CENPA介导的表观遗传调控在乳腺癌进展及转移中的作用及机制研究

Centromere protein A (CENPA), a critical protein regulating cell mitosis, is associated with carcinogenesis. However, the functional roles and molecular mechanisms of CENPA in cancer progression are unclear. Our previous study has demonstrated that CENPA is highly expressed in breast cancer tissues compared to normal tissues and overexpression of CENPA is positively correlated with poor patients' prognosis. Knockdown of CENPA expression showed markedly inhibition of breast cancer cell proliferation, migration and invasion. The analysis of microarray data obtained by CENPA siRNA/scramble control treated breast cancer cells indicated that EZH2 was a CENPA-downstream gene which regulated the Wnt/β-catenin signaling pathway. Various studies have shown that EZH2 can epigenetically active Wnt/β-catenin signaling pathway to promote malignant progression of breast cancer. As such, we propose that CENPA may play a critical role in breast cancer malignant progression by mediating EZH2-inducd Wnt/β-catenin activation through epigenetic regulation. In the current project, further investigation is needed to demonstrate the functional roles of CENPA in breast cancer progression at cellular level and animal level. Furthermore, it is going to investigate the molecular mechanisms that CENPA mediates epigenetic regulation and downstream pathways in breast cancer progression and metastasis. Moreover, we will explore correlation of the expression of CENPA and EZH2 and clinical significance in human breast cancers. Our study will provide solid theoretical basis to demonstrate that CENPA is a potential therapeutic target for breast cancer.

CENPA作为调控细胞有丝分裂的关键蛋白与肿瘤的发生相关，但在肿瘤中的作用及机制尚不明确。我们前期研究表明，CENPA在乳腺癌中高表达且与不良预后呈正相关；CENPA基因沉默显著抑制乳腺癌细胞增殖、迁移和侵袭；分析CENPA基因沉默及对照组乳腺癌细胞microarray数据表明：EZH2可能作为CENPA下游基因调控Wnt/β-catenin通路。而研究表明EZH2通过表观遗传调控Wnt/β-catenin通路的激活促进乳腺癌进展，因此，我们提出CENPA通过介导EZH2表观遗传调控激活Wnt/β-catenin，从而在乳腺癌进展中发挥重要作用。本项目拟在前期研究基础上，进一步在多种细胞及动物水平明确CENPA在乳腺癌进展及转移中的作用；从表观遗传调控及下游信号通路多角度探讨其相关机制；并结合乳腺癌标本分析CENPA及EZH2表达的临床意义，为针对CENPA进行靶向治疗提供坚实的理论基础。

着丝粒蛋白A (CENPA) 作为调控细胞有丝分裂的关键蛋白与肿瘤的发生相关，但在肿瘤中的作用及机制尚不明确。本项目研究内容分为三个部分。第一部分明确CENPA在乳腺癌中的表达情况及高表达的CENPA与乳腺癌不良预后的相关性。第二部分在细胞和实验动物水平明确异常高表达的CENPA在乳腺癌进展中的作用。第三部分探讨CENPA在乳腺癌进展中的分子机制；结合乳腺癌标本分析CENPA及EZH2表达的临床意义。研究结果表明：CENPA在乳腺癌中表达上调并与乳腺癌恶性程度相关，且异常高表达CENPA的乳腺癌患者预后较差；CENPA沉默表达可抑制乳腺癌细胞增殖和侵袭迁移能力，而CENPA过表达可促进乳腺癌细胞的增殖；EZH2是CENPA基因沉默后引起下游基因表达变化的top5转录调控因子之一，CENPA通过激活EZH2-Wnt/β-catenin信号通路在乳腺癌进展中发挥关键作用。本课题研究表明CENPA作为候选癌基因在乳腺癌中通过介导EZH2-Wnt/β-catenin信号通路促进乳腺癌细胞的增殖、侵袭和迁移能力，从而促进乳腺癌的进展，具有潜在治疗价值，为针对CENPA进行靶向治疗提供坚实的理论基础。