抑癌基因ESE3调节胰腺癌细胞迁移侵袭的分子机制研究

ESE3 (Epithelial-specific Ets 3) is an nuclear transcriptional factor belonging to Ets (E26 transforming sequence) family. Currently, ESE3 is considered as an suppressor gene that influences the differentiation and malignant transform of cells. However, the role of ESE3 protein in pancreatic cancer remains to be elucidated..In our previous study, we found that ESE3 protein was lower expression compared with adjacent tissues, and ESE3 expression was associated with prognosis and inverse correlation with lymph node metastasis. Furthermore, ESE3 was positive association with E-cadherin expression by mRNA microarray sequencing and in vitro experiments. In this proposal, we will explore the functions of ESE3 protein in the cell invasion and metastasis of pancreatic cancer at clinical case analysis, cellular level and animal model level, respectively. .In summary, the in-depth study of ESE3 protein and the regulatory mechanism of E-cadherin, would be expected to more understanding of the motility of pancreatic cancer cells, and provide novel mechanism for tumor metastasis, as well as potential novel target for the treatment of pancreatic cancer.

ESE3 (Epithelial-specific Ets 3)是核转录因子Ets(E26 transforming sequence)的家族成员，目前ESE3被认为是一种抑癌基因，在细胞的分化及恶性转化方面发挥重要功能，但ESE3在胰腺癌中的功能至今尚无文献报道。.前期发现，ESE3 在胰腺癌组织中表达减少，并影响患者的恶性预后且与淋巴结转移呈负相关；通过基因表达谱芯片测序及体外实验发现，ESE3与E-cadherin之间存在正相关性表达。故本课题拟从临床病例分析、细胞水平和动物模型三方面系统阐述ESE3在胰腺癌细胞迁移及侵袭中的功能，进一步探索ESE3是如何作为转录因子调节E-cadherin的表达，进而影响细胞的迁移侵袭能力的改变。.对ESE3及其对E-cadherin调控机制的深入研究，将丰富对胰腺癌细胞迁移运动功能的认识，为肿瘤转移机制研究提供新的思路，为其治疗提供新的潜在靶点。

上皮特异性Ets家族因子（Epithelial-specific Ets，ESE）3（ESE3）是核转录因子Ets(E26 transforming sequence)的家族成员，目前ESE3被认为是一种抑癌基因，在细胞的分化及恶性转化方面发挥重要功能，但ESE3在胰腺癌中的功能至今尚无文献报道。. 本课题通过体内外实验证实，ESE3蛋白通过直接结合E-cadherin基因启动子区的Ets结合位点（EBS），调节E-cadherin的表达，进而影响胰腺癌细胞迁移侵袭及患者恶性预后。研究内容主要包括：a)与癌旁组织相比较，在胰腺癌组织标本中ESE3表达减少，并且ESE3的表达与患者的无复发生存期（RFS）及总体生存期（OS）密切相关；b)胰腺癌中ESE3的表达减少与启动子区甲基化有关；c)ESE3抑制胰腺癌细胞的增殖、转移及浸润；d)ESE3与E-Cadherin的表达呈现正相关性；e)体内外实验证实ESE3通过直接调控E-Cadherin的表达抑制胰腺癌的转移。. 该课题的相关结果发表在《Cancer Research》（ESE3 Inhibits Pancreatic Cancer Metastasis by Upregulating E-Cadherin. Cancer Res. 2017;77(4):874-885）杂志上，这不仅是对细胞迁移侵袭理论的重要补充，而且有助于对胰腺癌转移机制的理论认识，并有望为胰腺癌早期诊断提供分子标志，为其治疗提供关键靶点，应用于临床将产生良好的社会效益和潜在的经济效益。