转录抑制因子ZFP57通过调控下游印记基因对乳腺癌作用及机制研究

The incidence and mortality of breast cancer are still in the front of malignant tumors in women. Distant metastasis is still the main cause of death in patients with breast cancer. Prediction research of breast cancer metastasis related markers is very important. We have established the "human breast -human bone" mouse model with human tumor microenvironment. This model can completely simulate metastasis from primary focal hyperplasia, into the bloodstream, until transfer to the bone and it also can provide specimens from metastasis. We obtained the in situ and metastases tumor specimens, compared the gene expression, and metastasis related target gene ZFP57 was obtained. ZFP57 is a kind of transcription inhibitory factor, which control imprinting genes’ expression. Imprinting disorders associated with tumor development. Preliminary experiments suggest that reduce ZFP57 gene expression in breast cancer may promote metastasis, while the expression of imprinting gene MEST is negatively related to the ZFP57 . So we hypothesized that ZFP57 influence breast cancer metastasis through regulating downstream imprinted gene MEST. We intend to explore the influence of ZFP57 to breast cancer metastasis and clarify the regulation mechanism of ZFP57. We would like to provide new targets for the monitoring and treatment of breast cancer, as well as provide new evidence for imprinting disorders of tumors.

乳腺癌发病率和死亡率均位于女性恶性肿瘤前列，远处转移仍然是导致乳腺癌患者死亡的主要原因。对乳腺癌转移相关标志物的预测研究越来越受重视。我们建立了具有人源性肿瘤微环境的“人乳腺-人骨”小鼠模型，能完整地模拟乳腺癌细胞从原发灶增殖、入血，转移到人骨的临床全过程并提供人源性骨转移灶标本。在此基础上我们对获取的原位及转移灶瘤体，进行原代培养及基因比对，得到了乳腺癌转移相关靶点基因ZFP57。ZFP57是一种转录抑制因子，能调控印记基因表达。印记失调与肿瘤发展相关。预试验提示在乳腺癌细胞中下调ZFP57基因的表达可能促进乳腺癌细胞的转移，印记基因MEST的表达与ZFP57呈负相关。因此我们提出假说：ZFP57通过调控下游印记基因MEST影响乳腺癌的转移。我们拟探究ZFP57对乳腺癌转移相关生物学表型的影响，阐明ZFP57调控下游印记基因的机制。为乳腺癌的监测和治疗提供新靶点，为肿瘤印记失调提供证据。

通过启动子低甲基化激活致癌基因在肿瘤发生中起着重要作用。锌指蛋白57 (ZFP57)是krabb - zfps的一个成员，可以维持胚胎干细胞(ESCs)的DNA甲基化，在本研究中，我们发现ZFP57的含量较低而过表达ZFP57可以通过抑制乳腺癌细胞的增殖抑制Wnt/β-catenin通路。经鉴定，MEST可能是ZFP57的直接靶基因通过保守DNA甲基化被ZFP57下调。此外，过度表达MEST可以恢复ZFP57的肿瘤抑制和Wnt/β-catenin通路的灭活作用。ZFP57-MEST和Wnt/β-catenin通路轴参与了乳腺肿瘤的发生，这可能是一种潜在的诊断性生物标志物为乳腺癌患者的新治疗策略提供了新的见解。