子宫内膜腺癌分化的新机制：同源盒基因HOXA10的功能研究

The molecular mechanism of differentiation of endometrial adenocarcinoma is still unclear, however, previous researches showed that the expression of HOXA10 is positively correlated with the level of tumor differentiation grade, when the expression of HOXA10 gene in poorly differentiated tumor cells was enhanced and the nude mice were inoculated, the neonatal tumor tissue in pathology took on arrangement of “glandular configuration ", such morphological structure is similar to medium / high differentiated endometrial adenocarcinoma. Subsequent studies showed that the WNT signal in tumor cells was activated, and that the expression of upstream ligand WNT1 in WNT signaling pathway increased. Bioinformatics predicted that in WNT1 gene promoter region there existed locus, which could combine with homeobox transcription factor.Therefore, our research group proposed the following hypothesis: through the induction of WNT1 expression, HOXA10 can activate the WNT signaling pathway, and promote the differentiation of endometrial adenocarcinoma cells. The research group plans to elucidate the molecular mechanism of the regulation of HOXA10 gene expression in endometrial adenocarcinoma differentiation from multiple levels such as molecules, cells, tissue, animal experiment, and so on, using the new perspective of HOXA10-WNT signal pathway-endometrial carcinoma differentiation to provide potential new targets for the therapy of endometrial cancer molecular targeting.

子宫内膜腺癌分化的分子机制尚不清楚。前期研究表明HOXA10基因表达水平的高低与肿瘤分化级别成正相关，增强HOXA10基因在低分化子宫内膜腺癌细胞中表达并接种裸鼠成瘤，新生肿瘤组织在病理学上呈现“腺体样结构”排列，这种形态结构与中/高分化子宫内膜腺癌类似。后续研究表明肿瘤细胞中WNT信号出现激活，WNT信号通路的上游配体分子WNT1表达增加，生物信息学预测出WNT1基因启动子区存在与同源盒转录因子结合的位点。因此，课题组提出如下假说：HOXA10通过诱导WNT1的表达，激活WNT信号通路，促进子宫内膜腺癌细胞分化。课题组拟从分子、细胞、组织、动物实验等多个层面，以HOXA10-WNT信号通路-子宫内膜腺癌分化这个新视角，以期阐明HOXA10基因调控子宫内膜腺癌分化的分子机制，为子宫内膜癌分子靶向治疗提供潜在新靶标。

子宫内膜腺癌的发生及分化分子机制尚不清楚。同源盒基因编码一簇保守的转录因子家族，参与调控胚胎发育，器官形成和肿瘤发生。我们既往研究发现HOXA10基因表达水平的高低与肿瘤分化级别成正相关，增强HOXA10基因在低分化子宫内膜腺癌细胞中表达并接种裸鼠成瘤，新生肿瘤组织在病理学上呈现“腺体样结构”排列，这种形态结构与中/高分化子宫内膜腺癌类似。本研究拟从分子，细胞，组织及动物实验等多个层面探索多种同源盒基因与子宫内膜癌分化的机制。结果发现：（1）HOXA10基因在子宫内膜腺癌组织中低表达，并且与肿瘤分化的水平下降呈正相关。小鼠成瘤实验证实HOXA10在肿瘤细胞中的表达能够促进细胞分化。增强HOXA10在内膜癌细胞中能够诱导WNT1的彪啊，激活WNT信号通路。（2）同源盒基因BP1在子宫内膜癌中高表达，BP1的表达升高与肿瘤的分化降低，侵袭，转移呈正相关。BP1高表达的患者预后更差。增强BP1的在子宫内膜癌细胞中的表达能够促进细胞的增殖，加快细胞周期进入S和G2期。促进肿瘤细胞的侵袭和转移。小鼠成瘤实验证实外源性增强BP1在肿瘤细胞中的表达，小鼠肿瘤负荷更大。BP1能够下调P15，P21和E-Cad的表达水平，上调cyclinD1和MMP-2的表达水平。（3）同源盒基因EMX1/2的表达水平与子宫内膜癌无明确相关。同源盒基因MSX1/2的表达能够促进子宫内膜癌对顺铂的敏感性。本研究针对同源盒基因在子宫内膜癌中的功能进行了较细致的研究，为子宫内膜癌的发生发展机制研究提供了新的线索和理论依据，并为其治疗提供了潜在干预靶标。