AURKA通过增强DROSHA的mRNA稳定性上调LDHA表达促进乳腺癌干细胞特性的机制研究

蛋白激酶AURKA可通过非激酶依赖的方式增强乳腺癌肿瘤干细胞（BCSC）特性，但其下游调控机制尚不明确。本项目前期通过分析RNA测序结果，初步发现BCSC中显著富集的DROSHA受到AURKA的表达调控，并验证AURKA通过非激酶依赖的作用增强DROSHA的mRNA稳定性，而敲降DROSHA显著抑制BCSC干性。基于前期研究发现的糖酵解及其限速酶LDHA是调控BCSC干性的关键分子（J Clin Invest 2019; Oncogene 2018），我们利用测序分析进一步筛选并鉴定出LDHA是AURKA-DROSHA的下游调控分子，并验证DROSHA通过LDHA增强BCSC干性。因此，本项目拟探究AURKA-DROSHA-LDHA对BCSC干性的调控作用，阐明AURKA稳定DROSHA促进LDHA表达的分子机制，最后结合临床标本分析三者的表达和预后相关性，为肿瘤干细胞靶向治疗提供新策略。

Protein kinase AURKA could enhance breast cancer stem cell (BCSC) properties in a kinase-independent manner. However, the AURKA-regulated downstream target and mechanisms in BCSC maintenance remains unclear. Using RNA-seq analysis, our preliminary data showed that BCSC-enriched DROSHA is regulated by AURKA. AURKA enhanced DROSHA mRNA stability to elevate its expression in a kinase-independent manner. Silencing of DROSHA significantly inhibited BCSC traits. As our previous studies reveal that glycolysis or glycolytic enzyme LDHA plays a critical role in BCSC characteristics (J Clin Invest 2019; Oncogene 2018), we further analyzed RNA-seq results and found that LDHA was screened out as the downstream target of AURKA-DROSHA axis. We also found that DROSHA enhanced BCSC properties via LDHA. Overall, our project will investigate that AURKA-DROSHA-LDHA axis enhances BCSC phenotype. We will further explore the mechanism of how AURKA stabilizes DROSHA mRNA to promote LDHA expression. Moreover, the expression and correlation of AURKA, DROSHA and LDHA will be validated in breast tumor specimens. Our study will provide a new strategy for targeting BCSCs.