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

子宫内膜癌发生的分子机制及其在新型分子靶向治疗中的应用

基本信息

批准号：
12470344
负责人：
WAKE Norio
金额：
$ 10.5万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470344/
关键词：
Endometrial cancer tumor suppressor gene chromosome 1q42 Ras ERα p53 Cell senescence MDM2 Chromosome 1 Endometrium K-Ras H-Ras

项目摘要

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.

1. 我们已经确定1q42区域是子宫内膜癌抑制基因位点。三种基因（ORF12、HUBCEP 70和ENST27746）参与该区域。现在，我们正通过转染子宫内膜癌细胞来研究这些基因的抑癌功能。k - ras和H-Ras介导大鼠子宫内膜细胞（RENT4）的增殖信号。然而，K-Ras通过激活MAPK诱导凋亡，反过来，H-Ras保护RENT4免于凋亡。数据表明，每种Ras蛋白具有不同的功能。ERα在K-Ras下游起作用。激活的[12Val] K-Ras表达通过激活ERα活性作为转录因子导致NIH3T3细胞（K12V细胞）转化。ERα在K12V细胞中呈显性负表达，导致细胞生长受到抑制，进而诱导细胞衰老。p21通过DNERα-MDM2-p53信号的上调与细胞衰老的诱导相对应。ERα在NIH3T3细胞中的表达通过c-Jun参与MDM2的上调。这些数据暗示了ERα到p53的信号传导，在NIH3T3细胞中调节细胞衰老。NaB（丁酸钠）在pRb蛋白完整的子宫内膜和卵巢癌中通过p53独立的p21上调引发G0/G1停滞和随后的衰老。NaB在G0/G1和G2/M期阻滞pRb宫颈癌细胞，诱导细胞衰老。衰老癌细胞中ECM及其受体响应NaB上调。