State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.
Gastroenterology. 2011 Jan;140(1):322-31. doi: 10.1053/j.gastro.2010.10.006. Epub 2010 Oct 15.
BACKGROUND & AIMS: We investigated mechanisms of hepatocellular carcinoma (HCC) metastasis and identified an antimetastatic microRNA (miRNA), miR-139, that is down-regulated in human HCC samples.
Effects of stable and transient expression of miRNA-139 and its inhibitors were studied in the human HCC cell lines SMMC-7721 and BEL7402; cells were analyzed for migration and invasion. Liver samples from patients with metastatic HCC were analyzed for levels of miRNA-139; data were compared with survival data using the Kaplan-Meier method and compared between groups by the log-rank test. Tumor formation and metastasis from human HCC MHCC97L cells that did or did not express miR-139 were analyzed in mice.
Down-regulation of miR-139 in HCC was associated significantly with poor prognosis of patients and features of metastatic tumors, including venous invasion, microsatellite formation, absence of tumor encapsulation, and reduced differentiation. miR-139 expression was reduced in metastatic HCC tumors compared with primary tumors. Overexpression of miR-139 in HCC cells significantly reduced cell migration and invasion in vitro and the incidence and severity of lung metastasis from orthotopic liver tumors in mice. miR-139 interacted with the 3' untranslated region of Rho-kinase 2 (ROCK2) and reduced its expression in HCC cells. Levels of miR-139 were correlated inversely with ROCK2 protein in human HCC samples. Overexpression of miR-139 did not inhibit HCC cell motility when ROCK2 was knocked down.
The microRNA miR-139 interacts with ROCK2 and reduces its expression in HCC cells. Down-regulation of miR-139 increased the invasive abilities of HCC cells in vitro and HCC metastasis in vivo. Expression of miR-139 is reduced in human metastatic HCC samples and correlates with prognosis.
我们研究了肝细胞癌（HCC）转移的机制，并鉴定出一种抗转移微小 RNA（miRNA），miR-139 在人 HCC 样本中下调。
在人 HCC 细胞系 SMMC-7721 和 BEL7402 中研究了 miRNA-139 的稳定和瞬时表达及其抑制剂的作用；分析了细胞的迁移和侵袭。分析转移性 HCC 患者肝组织中 miR-139 的水平；使用 Kaplan-Meier 方法将数据与生存数据进行比较，并通过对数秩检验在组间进行比较。分析表达或不表达 miR-139 的人 HCC MHCC97L 细胞在小鼠中的肿瘤形成和转移。
HCC 中 miR-139 的下调与患者的不良预后和转移性肿瘤的特征显著相关，包括静脉侵犯、微卫星形成、缺乏肿瘤包膜和分化减少。与原发性肿瘤相比，转移性 HCC 肿瘤中 miR-139 的表达降低。在 HCC 细胞中过表达 miR-139 可显著降低细胞在体外的迁移和侵袭能力，以及小鼠原位肝肿瘤肺转移的发生率和严重程度。miR-139 与 Rho-kinase 2（ROCK2）的 3'非翻译区相互作用并降低其在 HCC 细胞中的表达。miR-139 的水平与人 HCC 样本中的 ROCK2 蛋白呈负相关。当 ROCK2 被敲低时，miR-139 的过表达并不抑制 HCC 细胞的迁移能力。
微小 RNA miR-139 与 ROCK2 相互作用并降低其在 HCC 细胞中的表达。miR-139 的下调增加了 HCC 细胞在体外的侵袭能力和体内 HCC 转移。miR-139 在人转移性 HCC 样本中的表达降低，并与预后相关。
