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

1.我们已确定1q42区域为子宫内膜癌抑制基因位点。该区域涉及三种基因(ORF12、HUBCEP 70和ENST27746)。现在，我们正在通过将这些基因导入子宫内膜癌细胞系来研究它们的肿瘤抑制功能。K-RAS和H-RAS共同介导的大鼠子宫内膜细胞增殖信号(RENT4)。而K-RAS通过激活MAPK诱导RENT4细胞凋亡，H-RAS则保护RENT4免受细胞凋亡的影响。这些数据表明，每个RAS蛋白都具有识别功能。ER-α在K-RAS下游发挥作用。激活的[12Val]K-RAS的表达通过激活转录因子ERα活性而导致NIH3T3细胞(K12V细胞)转化。显性负性ERα在K12V细胞中的表达导致细胞生长抑制和随后的细胞衰老。α-MDM2-P53信号通过DNERP21表达上调对应于该细胞的衰老诱导。NIH3T3细胞中ERα的表达通过c-jun上调mdm2。这些数据暗示了从ERα到P53的信号转导，从而调节了NIH3T3细胞的衰老。在具有完整pRb蛋白的子宫内膜癌和卵巢癌中，丁酸钠通过P53非依赖性的p21上调诱导G0/G1期停滞和随后的衰老。NAB使宫颈癌细胞同时处于G0/G1期和G2/M期，并诱导细胞衰老。细胞外基质及其受体上调衰老癌细胞对NAB的反应。

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.