The tumor suppressive miR-26a regulation of FBXO11 inhibits proliferation, migration and invasion of hepatocellular carcinoma cells
The tumor suppressive miR-26a regulation of FBXO11 inhibits proliferation, migration and invasion of hepatocellular carcinoma cells
复制标题
DOI：
10.1016/j.biopha.2018.02.118
复制
发表时间：
2018-05-01
影响因子：
7.5
通讯作者：
Wang, Hongsheng
中科院分区：
文献类型：
--
作者：
Ma, Yue;Deng, Fang;Wang, Hongsheng
越来越多的研究发现，microRNA-26a （miR-26a）在肝细胞癌（HCC）中具有抑癌作用。F-box蛋白11 （FBXO11）是miR-26a的预测靶基因，是E3泛素连接酶和II型甲基转移酶，是肿瘤发生和进展的关键调节因子。本研究旨在探讨miR-26a对FBXO11表达的调控作用，探讨FBXO11在HCC中的临床意义及功能作用。与匹配的肿瘤邻近组织相比，HCC组织中miR-26a的表达水平显著下调。MiR-26a在HCC细胞中负调控FBXO11丰度。因此，miR-26a可以直接靶向FBXO11 mRNA的3'UTR抑制其表达。基因表达综合（GEO）数据库（GSE54236和GSE45436）和我们的数据显示FBXO11在HCC组织中表达上调。HCC标本中FBXO11 mRNA水平与miR-26a表达呈负相关。FBXO11高表达与肝癌患者肿瘤大小、静脉浸润及肿瘤分期晚期呈正相关。临床预后分析表明，FBXO11高表达预示HCC患者生存期较差。在体外，FBXO11敲低可抑制肝癌细胞的增殖、集落形成、迁移和侵袭。此外，miR-26a过表达与FBXO11敲低对HCC细胞这些恶性行为的影响一致。值得注意的是，FBXO11修复逆转了miR-26a对HCC细胞增殖、集落形成、迁移和侵袭的抑制作用。综上所述，这些结果表明miR-26a对FBXO11的调控在HCC中具有致癌作用。抑制FBXO11可能成为HCC的治疗靶点。
Accumulating researches identify microRNA-26a (miR-26a) as a tumor suppressor in hepatocellular carcinoma (HCC). F-box protein 11 (FBXO11), a predicted target gene of miR-26a, is an E3 ubiquitin ligase and a type II methyltransferase, and functions as a key regulator of tumor initiation and progression. This study was aimed to investigate the regulatory role of miR-26a in FBXO11 expression and explored the clinical significance as well as functional role of FBXO11 in HCC. The expression levels of miR-26a were prominently downregulated in HCC tissues compared to matched tumor-adjacent tissues. MiR-26a inversely regulated FBXO11 abundance in HCC cells. Hereby, miR-26a could directly target 3'UTR of FBXO11 mRNA to suppress its expression. Gene Expression Omnibus (GEO) database (GSE54236 and GSE45436) and our data demonstrated that the expression of FBXO11 was up-regulated in HCC tissues. The level of FBXO11 mRNA was inversely correlated with miR-26a expression in HCC specimens. High FBXO11 expression was positively correlated with large tumor size, venous infiltration and advanced tumor stage of HCC patients. Clinical prognostic analysis illustrated that high FBXO11 expression predicted a poor survival of HCC patients. In vitro, FBXO11 knockdown inhibited cell proliferation, colony formation, migration and invasion of HCC cells. Additionally, miR-26a overexpression showed a consistent effect with FBXO11 knockdown on these malignant behaviors of HCC cells. Notably, FBXO11 restoration reversed the inhibitory effect of miR-26a on HCC cell proliferation, colony formation, migration and invasion. In summary, these results indicated that miR-26a regulation of FBXO11 exhibited an oncogenic role in HCC. Inhibition of FBXO11 might serve as a therapeutic target for HCC.