三阴性乳腺癌中ZNF695高表达促进肿瘤细胞干性和转移的分子功能与机制研究

It has been demonstrated that zinc finger proteins play important roles in the development and progression of cancer. However, the correlation between ZNF695, a newly identified zinc finger protein, and cancer metastasis has been not reported. Recently, we found that ZNF695 proteins were overexpressed in triple negative breast cancer (TNBC) compared to non-TNBC and normal breast tissue. Furthermore, our preliminary data, obtained from in vitro and in vivo experimental systems, showed that the downregulation of ZNF695 reduced epithelial-mesenchymal transition (EMT), inhibited the cancer stem cell properties of TNBC cells, and decreased the.metastatic potential of TNBC cells. These results suggested that ZNF695 might be a key factor in cancer metastasis. Moreover, we demonstrated that NFκB/p65 could elevate the expression of ZNF695 and ZNF695 could bind to the promoter of TGF-β1/GOLPH3/E2F8 and transactivate them, thus active TGF-β/Smad, Wnt/β-catenin and E2F/Rb pathways, which are involved in cancer metastasis and.tumorigenicity. In the current project, we investigate the multi-dimensional mechanisms of ZNF695-induced TNBC metastasis by combining in vivo and in vitro experimental systems with data from clinical samples. This work may identify novel diagnostic markers and therapeutic targets for TNBC metastases.

大量研究证明锌指蛋白与肿瘤的发生发展密切相关。我们通过临床三阴性乳腺癌样品的分析，发现ZNF695在三阴性乳腺癌组织中的表达水平高于非三阴性乳腺癌组织；体内体外预实验结果显示：ZNF695低表达可抑制三阴性乳腺癌的①上皮细胞间质化(EMT)，②“肿瘤干细胞”特性，③远处转移能力。这些结果表明ZNF695 在三阴性乳腺癌转移过程中具有重要的生物学功能，而ZNF695促进三阴性乳腺癌转移的分子机制尚不清楚。进一步预实验数据显示，NFκB/p65能够上调ZNF695的表达，而ZNF695作为转录因子可与TGF-β1、GOLPH3和E2F8启动子区域结合，并激活与转移密切相关的TGF-β/Smad、Wnt/β-catenin和E2F/Rb信号通路。本研究将深层次解析锌指蛋白ZNF695 多层面驱动三阴性乳腺癌转移及维持肿瘤细胞自我更新的分子机制，为三阴性乳腺癌转移提供新的诊断标记物及治疗靶位点。

大量研究证明锌指蛋白在肿瘤的发生发展中发挥重要的作用。课题组探讨锌指蛋白ZNF695在乳腺癌中的调控机制，阐明其在肿瘤干细胞特性维持中的作用，不仅为肿瘤发生发展提供新的理论依据，并且将为肿瘤治疗提供新的潜在靶位点。本研究组发现：（1）在研究TGF-β通路时，ZNF695相关蛋白ALG3通过诱导TGF-β受体II的糖基化来促进乳腺癌辐射抗性和肿瘤的干性。更为重要的是，课题组发现衣霉素对糖基化的抑制和LY2109761对TGFBR2的抑制都不同程度地取消了ALG3过表达对肿瘤干性和辐射抗性的刺激作用。ALG3未来有可能作为乳腺癌治疗新的治疗靶点。（Journal of experimental & clinical cancer research : CR.通讯作者）（2）在研究EMT过程时，课题组发现ZNF695相关蛋白IQGAP3在乳腺癌肿瘤组织中高表达，并且其在放疗抵抗的患者中表达上调，其表达水平与乳腺癌的临床预后密切相关，提示IQGAP3有望成为克服乳腺癌放疗抵抗的靶点之一。（Frontiers in pharmacology.通讯作者）（3）课题组在分析ZNF695与乳腺癌患者临床相关性时，团队发现肌肉减少症和炎症均可以影响乳腺癌患者的预后。研究结果支持骨骼肌指数（Current problems in cancer.通讯作者）、术前预后营养指数（Frontiers in oncology.通讯作者）、术前全身炎症反应指数（Current problems in cancer.通讯作者）、术前全身免疫炎症指数(Frontiers in oncology.通讯作者)、术前白蛋白与碱性磷酸酶比值 (Cancer management and research.通讯作者)能影响乳腺癌生存的独立预后因素，提供个性化的预测，并帮助制定临床治疗策略。项目研究期间共发表（共同通讯/第一作者）SCI文章15篇， 2篇> 10分，11篇IF＞5。培养博士生1名，硕士生4名。