MiR-506在VPA抑制乳腺癌中的调控机制及预后评估意义

To find the effective prognostic biomarkers and therapeutic targets can enhance the survival time and quality of life for breast cancer patients. It is well known that microRNAs (miRNAs) are serving as oncogenes or tumor suppressor genes via involving the tumor progression, and the differential expression of miRNAs could be used as the prognostic biomarkers and therapeutic targets in some malignant tumors. Moreover, histone deacetylase (HDAC) inhibitor, VPA, could inhibit the proliferation and invasion of cancers, but the effects of VPA and the regulating mechanism between VPA and miRNAs are not clear. We previously found that VPA could significantly inhibit the progression of breast cancer, and the expression level of miR-506 in VPA treated breast cancer cells is different from the untreated cells, indicating that the inhibition effects of VPA on breast cancer might be related with the molecular regulating mechanism of miR-506. Thus, this study intends to confirm the biomarker value of miR-506 on prognostic evaluation of breast cancer and demonstrate the molecular regulating mechanism of miR-506 in the course of breast cancer inhibition by VPA treatment. It'll be helpful to provide new evidences to support VPA used as the anti-tumor drug in clinic. Meanwhile, the biomarker value as the prognostic evaluation of the detection of miR-506 differential expression will be investigated by combining the analysis of detailed clinicobiological characteristics.

寻找有效的乳腺癌预后评估分子标志物并开展分子靶向治疗可以明显提高乳腺癌患者的生存期和生存质量。现已公认microRNA在肿瘤发生发展过程中起重要的癌基因与抑癌基因作用，其差异表达检测可以作为某些肿瘤的预后评估标志物及治疗靶点；另外，组蛋白去乙酰化酶（HDAC）通路抑制剂丙戊酸（VPA）可以抑制多种肿瘤的增殖与侵袭，但其抑制乳腺癌的作用及其与miRNAs调控之间的关系尚不清楚。我们的前期研究发现：VPA可以明显抑制乳腺癌发展，且miR-506在 VPA作用前后变化显著，提示VPA抑制乳腺癌可能与miR-506分子调控有关。因此，本项目设计深入研究miR-506对于乳腺癌的预后评估意义及其在VPA抑制乳腺癌中的具体分子调控机制，推动VPA在乳腺癌靶向治疗中的应用；同时，通过结合分析乳腺癌临床生物学行为特点，明确miR-506差异表达检测在乳腺癌临床预后评估中的标志物作用。

乳腺癌发病率居女性恶性肿瘤的首位，寻找乳腺癌预后评估相关分子标记物并开展肿瘤靶向治疗可以明显提高乳腺癌患者生存期和生存质量。我们的前期研究发现：组蛋白去乙酰化酶（HDAC）通路抑制剂丙戊酸（VPA）则明显抑制乳腺癌；且VPA作用可明显抑制乳腺癌，并发现VPA对胃癌等肿瘤也具有明显的抑制作用。研究发现，VPA可通过诱导肿瘤细胞凋亡与自噬，抑制PI3K/AKT通路等机制抑制肿瘤细胞增殖、迁移及浸润，并可以明显抑制荷瘤小鼠的肿瘤增长。此外，还发现VPA可能通过磷酸戊糖途径关键酶调节肿瘤细胞代谢水平来抑制肿瘤增殖。在项目开展过程中，共培养博士研究生2名，硕士研究生3名，发表论文7篇，申请获得1项国家自然基金地区基金。因此，本项目初步阐明VPA抑制肿瘤中的具体分子调控机制，推动HDAC抑制剂VPA在乳腺癌靶向治疗中的应用；同时，通过结合乳腺癌临床生物学行为特点，阐明VPA调控的相关蛋白的差异表达在乳腺癌临床预后评估的标志物作用。