MicroRNA-135a contributes to the development of portal vein tumor thrombus by promoting metastasis in hepatocellular carcinoma
MicroRNA-135a contributes to the development of portal vein tumor thrombus by promoting metastasis in hepatocellular carcinoma
复制标题
MicroRNA-135a通过促进肝细胞癌的转移来促进门静脉肿瘤血栓的形成。
DOI：
10.1016/j.jhep.2011.08.008
复制
发表时间：
2012-02-01
影响因子：
25.7
通讯作者：
Liu, Shanrong
中科院分区：
文献类型：
--
作者：
Liu, Shupeng;Guo, Weixing;Liu, Shanrong
背景与目的：已有研究表明，门静脉癌栓与肝细胞癌预后不良有关。约50-80%的肝细胞癌伴有门静脉或肝静脉侵犯。PVTT发生的潜在机制尚不清楚。本研究旨在阐明miR-135a在PVTT肿瘤发生中的作用。方法：本研究利用先进的microRNA和基因芯片技术，研究了microRNAs和mRNAs在PVTT组织中的表达。MicroRNA(MiR)-135a在PVTT和CSQT-2细胞中高表达，并被选作进一步研究。我们在体外和体内鉴定了miR-135a的功能。我们还分析了miR-135a与肝细胞癌合并PVTT患者预后和生存的临床相关性。结果：我们的分析发现，PVTT的miRNA和mRNA的表达谱不同于实质性肿瘤。MiR-135a的过表达有利于体外侵袭和转移行为。此外，在CSQT-2原位移植裸鼠模型中，阻断miR-135a显著降低了PVTT的发生率。我们还发现miR-135a是由叉头盒M1(FOXM1)转录的，转移抑制因子1(MTSS1)被确定为miR-135a的直接和功能靶点。此外，队列分析还揭示了miR-135a与肝癌合并PVTT患者的预后和生存的相关性。结论：miR-135a在促进PVTT的发生发展中起着重要作用，提示miR-135a在PVTT治疗中具有潜在的应用价值。(C)2011年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background & Aims: Portal vein tumor thrombus (PVTT) has previously been demonstrated to correlate with poor prognosis of hepatocellular carcinoma. Approximately 50-80% of HCC is accompanied by portal or hepatic vein invasion. The underlying mechanisms of PVTT development remain unclear. This study aimed to elucidate the role of miR-135a in PVTT tumorigenesis.Methods: In the present study, we investigated the expression of microRNAs and mRNAs in PVTT tissues using advanced microRNA and cDNA microarray techniques. MicroRNA (miR)-135a was noted to be highly over-expressed in PVTT and the cell line CSQT-2 and was selected for further study. We characterized the function of miR-135a in vitro and in vivo. We also analyzed the clinical relevance of miR-135a in relation to the prognosis and survival of HCC patients with PVTT.Results: Our analyses found that the miRNA and mRNA expression profiles of PVTT were distinct from the parenchyma tumor. Overexpression of miR-135a favors invasive and metastatic behavior in vitro. Furthermore, in a CSQT-2 orthotopic transplantation nude mouse model, blockade of miR-135a significantly reduced PVTT incidence. We also found that miR-135a was transcribed by forkhead box M1 (FOXM1), and metastasis suppressor 1 (MTSS1) was identified as the direct and functional target of miR-135a. Additionally, the cohort analysis revealed the relevance of miR-135a with respect to the prognosis and survival of HCC patients with PVTT.Conclusions: Our data suggest an important role for miR-135a in promoting PVTT tumorigenesis and indicate the potential application of miR-135a in PVTT therapy. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.