Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and therapeutic agents for this malignancy are lacking. MicroRNAs play critical roles in carcinogenesis and present tremendous therapeutic potential. Here, we report that microRNA-206 is a robust tumor suppressor that plays important roles in the development of HCC by regulating cell-cycle progression and the cMet signaling pathway. MicroRNA-206 was underexpressed in livers of two HCC mouse models, human individuals bearing HCC, and human HCC cell lines. Combining bioinformatic prediction and molecular and cellular approaches, we identified cMET (Met proto-oncogene), cyclin D1 (CCND1), and cyclin-dependent kinase 6 (CDK6) as functional targets of microRNA-206. By inhibiting expression of cMET, CCND1, and CDK6, microRNA-206 delayed cell-cycle progression, induced apoptosis, and impaired proliferation of three distinct human HCC cell lines. Systemic administration of microRNA-206 completely prevented HCC development in both cMyc and V-Akt murine thymoma viral oncogene homolog 1/neuroblastoma RAS viral oncogene homolog (AKT/Ras) HCC mice, whereas 100% of control mice died from lethal tumor burdens. Conversely, reintroduction of cMet or Cdk6 into livers of cMyc and AKT/Ras HCC mice recovered growth of HCC inhibited by microRNA-206. These results strongly suggested that cMet and Cdk6 were two functional targets that mediated the inhibitory effect of microRNA-206 on the development of HCC. MicroRNA-206 overexpression demonstrated a profound therapeutic effect on HCC in xenograft and cMyc HCC mice. Conclusion: In summary, this study defines a potentially critical role of microRNA-206 in preventing the growth of HCC and suggests its use as a potential therapeutic strategy for this malignancy. (Hepatology 2017;66:1952–1967)

中文翻译：

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MicroRNA-206通过调节met原癌基因和细胞周期蛋白依赖性激酶6在小鼠中的表达来预防肝细胞癌的发病机理

肝细胞癌（HCC）是世界上最致命的癌症之一，并且缺乏用于这种恶性肿瘤的治疗剂。MicroRNA在致癌作用中起关键作用，并具有巨大的治疗潜力。在这里，我们报道microRNA-206是一种强大的肿瘤抑制因子，它通过调节细胞周期进程和cMet信号通路在肝癌的发展中发挥重要作用。在两种HCC小鼠模型，携带HCC的人类个体和人类HCC细胞系的肝脏中，MicroRNA-206的表达不足。结合生物信息学预测与分子和细胞方法，我们确定了cMET（Met原癌基因），cyclin D1（CCND1）和cyclin依赖性激酶6（CDK6）。）作为microRNA-206的功能靶标。通过抑制cMET，CCND1和CDK6的表达，microRNA-206延迟了细胞周期进程，诱导了细胞凋亡，并损害了三种不同的人类HCC细胞系的增殖。microRNA-206的系统性给药完全阻止了cMyc和V-Akt鼠胸腺瘤病毒癌基因同源物1 /神经母细胞瘤RAS病毒癌基因同源物（AKT / Ras）HCC小鼠的HCC发育，而100％的对照小鼠死于致死的肿瘤负担。相反，将cMet或Cdk6重新引入cMyc和AKT / Ras HCC小鼠的肝脏中可恢复受microRNA-206抑制的HCC生长。这些结果强烈表明cMet和Cdk6介导microRNA-206抑制肝癌发生的两个功能靶标。MicroRNA-206过表达证明在异种移植和cMyc HCC小鼠中对HCC具有深远的治疗作用。结论：总而言之，这项研究确定了microRNA-206在预防HCC生长中的潜在关键作用，并建议将其用作该恶性肿瘤的潜在治疗策略。（肝病学， 2017年； 66：1952–1967年）