Han Tao, Zhang Yue, Yang Xiaodan, Han Lei, Li Hengyu, Chen Tingsong, Zheng Zhendong
Department of Oncology, General Hospital of Northern Theater Command, Shenyang, 110016 Liaoning Province, China; Department of Oncology, Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, Liaoning Province, China.
Department of Oncology, General Hospital of Northern Theater Command, Shenyang, 110016 Liaoning Province, China; Graduate School, Jinzhou Medical University, Jinzhou, 121000 Liaoning Province, China.
Mol Ther Nucleic Acids. 2020 Mar 6;19:1073-1085. doi: 10.1016/j.omtn.2019.12.043. Epub 2020 Jan 15.
MicroRNAs (miRNAs) are involved in tumorigenesis, progression, recurrence, and drug resistance of hepatocellular carcinoma (HCC). However, few miRNAs have been identified and entered clinical practice. Herein, we report that microRNA (miR)-552 is upregulated in HCC tissues and has an important function in liver tumor-initiating cells (T-ICs). Functional studies revealed that a forced expression of miR-552 promotes liver T-IC self-renewal and tumorigenesis. Conversely, miR-552 knockdown inhibits liver T-IC self-renewal and tumorigenesis. Mechanistically, miR-552 downregulates phosphatase and tensin homolog (PTEN) via its mRNA 3' UTR and activates protein kinase B (AKT) phosphorylation. Our clinical investigations elucidated the prognostic value of miR-552 in HCC patients. Furthermore, miR-552 expression determines the responses of hepatoma cells to sorafenib treatment. The analysis of patient cohorts and patient-derived xenografts (PDXs) further demonstrated that miR-552 may predict sorafenib benefits in HCC patients. In conclusion, our findings revealed the crucial role of the miR-552 in liver T-IC expansion and sorafenib response, rendering miR-552 an optimal target for the prevention and intervention in HCC.
微小RNA（miRNA）参与肝细胞癌（HCC）的肿瘤发生、进展、复发及耐药过程。然而，仅有少数miRNA被鉴定并应用于临床实践。在此，我们报告miR-552在HCC组织中上调，且在肝脏肿瘤起始细胞（T-IC）中发挥重要作用。功能研究表明，miR-552的强制表达促进肝脏T-IC自我更新及肿瘤发生。相反，敲低miR-552可抑制肝脏T-IC自我更新及肿瘤发生。机制上，miR-552通过其mRNA的3'非翻译区下调磷酸酶及张力蛋白同源物（PTEN），并激活蛋白激酶B（AKT）磷酸化。我们的临床研究阐明了miR-552在HCC患者中的预后价值。此外，miR-552表达决定肝癌细胞对索拉非尼治疗的反应。对患者队列及患者来源异种移植瘤（PDX）的分析进一步表明，miR-552可能预测HCC患者对索拉非尼治疗的获益情况。总之，我们的研究结果揭示了miR-552在肝脏T-IC扩增及索拉非尼反应中的关键作用，使miR-552成为HCC预防及干预的理想靶点。
