EZH2调控miRNAs促进舌鳞癌侵袭转移的分子机制

Histone modifications and miRNAs play pivotal role in cancer development and progression. In our previous study, we confirmed that EZH2 and Snai2 could promote invasion and metastasis by suppressing E-cadherin expression in tongue squamous cell carcinoma. We also found that EZH2 could enhance the expression of Snai2 and Suz12 which may be mediated by miRNAs. Therefore, we propose that EZH2 mediated loss of miRNAs may regulate EMT related transcriptional factors and/or metastasis associated genes to promote invasion and metastasis in tongue squamous cell carcinoma. In this project, we aim to investigate the molecular mechanism which EZH2 regulates miRNAs to promote invasion and metastasis in tongue squamous cell carcinoma.

组蛋白修饰和miRNAs在肿瘤恶性进展中起着重要作用。我们前期研究证实:转录因子Snai2和组蛋白甲基化修饰因子EZH2能够抑制E-cadherin表达调控EMT，促进舌鳞癌侵袭转移；同时，我们还发现EZH2能够调控Snai2和Suz12的表达；进一步研究提示miRNAs(如miR-204和miR-320)可能参与此过程。因此，我们推测EZH2可通过表观遗传机制影响miRNAs的表达进而调控Suz12及Snai2和/或其它肿瘤转移相关信号通路，促进舌鳞癌侵袭转移。本课题拟在这些工作的基础上，深入研究EZH2及其调控的miRNAs和EMT相关调控因子在舌鳞癌中的表达和生物学功能，探讨EZH2调控miRNAs促进舌鳞癌EMT及侵袭转移的分子机制。

PRC2家族成员（主要包括EZH2、Suz12和EED）和miRNA在肿瘤恶性进展中起着重要调控作用，二者可以“交互对话”调控肿瘤细胞侵袭、迁移、增殖、凋亡及干性。本研究主要采用激光显微捕获切割技术和miRNA芯片技术获得舌鳞癌侵袭转移相关的miRNA表达谱，以EZH2及PRC2为切入点探讨其二者相互作用调控舌鳞癌侵袭转移的分子机制。结果证实PRC2的关键蛋白EZH2在舌鳞癌中表达上调并可抑制E-cadherin表达促进舌鳞癌侵袭转移；发现Tumor budding与早期舌鳞癌患者隐匿性颈淋巴结转移成正相关，且EZH2在Tumor budding中的表达相对于癌巢中央上调；基于上述研究结果，我们采用激光显微捕获技术获得Tumor budding、癌巢中央组织、淋巴结转移癌组织和癌旁非肿瘤性上皮组织，应用miRNA芯片分析获得舌鳞癌侵袭转移相关miRNA表达谱，通过系列体内、外实验证实miR-320靶向抑制Suz12调控舌鳞癌侵袭转移；EZH2抑制miR-204促进舌鳞癌侵袭转移。该系列研究结果证实PRC2-miRNA“交互对话”在舌鳞癌侵袭转中起重要调控作用，可望作为治疗舌鳞癌侵袭转移的潜在分子标靶。