MicroRNA-451: epithelial-mesenchymal transition inhibitor and prognostic biomarker of hepatocelluar carcinoma.
MicroRNA-451: epithelial-mesenchymal transition inhibitor and prognostic biomarker of hepatocelluar carcinoma.
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MicroRNA-451：上皮间质转化抑制剂和肝细胞癌的预后生物标志物
DOI：
10.18632/oncotarget.4317
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发表时间：
2015-07-30
期刊：
影响因子：
--
通讯作者：
Chen LB
中科院分区：
文献类型：
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作者：
Huang JY;Zhang K;Chen DQ;Chen J;Feng B;Song H;Chen Y;Zhu Z;Lu L;De W;Wang R;Chen LB
越来越多的证据表明microRNAs（miRNAs）的调控异常在恶性转化和肿瘤进展中起着关键作用。以前，我们已经表明microRNA-451（miR-451）抑制生长，增加化疗或放射敏感性，并逆转肺癌中的上皮间质转化（EMT）。然而，miR-451在肝细胞癌（HCC）进展和转移中的作用仍不清楚。观察到HCC组织中miR-451的减少与晚期临床分期、转移和更差的无病生存期或总生存期显著相关。通过功能获得和丧失实验，我们证明了miR-451抑制HCC细胞生长，诱导G 0/G1期阻滞并促进细胞凋亡。重要的是，miR-451可以通过调控EMT过程抑制肝癌细胞的体外迁移和侵袭，以及体内转移。此外，癌基因c-Myc被鉴定为HCC细胞中miR-451的直接和功能性靶点。c-Myc的敲除可模拟miR-451对HCC细胞EMT和转移的影响，而c-Myc的过表达可部分减弱miR-451的修复功能。此外，miR-451下调诱导的c-Myc过表达导致Erk 1/2信号转导激活，其通过调节GSK-3β/snail/E-cadherin和增加HCC细胞中MMPs家族成员的表达诱导EMT表型的获得。总的来说，这些数据表明miR-451是HCC患者的一种新的预后生物标志物，并且通过激活Erk 1/2信号传导（至少部分通过靶向c-Myc）在HCC细胞中发挥潜在的转移抑制剂的作用。因此，靶向miR-451/c-Myc/Erk 1/2轴可能是治疗转移性HCC的一个潜在策略。
Increasing evidence indicates that dysregulation of microRNAs (miRNAs) plays critical roles in malignant transformation and tumor progression. Previously, we have shown that microRNA-451 (miR-451) inhibits growth, increases chemo- or radiosensitivity and reverses epithelial to mesenchymal transition (EMT) in lung cancer. However, the roles of miR-451 in hepatocelluar carcinoma (HCC) progression and metastasis are still largely unknown. Reduced miR-451 in HCC tissues was observed to be significantly correlated with advanced clinical stage, metastasis and worse disease-free or overall survival. Through gain- and loss-of function experiments, we demonstrated that miR-451 inhibited cell growth, induced G0/G1 arrest and promoted apoptosis in HCC cells. Importantly, miR-451 could inhibit the migration and invasion in vitro, as well as in vivo metastasis of HCC cells through regulating EMT process. Moreover, the oncogene c-Myc was identified as a direct and functional target of miR-451 in HCC cells. Knockdown of c-Myc phenocopied the effects of miR-451 on EMT and metastasis of HCC cells, whereas overexpression of c-Myc partially attenuated the functions of miR-451 restoration. Furthermore, miR-451 downregulation-induced c-Myc overexpression leads to the activation of Erk1/2 signaling, which induces acquisition of EMT phenotype through regulation of GSK-3β/snail/E-cadherin and the increased expression of MMPs family members in HCC cells. Collectively, these data demonstrated that miR-451 is a novel prognostic biomarker for HCC patients and that function as a potential metastasis inhibitor in HCC cells through activation of the Erk1/2 signaling, at least partially by targeting c-Myc. Thus, targeting miR-451/c-Myc/Erk1/2 axis may be a potential strategy for the treatment of metastatic HCC.