磷酸胆碱通过RAB27A激酶上调外泌体释放hsa_circ_0054903干预NOTCH信号通路促进子宫内膜癌间质上皮转化的机制研究

间质上皮转化MET与子宫内膜癌EC侵袭转移密切相关。前期代谢组学发现磷酸胆碱PCho在患者血清中表达显著升高并促进MET。为阐明其机制，进行全转录组测序，显示PCho处理组EC细胞hsa_circ_0054903、NOTCH阻遏分子CIR1、RAB27A表达上调，hsa-miR-301b-3p表达下调，进一步研究发现RAB27A过表达EC细胞上清液中外泌体表达hsa_circ_0054903、CIR1及MET分子上调。据此提出科学假说：PCho上调RAB27A促进外泌体释放hsa_circ_0054903通过干预hsa-miR-301b-3p抑制NOTCH信号通路从而促进EC MET。为验证该假说，拟在临床样本中验证以上各分子及NOTCH调控、效应分子的表达，利用体内外实验探讨PCho通过RAB27A调控外泌体介导RNA海绵调控促进EC MET机制，以期为EC靶向治疗提供新的理论依据。

It is reported mesenchymal-epithelial transition (MET) promotes proliferation of endometrial carcinoma (EC). Our previous metabolomics study revealed that expression of phosphocholine (PCho) significantly increased in serum of EC patients and was associated with MET. Competing endogenous RNA sequencing showed that the expressions of hsa_circ_0054903, CIR1mRNA and RAB27AmRNA in EC cells cultured with PCho were significantly up-regulated, while the expression of hsa-mir-301b-3p was down-regulated. Subsequently, it was shown that the expression of hsa_circ_0054903 in the exosome, as well as the transcription of CIR1 and MET biomarker were also up-regulated in RAB27Aoverexpressed EC cells. Based on previous studies and the pilot data, a scientific hypothesis was proposed: PCho stimulated hsa_circ_0054903 secretion from exosomes by upregulation of RAB27A and this intervened the effect of hsa-mir-301b-3p and thereby might inhibit NOTCH signaling pathway, which then promoted MET ofEC. In order to verify the hypothesis, we plan first to verify the expressions of RAB27A, hsa_circ_0054903, hsa-mir-301b-3p and the regulators and the effectors in NOTCH signaling pathway in clinical samples, and then further investigate the mechanism of EC MET in vivo and in vitro that stimulated by PCho, which was mediated by RNA sponge regulation network through RAB27A-stimulated exosome secretion,to provide a novel rationale for EC treatment.