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The ASH1-miR-375-YWHAZ signaling axis regulates tumor properties in hepatocellular carcinoma
Molecular Therapy - Nucleic Acids ( IF 8.8 ) Pub Date : 2018-04-25
Juan-Feng Zhao, Qiu Zhao, Hui Hu, Jia-Zhi Liao, Ju-Sheng Lin, Chao Xia, Ying Chang, Jing Liu, An-Yuan Guo, Xing-Xing He

Hepatocellular carcinoma (HCC) is a worldwide malignance and the underlying mechanisms of this disease are not fully elucidated. In this study, the existence and function of ASH1-miR-375-YWHAZ signaling axis in HCC were determined. Our experiments and TCGA sequencing data analyses showed that ASH1 and miR-375 were significantly down-regulated, while YWHAZ was significantly up-regulated in HCC. Furthermore, we found that ASH1 positively regulates miR-375, and miR-375 directly down-regulates its target YWHAZ. Gain- and loss-of-function study demonstrated ASH1 and miR-375 function as tumor suppressors, while YWHAZ acts as an oncogene in HCC. Animal experiment indicated that si-YWHAZ delivered by nanoliposomes could suppress the growth of hepatoma xenografts and was well tolerant by nude mice. Further studies revealed that YWHAZ was involved in several protein networks such as cell autophagy, EMT, apoptosis, cell cycle, invasion and migration. In addition, the patient group with ASH1-high-expression-miR-375-high-expression-YWHAZ-low-expression was correlated with a better clinical prognosis compared with the opposite expression group. In conclusion, we proved the existence of ASH1-miR-375-YWHAZ signaling axis and interpreted its important role in driving HCC tumor progression.



中文翻译:

ASH1-miR-375-YWHAZ信号轴调节肝细胞癌的肿瘤特性

肝细胞癌(HCC)是一种世界范围的恶性肿瘤,尚未完全阐明该疾病的潜在机制。在这项研究中,确定了HCC中ASH1-miR-375-YWHAZ信号转导轴的存在和功能。我们的实验和TCGA测序数据分析表明,在肝癌中ASH1和miR-375显着下调,而YWHAZ显着上调。此外,我们发现ASH1积极调节miR-375,而miR-375直接下调其目标YWHAZ。功能获得和功能丧失研究表明ASH1和miR-375可作为肿瘤抑制因子,而YWHAZ可作为HCC中的癌基因。动物实验表明,纳米脂质体递送的si-YWHAZ可以抑制异种肝癌的生长,并且对裸鼠具有良好的耐受性。进一步的研究表明,YWHAZ参与了多种蛋白质网络,例如细胞自噬,EMT,细胞凋亡,细胞周期,侵袭和迁移。此外,与相对表达组相比,具有ASH1-高表达-miR-375-高表达-YWHAZ-低表达的患者组具有更好的临床预后。总之,我们证明了ASH1-miR-375-YWHAZ信号轴的存在,并解释了其在驱动HCC肿瘤进展中的重要作用。

更新日期:2018-04-25
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