表观遗传调控的锌指蛋白ZMYND10在乳腺癌中的抑癌作用及其对ZIC2/NEDD9通路的调控机制研究

Breast cancer is the most prevalent malignancy and the leading cause of cancer-related death in females worldwide. Understanding the molecular mechanism of breast cancer in chemoresistance and early metastasis is crucial for improving patient survival. Our preliminary studies suggest the zinc-finger protein ZMYND10 as a potential tumor suppressor that is silenced by aberrant promoter methylation in breast cancer. Silencing ZMYND10 results in higher proliferation, invasion and metastasis capacity. Furthermore, we found that ZMYND10 up-regulates the expression of ZIC2 and p53, and down-regulates that of NEDD9. Thus, we hypothesize that ZMYND10 is a potential tumor suppressor that is epigenetically silenced in breast cancer and the tumor suppressing function of ZMYND10 may involve modulation of the ZIC2/NEDD9 pathway. In this application, by in vitro and in vivo experiments, we plan to validate ZMYND10 expression and methylation status in breast cancer cell lines and tumor tissues, and investigate how ZMYND10 suppresses proliferation, metastasis and angiogenesis, particularly the mechanism involving the ZIC2/NEDD9 pathway. In addition, we will analyze a large size of clinical samples to investigate the relationship between ZYMND10 gene methylation and clinical pathological characteristics and prognosis of breast cancer patients. The outcome will help to identify biomarkers for prediction and early diagnosis, and therapeutic targets for drug discovery against breast cancer.

乳腺癌的发病率及死亡数居女性恶性肿瘤首位，阐明其耐药及转移的机制是提高患者存活率的关键环节。我们的前期研究发现，DNA甲基化可致乳腺癌中ZMYND10基因表达沉默，外源性表达该基因可抑制乳腺癌细胞生长及转移。基因表达谱研究发现ZMYND10可上调p53和ZIC2及下调NEDD9的表达。本课题拟通过体内外实验，研究ZMYND10基因表达及其对乳腺癌侵袭转移和血管生成的影响，重点阐明其通过调节p53和 ZIC2/NEDD9通路抑制乳腺癌侵袭转移的机理，并利用临床大样本分析ZYMND10基因甲基化与患者临床病理特征及预后的关系。结果将有助于发现乳腺癌发病的预警基因及控制乳腺癌侵袭转移的药物开发的新靶点.

乳腺癌是女性最常见的恶性肿瘤,发病率及死亡数居女性恶性肿瘤首位，其高异质性和易转移给临床治疗带来了极大地挑战。阐明其转移机制是提高患者存活率的关键环节。我们研究发现DNA甲基化可导致ZMYND10在乳腺癌中表达沉默，外源性过表达ZMYND10可以明显抑制乳腺癌细胞株的增殖和克隆形成能力，诱导细胞阻滞于G2/M期和细胞凋亡。通过降低NEDD9的表达而抑制乳腺癌细胞的迁移和侵袭。体内裸鼠成瘤实验，ZMYND10过表达也可以明显抑制移植瘤的增殖。机理上，ZMYND10可以上调miR145-5p的表达，从而进一步抑制NEDD9这一促转移蛋白的表达最终抑制了乳腺癌的侵袭转移。总的来说，我们首次证实ZMYND10/miR145-5p/NEDD9这一新的信号轴是ZMYND10在乳腺癌中发挥抗肿瘤功能的潜在机制的一部分，这一新发现的信号通路可能是一个有效的小分子靶点，可能有助于开发新的治疗方法，更好地抑制乳腺癌转移。