LncRNA-ROR/AUF-1/Aurora-A信号轴在肝细胞癌恶性生物学行为中的作用及其机制研究

Aurora-A is an important member of newly identified serine/threonine kinase family. Previously, we have investigated the clinical significance of Aurora-A and its functions in hepatocelluar cancer (HCC). With the help of previous funds, we have elucidated the roles of HIF-1α and miR-129-3p in regulation of Aurora-A overexpression in HCC at transcriptional or post-transcriptional level, but the roles of long non-coding RNAs (lncRNAs) in regulation of Aurora-A expression and its possible molecular mechanisms are unknown. On the basis of high-throughput lncRNA or mRNA chip screening, mass spectrum and bioinformatic analyses, we will investigate the molecular mechanisms of lncRNA-ROR-promoting activation of Aurora-A protein by antagonizing the binding of RNA binding protein (AUF-1) with Aurora-A mRNA and subsequently inhibiting its mRNA degradation and further exploit the roles of lnc-ROR/AUF-1/Aurora-A axis signaling in malignant phenotypes of HCC cells. This will be helpful to provide experimental basis for further improving the molecular regulatory networks of Aurora-A overexpression in HCC.

Aurora-A是丝氨酸/苏氨酸激酶家族一个重要分子，课题组前期针对其在肝细胞癌中的临床病理意义及功能进行了相关研究，并在前期基金资助下分别阐明了HIF-1α和miR-129-3p参与调控Aurora-A过表达的转录和转录后水平分子机制。然而，长链ncRNA(lncRNA)在肝细胞癌中Aurora-A表达激活中的调控作用及其可能的分子机理尚不清楚。基于此，本课题拟在前期高通量lncRNA和mRNA芯片、质谱及生物信息学分析基础上，运用RNA pull-down、RNA免疫共沉淀等方法验证肝癌细胞中lncRNA-ROR通过拮抗AUF-1蛋白与Aurora-A mRNA结合抑制其降解从而促进Aurora-A蛋白表达的分子机制，并探索lnc-ROR/AUF-1/Aurora-A信号轴在肝细胞癌恶性生物学行为中的作用，为进一步完善肝细胞癌中Aurora-A基因表达紊乱的分子调控网络提供理论依据。

Aurora-A是丝氨酸/苏氨酸激酶家族一个重要分子，课题组前期针对其在肝细胞癌中的临床病理意义及功能进行了相关研究，并在前期基金资助下分别阐明了HIF-1α和miR-129-3p参与调控Aurora-A过表达的转录和转录后水平分子机制。然而，长链ncRNA(lncRNA)在肝细胞癌中Aurora-A表达激活中的调控作用及其可能的分子机理尚不清楚。基于此，本课题拟在前期高通量lncRNA和mRNA芯片、质谱及生物信息学分析基础上，运用RNA pull-down、RNA免疫共沉淀、RNA干涉等方法验证lnc-ROR/AUF-1/Aurora-A及lnc-ROR/HNRNPK/DEPDC1信号通路参与调控肝细胞癌的多种恶性生物学行为包括增殖、放疗抵抗、侵袭转移以及血管形成等，本研究的完成为进一步阐明和完善肝细胞癌中以lnc-ROR和Aurora-A基因为中心的分子调控网络并为发掘肝细胞癌治疗的新靶标提供理论依据。