ASH1-miR-375-YWHAZ信号轴在肝癌中的作用机制研究

The most critical component for revitalizing hepatocellular carcinoma (HCC) treatment strategies is identification of novel molecular hubs (proteins/genes) in signaling pathways involved in HCC initiation and progression. Our previous studies demonstrated that miR-375 was one of the most downregulated miRNAs in HCC, and inhibited cell proliferation, autophagy, clonogenicity, migration/invasion and also induced G1 arrest and apoptosis by targeting AEG-1 and ATG7, which revealed that miR-375 is a core miRNA and an attractive therapeutic target for HCC. Our preliminary experiments and bioinformatic analysis indicated that ASH1-miR-375-YWHAZ signaling axis existed in HCC, and acted as hub moleculars to regulate multiple pathways involved in tumor. In the present study, we will first propose and prove ASH1-miR-375-YWHAZ signaling axis exists, and further reveal the important role and clinical significance of this signaling axis in HCC by using bioinformatic analysis, molecular biology and nanotechnology. The main contents of this study include: ① The expression and correlation analysis of ASH1，miR-375 and YWHAZ in HCC, and the molecular regulation of ASH1-miR-375-YWHAZ signaling axis in HCC. ② To reveal the functional effects and downstream pathways of the ASH1-miR-375-YWHAZ signaling axis in HCC. ③ Survival analysis of the ASH1-miR-375-YWHAZ axis in HCC and therapeutic exploration of the ASH1-miR-375-YWHAZ axis in HCC mouse models. This study will provide us a better understanding of the molecular mechanisms and novel molecular hubs of HCC, which may benefit the prognosis and treatment strategies for patients with HCC.

振兴肝癌治疗策略的关键是识别参与肝癌发生发展信号通路中新的分子枢纽。我们前期研究发现：miR-375是肝癌发生中的一个核心miRNA和分子治疗靶点，其在肝癌中显著下调，通过负调控AEG-1、ATG7等多个靶基因而抑制肝癌细胞的恶性表型。我们的预实验和生物信息学分析提示：ASH1-miR-375-YWHAZ信号轴在肝癌中存在分子调控关系，且作为分子枢纽，密切参与癌症相关的多个信号通路。本研究拟应用生物信息学、分子生物学及纳米技术研究ASH1-miR-375-YWHAZ信号轴在肝癌中的重要作用和临床价值，主要内容包括：①阐明ASH1、miR-375、YWHAZ的表达、相关性及分子调控关系；②解析ASH1-miR-375-YWHAZ信号轴在肝癌中的功能作用和分子机制；③评估ASH1-miR-375-YWHAZ信号轴在肝癌预后及干预治疗方面的价值。通过这些研究，为肝癌预后和干预治疗提供新的策略。

振兴肝癌治疗策略的关键是识别参与肝癌发生发展信号通路中新的分子枢纽。本项目应用生物信息学、分子生物学及纳米技术研究了ASH1-miR-375-YWHAZ信号轴在肝癌中的重要作用和临床价值，主要内容包括：①阐明了ASH1、miR-375、YWHAZ的表达、相关性及分子调控关系。我们的实验和TCGA生信分析表明，ASH1和miR-375在肝癌中显著下调，而YWHAZ在肝癌中显著上调。此外，我们发现ASH1正向调节miR-375，而miR-375直接负调控其靶基因YWHAZ。②研究了ASH1-miR-375-YWHAZ信号轴在肝癌中的重要功能和作用。功能获得和功能丧失实验揭示了ASH1和miR-375在肝癌中作为肿瘤抑制因子而发挥作用，而YWHAZ在肝癌中作为促癌因子发挥作用。③解析了ASH1-miR-375-YWHAZ信号轴在肝癌中的下游通路与分子机制。对YWHAZ的潜在下游分子进行了探索，表明YWHAZ参与了细胞自噬、EMT、凋亡、细胞周期、侵袭和迁移等信号通路。④评估了ASH1-miR-375-YWHAZ信号轴在肝癌临床预后及干预治疗方面的价值。与对照组相比，ASH1高表达-miR-375高表达-YWHAZ低表达患者组的临床预后更好。动物实验表明，纳米脂质体介导的si-YWHAZ可抑制异种肝癌移植瘤的生长，并对裸鼠具有良好的耐受性。总之，我们证明了ASH1-miR-375-YWHAZ信号轴在肝癌中的存在，并解释了其在推动HCC肿瘤进展中的重要作用。通过这些研究，为肝癌预后和干预治疗提供了新的策略。