Pokemon 在乳腺癌侵袭转移中的作用及机制研究

Breast cancer is one of the most malignant tumors in female , and the early tumor cell invasion and metastasis is the main cause for the death of breast cancer patients. Our previous work showed that:TGF-β could induce the expression of Pokemon via PI3K/Akt pathway in MCF-7 cells; Pokémon could negatively regulate the expression of E-cadherin in MCF-7 cells; the high expression of Pokemon was positively associated with lymph node metastasis .The role of Pokemon in breast cancer metastasis remains to be elucidated . This project will focus on: the effect of Pokemon on breast cancer invasion and metastasis ,the role of Pokemon in breast tumor epithelial mesenchymal transition, the associated mechanisms of Pokemon induced breast cancer metastasis, the correlation of Pokemon, E-cadherin and Vimentin expression in breast cancer and its association with the initiation, metastasis and prognosis of breast cancer. The completion of this project would uncover the role of TGF-β-PI3K/ Akt-Pokemon- E-cadherin pathway in breast cancer epithelial mesenchymal transition (EMT) and metastasis,and provide novel diagnostic and therapeutic approaches for breast cancer patients.

乳腺癌是女性最常见恶性肿瘤之一，乳腺癌易发生隐匿性转移是乳腺癌患者的主要致死原因。课题组前期研究表明: TGF-β在乳腺癌细胞中可通过PI3K/Akt通路诱导Pokemon的表达，在乳腺癌细胞中Pokemon对E-cadherin的表达存在负性调控作用，而乳腺癌淋巴结转移与Pokemon的高表达呈正相关。目前Pokemon在乳腺癌转移过程中的作用及机制尚不明确。本课题拟揭示Pokemon 对乳腺癌细胞侵袭转移能力和乳腺癌上皮间质化的影响，阐明Pokemon促进乳腺癌发生侵袭转移的作用机制，分析在乳腺癌中Pokemon、E-cadherin 和Fibronectin 等表达的相关性，并探讨其是否与乳腺癌发生、转移和预后相关。本课题的完成将能明确TGF-β-PI3K/Akt -Pokemon - E-cadherin通路在乳腺癌上皮间质转化和侵袭转移中的作用，可为乳腺癌防治提供新的思路。

本项目证实了TGF-β在乳腺癌细胞中通过PI3K通路上调Pokemon的表达及Pokemon对TGF-β通路的反馈抑制作用，揭示了Pokemon可通过TGF-β-Pokemon-SMAD4通路在乳腺癌侵袭过程中发挥重要作用；实验证实了Pokemon可抑制乳腺癌干细胞的形成，减少乳腺癌细胞中干性样细胞的比率；通过基因芯片和Chip-seq技术获得了Pokemon在乳腺癌细胞中可能调控的miRNAs和基因谱，在全基因组水平明确了Pokemon在乳腺癌细胞中与被调控基因结合的位点图谱，进一步证实了TGF-β通路是Pokemon调控的重要靶点；通过对临床标本的分析揭示了TGF-β、Pokemon和SMAD4在不同乳腺癌细胞系和不同乳腺癌亚型组织中的表达模式，并分析了它们的临床相关性，发现在Luminal A型乳腺癌组织中Pokemon的表达量明显高于Basal型，在乳腺癌组织中Pokemon与TGF-β、SMAD4和ER的表达均呈现正相关性。项目从细胞、分子和临床多层面揭示了Pokemon在乳腺癌侵袭转移过程中的作用及其机制，明确了Pokemon在乳腺癌发展中存在的复杂作用和功能，为进一步研究乳腺癌侵袭转移中所涉及的信号网络提供了实验基础和理论依据。