TrkB-miR-107-ERα轴通过调控ERα促进子宫内膜癌恶性进展？

Lacking nuclear estrogen receptor alpha (ER alpha) is one of the main theory to explain the high aggressive and being not sensitive to hormone therapy for poor prognosis of endometrial carcinoma (EC), especially type II EC. However, with contradictory to the theory that is "estrogen with no antagonism is the exact carcinogenic factor in this cancer". We previously reported that upregulation of TrkB promotes anoikis resistance in EC. Further study confirmed that increased activity of TrkB consitutively represss miR-204-5p. In the absence of sufficient miR-204 activity. TrkB is left uncontrolled, thereby leading to carcinogenesis. Thus we speculate that TrkB may upregulate the specific miRNA to suppress ER alpha and promote tumor metastasis. Subject on the basis of preliminary expriment, we use the miRNA Chips combined with bioinformatics to select miR-107 who targeting ER alpha with successfully established over-expression/knockdown TrkB endometrial cancer cells. Through in vivo and in vitro, ChIP, Tet-on system etc. expriments, we designed to validate TrkB induce intracellular transcription factor P53 to upregulate miR-107 expression, which controls ER alpha valve. The results can be converted into the key marker between two types of endometrial carcinoma.

不良预后的子宫内膜癌（尤其II型内膜癌）缺乏雌激素核受体α（ERα）是解释其高侵袭和对性激素治疗不敏感的主要理论之一；但与“无拮抗雌激素是确切的致癌因子”理论矛盾。前期我们证实TrkB激活赋予癌细胞抗失巢凋亡能力并促使其播散；近一步研究发现TrkB通过抑制下游miRNAs，使调控其表达的miR-204-5p下调而发生持续活化。由此我们推测TrkB是否通过上调特异miRNA来抑制ERα以促进肿瘤转移？本项目在预实验基础上，拟以成功建立的过表达/干扰TrkB的内膜癌细胞为研究对象，利用miRNA芯片结合生物信息学方法筛选出靶向ERα的miR-107，采用体内外实验、ChIP、Tet-On系统等方法，旨在验证TrkB能通过胞内转录因子P53，精确调控miR-107表达水平，实现对ERα阀门控制的分子机制。研究结果可转化为区别两型内膜癌的关键标志物。

不良预后的子宫内膜癌（尤其II型内膜癌）缺乏雌激素核受体α（ERα）是解释其高侵袭和对性激素治疗不敏感的主要理论之一；但与“无拮抗雌激素是确切的致癌因子”理论矛盾。前期我们证实TrkB激活赋予癌细胞抗失巢凋亡能力并促使其播散；近一步研究发现TrkB通过抑制下游miRNAs，使调控其表达的miR-204-5p下调而发生持续活化。由此我们推测TrkB是否通过上调特异miRNA来抑制ERα以促进肿瘤转移？本项目在预实验基础上，拟以成功建立的过表达/干扰TrkB的内膜癌细胞为研究对象，利用miRNA芯片结合生物信息学方法筛选出靶向ERα的miR-107，我们发现TrkB并不能通过直接激活胞内转录因子P53来调控miR-107表达水平，而P53可以调控REGr来实现对于内膜癌转移的调控。miR-107在内膜癌中显著降低，其可以调控ERα的表达水平，研究结果可转化为区别两型内膜癌的关键标志物。