PRMT2在乳腺癌有氧糖酵解中的作用及机制研究

Aerobic glycolysis is a significant characteristic of malignant tumors energy metabolism, and recently specific inhibition of tumor energy metabolism has become an important means for the treatment of tumor. High mobility group A1 (HMGA1) is a structural transcription factor involved in tumor progression, drug resistance and prognosis. Our previous studies found that PRMT2 could inhibit the proliferation of breast cancer cells, and loss of PRMT2 expression could upregulate significantly the expression of HMGA1, and significantly affect the aerobic glycolysis process of breast cancer cell. For this, we propose that "PRMT2 is involved in the energy metabolism of breast cancer cells by inhibiting HMGA1-mediated aerobic glycolysis." In this project we would intend to study the four aspects of molecules, cells, animals and tissues with multiple metheds: to clarify the role of PRMT2 in the process of aerobic glycolysis of breast cancer cells, to reveal the molecular mechanism of PRMT2 in breast cancer cells to regulate the expression of HMGA1, to understand the molecular mechanism of PRMT2 suppress HMGA1 mediated aerobic glycolysis of breast cancer cells, to reveal the clinical significance of PRMT2 in the initiation of breast cancer. The completion of the project would clarify the role and molecular mechanism of PRMT2 in regulation of energy metabolism of breast cancer, and for providing new experimental evidences and strategies for targeted therapy of breast cancer.

有氧糖酵解是恶性肿瘤能量代谢的显著特征，特异性抑制肿瘤能量代谢成为近年肿瘤治疗的重要手段。高迁移率族A1(HMGA1)是一种结构性转录因子，参与肿瘤的进展、耐药与预后。我们前期研究发现精氨酸甲基转移酶2(PRMT2)抑制乳腺癌细胞增殖，其表达缺失能上调HMGA1的表达，并显著影响乳腺癌细胞有氧糖酵解过程。为此，我们提出“PRMT2通过抑制HMGA1介导的有氧糖酵解参与乳腺癌细胞能量代谢过程”。本课题拟采用多种方法从分子，细胞，动物及组织四个方面研究，明确PRMT2在乳腺癌细胞有氧糖酵解过程中的作用，揭示PRMT2在乳腺癌细胞中调控HMGA1表达的分子机理，阐明PRMT2抑制HMGA1介导的乳腺癌细胞糖酵解的分子机制，探讨PRMT2与HMGA1在乳腺癌发生过程中的临床意义。本项目的顺利完成有望阐明PRMT2在调控乳腺癌细胞能量代谢中的作用及分子机制，为乳腺癌靶向治疗提供新的实验依据和策略。

有氧糖酵解是恶性肿瘤能量代谢的显著特征，特异性抑制肿瘤能量代谢成为近年肿瘤治疗的重要手段。高迁移率族A1(HMGA1)是一种结构性转录因子，参与肿瘤的进展、耐药与预后。本项目采用乳腺癌细胞慢病毒感染，裸鼠尾静脉成瘤，敲基因小鼠模型及临床乳腺癌患者组织芯片检测等多种方法分别从分子、细胞、动物及组织四个方面，研究精氨酸甲基转移酶2(PRMT2)与HMGA1在乳腺癌细胞有氧糖酵解过程中的作用与机制，结果表明：1）PRMT2与HMGA1均能通过有氧糖酵解促进乳腺癌细胞侵袭迁移，2）通过质谱鉴定、免疫共沉淀、rescue回复实验等证实PRMT2与NF-YC互作，通过HMGA1调控乳腺癌细胞有氧糖酵解而影响乳腺癌细胞侵袭迁移，3）通过裸鼠尾静脉成瘤，敲基因小鼠等体内实验证实PRMT2通过乳腺癌细胞有氧糖酵解而影响乳腺癌细胞侵袭迁移，4）证实HIF1a通过PRMT2/NF-Y/HMGA1轴调控乳腺癌细胞糖酵解，5）采用乳腺癌组织芯片，免疫组化检测乳腺癌组织中PRMT2与HMGA1的表达并进行相关性分析，生物信息学分析TCGA数据库中，PRMT2与HMGA1及各糖酵解因子在乳腺癌患者各临床指标间的相关性。阐明PRMT2、HMGA1和乳腺癌患者相关指标间的关系，为PRMT2与HMGA1联合作为乳腺癌治疗靶分子和/或预后指标提供了实验依据。