SND1通过改变染色质拓扑构象对乳腺癌EMT进程影响的研究

Metastasis is the leading cause of death in breast cancer patients， epithelial-mesenchymal transition (EMT) is essential for metastasis. Our previous work showed that SND1, HMGA2 and CTCF both co-up-regulated and bound with each other, overexpression of the three genes were related with abnormal chromatin conformation change, EMT and metastatic phenotype of breast cancer cells. According to these results, we propose the hypothesis that there is an abnormal positive feedback loop of SND1/HMGA2/CTCF crosstalk regulation in the EMT process of breast cancer cells, which promote breast cancer EMT via changing the topological conformation of EMT related gene loci. The central ideas of this project are: ⑴ finding out the key intermedia proteins involved in the SND1/HMGA2/CTCF pathway dis-organization loop; ⑵ conforming the key downstream EMT related targets factors of the abnormal positive feedback loop; ⑶ revealing the detail EMT inducing molecular mechanism of the abnormal positive feedback loop. Through the research of this subject, we try to provide additional proof for the molecular mechanisms of breast cancer metastasis, we also hope we could provide more objective evidence for developing new technology of the diagnosis and treatment of metastatic breast cancer.

乳腺癌患者主要死于转移，上皮间质化(EMT)是其转移的必由步骤。我们发现在乳腺癌细胞SND1/HMGA2/CTCF既相互上调又相互结合，三者过表达与乳腺癌细胞EMT相关基因染色质拓扑构象异常、EMT发生及转移密切相关。据此我们提出乳腺癌细胞EMT过程存在SND1/HMGA2/CTCF异常交互性正反馈调控环路，三者相互作用可改变EMT相关基因染色质拓扑构象影响其表达，并促进乳腺癌细胞EMT的研究假说。本项目拟解决的关键科学问题是: ⑴确定乳腺癌细胞SND1/HMGA2/CTCF异常调控环路信号传递的关键中介蛋白及其作用方式；⑵确定该异常调控环路促进乳腺癌细胞EMT的下游关键效应因子及其作用地位；⑶阐明该异常调控环路促进乳腺癌细胞EMT的分子机制。旨在为最终阐明乳腺癌转移分子机制提供重要线索，为研发乳腺癌转移诊疗新技术提供客观依据。

乳腺癌患者主要死于转移，上皮间质化(EMT)是其转移的必由步骤。我们发现在乳腺癌细胞SND1/HMGA2既相互上调又相互结合，三者过表达与乳腺癌细胞EMT相关基因染色质拓扑构象异常、EMT发生及转移密切相关。据此我们提出乳腺癌细胞EMT过程存在SND1/HMGA2/CTCF异常交互性正反馈调控环路，三者相互作用可改变EMT相关基因染色质拓扑构象影响其表达，并促进乳腺癌细胞EMT的研究假说。本项目经研究发现: ⑴确定乳腺癌细胞SND1/HMGA2/CTCF异常调控环路信号传递的关键中介通路为TGFβ通路；⑵确定SND1通过诱导Smad蛋白表达异常促进乳腺癌细胞EMT；⑶SND1通过干预CDH1基因甲基化促进乳腺癌细胞EMT的分子机制。旨在为最终阐明乳腺癌转移分子机制提供重要线索，为研发乳腺癌转移诊疗新技术提供客观依据。