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.

中文翻译：

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miR-552 调节肝脏肿瘤起始细胞扩张和索拉非尼耐药


MicroRNA (miRNA) 参与肝细胞癌 (HCC) 的肿瘤发生、进展、复发和耐药性。然而，很少有 miRNA 被鉴定并进入临床实践。在此，我们报道 microRNA (miR)-552 在 HCC 组织中上调，并且在肝肿瘤起始细胞 (T-IC) 中具有重要功能。功能研究表明，miR-552 的强制表达可促进肝脏 T-IC 自我更新和肿瘤发生。相反，miR-552 敲低会抑制肝脏 T-IC 自我更新和肿瘤发生。从机制上讲，miR-552 通过其 mRNA 3' UTR 下调磷酸酶和张力蛋白同源物 (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 对 HCC 患者的预后价值。此外，miR-552的表达决定肝癌细胞对索拉非尼治疗的反应。对患者队列和患者来源的异种移植物 (PDX) 的分析进一步证明，miR-552 可以预测索拉非尼对 HCC 患者的益处。总之，我们的研究结果揭示了 miR-552 在肝脏 T-IC 扩张和索拉非尼反应中的关键作用，使 miR-552 成为预防和干预 HCC 的最佳靶点。