Tudor-SN蛋白在人卵巢癌转移及化疗敏感性中的作用机制研究

Ovarian cancer cure rate is very low. Mainly because most patients are diagnosed with abdominal cavity metastasis, and the cancer cell is easy to produce resistance to chemotherapy drugs. The expression of Tudor - SN protein increases in a variety of tumors, affecting cell proliferation, invasion, and angiogenesis. Our previous studies have shown that Tudor - SN highly expresses in clinical ovarian cancer samples and its expression positive correlates with tumor malignant degree. Knockdown Tudor - SN decreases invasive migration ability in cell lines, at the same time helps to enhance the sensitivity to chemotherapy drugs. In our expression profile microarray, the results show that the expression of Tudor - SN affect Epithelial-mesenchymal transition （EMT） related genes’ expression, negative correlation with the CDH1 and CLDN1, positive orrelation with CDH2, VIM and EMT repressor SLUG. This project was designed to investigate Tudor - SN regulates EMT through activating SLUG. In addition, Tudor-SN transcriptionally promotes SLUG by epigenetics. Furthermore, whether Tudor - SN can participate in chemotherapy sensitivity through regulation of EMT or other pathways.

卵巢癌治愈率低的主要原因是多数病人在确诊时癌细胞已向腹腔转移，且易对化疗药物产生抵抗。Tudor-SN蛋白在多种肿瘤中高表达，影响细胞的增殖、侵袭和血管生成能力。我们前期研究表明Tudor-SN蛋白高表达于临床卵巢癌组织且表达量与肿瘤恶性程度正相关。在细胞系中敲低Tudor-SN明显降低细胞的侵袭迁移能力，同时有助于增加对化疗药物的敏感性。表达谱芯片的结果表明，Tudor-SN的表达影响上皮间质转化（EMT）相关基因的表达，如负向调控CDH1、CLDN1，正向调控CDH2、VIM及EMT的转录抑制因子SLUG。故本项目旨在探讨1）Tudor-SN通过SLUG调控EMT。2）Tudor-SN通过表观遗传学方式促进SLUG的表达。3）Tudor-SN是否可以通过调控EMT或凋亡自噬等通路参与化疗敏感性。

Tudor-SN作为一种新发现的肿瘤蛋白涉及多种过程肿瘤发生过程，包括增殖、血管生成和转移。然而，潜在的转移机制在很大程度上仍是未知的。我们利用具有高转移能力的卵巢癌细胞株SKOV3，发现SND1功能的丧失显著抑制了SKOV3细胞的侵袭和迁移。随后我们进行基因表达谱分析，通过定量PCR和Western blot进一步验证Tudor-SN功能缺失导致E-cadherin、claudin 1等上皮标志物上调，N-cadherin、vimentin等间质标志物下调。此外，我们还发现SLUG是参与上皮-间质转化和转移的关键转录因子，通过调控N-CAD和VIM的表达及抑制E-CAD和CLDN1，促进上皮-间质转化过程的重要效应因子。其潜在的分子机制表明，SND1通过募集乙酰转移酶GCN5和CBP/p300到SLUG启动子近端区域，增加染色质的可达性，调控SLUG的基因转录激活。总之，SND1被认为是一种新型的上游调节器，在调节E-CAD/N-CAD表达开关方面发挥着重要作用。Tudor-SN在SLUG上游起调节SKOV3细胞上皮间质转化(EMT)的作用。