性p21上调引起G 0/G1停滞和随后的衰老。与此相反，NaB使pRb作用的宫颈癌细胞阻滞于G 0/G1和G2/M期，并诱导细胞衰老。ECM及其受体在衰老癌细胞中响应NaB而上调。

1. We have identified the 1q42 region as an endometrial cancer suppressor gene locus. Three kinds of genes (ORF12, HUBCEP 70 and ENST27746) are involved in this region. Now, we are investigating the tumor suppressor function of these genes by the transfection into endometrial cancer cell lines.2.a. Both K-and H-Ras mediated proliferative signals in Rat endometrial cells(RENT4). However, K-Ras elicited the apoptosis through activating MAPK and in turn, H-Ras protected RENT4 from apoptosis. The data suggest that each Ras protein has distint function.b. ERα functions downstream of K-Ras. Expression of activated [12Val] K-Ras resulted in the NIH3T3 cell (K12V cells) transformation through activating ERα activity as a transcription factor. Dominant-negative ERα expression in K12V cells resulted in cell growth suppression and subsequent cell senescence induction. p21 upregulation through DNERα-MDM2-p53 signalling corresponded this cell senescence induction. ERα expression in NIH3T3 cells contributed to the upregulation of MDM2 through c-Jun. These data implicate the signalling from ERα to p53, regulating cell senescence in NIH3T3 cells.c. NaB(Sodium Butyrate) elicited G0/G1 arrest and subsequent senescence through p53-independent p21 upregulation in endometrial and ovarian cancer with intact pRb protein. In contrast, NaB arrested cervical cancer cells with pRb both at G0/G1 and G2/M phase and induced cell senescence. ECM and its receptors upregulated in senescence cancer cells in response to NaB.