MicroRNA-197 Promotes Metastasis of Hepatocellular Carcinoma by Activating Wnt/-Catenin Signaling
MicroRNA-197 Promotes Metastasis of Hepatocellular Carcinoma by Activating Wnt/-Catenin Signaling
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MicroRNA-197 通过激活 Wnt/β-Catenin 信号促进肝细胞癌转移
DOI：
10.1159/000495242
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Xie, Chan
中科院分区：
文献类型：
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作者：
Hu, Zhaoxia;Wang, Peipei;Xie, Chan
背景/目的：MicroRNA-197（miR-197）已被证明在上皮间质转化（EMT）和转移中发挥作用。Wnt/β-catenin通路与EMT相关，但miR-197是否调节Wnt/β-catenin仍不清楚。本研究旨在探讨miR-197在肝细胞癌（HCC）Wnt/β-catenin通路中的作用。研究方法：采用定量逆转录聚合酶链反应（qRT-PCR）检测105例HCC标本和15株HCC细胞系中miR-197的表达。我们使用遗传报告系统测试了miR-197的预测靶基因。分析了miR-197在HCC细胞侵袭和迁移（通过Transwell测定的伤口愈合和细胞侵袭和迁移）以及HCC异种移植模型中的作用。结果如下：使用HCC标本的miRNA微阵列分析并与非转移性HCC相比，miR-197被鉴定为转移性HCC中上调最多的miRNA之一。miR-197的表达与肝癌细胞系的侵袭力呈正相关。具有高miR-197表达的转移性HCC细胞具有Wnt/β-catenin信号传导激活。高水平的miR-197表达也促进了体外和体内HCC细胞的EMT和侵袭。miR-197直接靶向Axin-2、裸角质层1（NKD 1）和Dickkopf相关蛋白2（DKK 2），导致Wnt/β-连环蛋白信号传导的抑制。在门静脉转移患者的HCC标本中发现高miR-197表达;高miR-197表达与Axin 2、NKD 1和DKK 2的表达相关。结论：miR-197通过激活Wnt/β-catenin信号通路促进HCC侵袭转移。miR-197有可能作为HCC的预后标志物和治疗靶点。
Background/Aims: MicroRNA-197 (miR-197) has been shown to play roles in epithelialmesenchymal transition (EMT) and metastasis. The Wnt/-catenin pathway is associated with EMT, but whether miR-197 regulatesWnt/-catenin remains unclear. This study was to demonstrate the role of miR-197 on the Wnt/-catenin pathway in hepatocellular carcinoma (HCC). Methods: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-197 in 105 HCC specimens and 15 HCC cell lines. We tested the predicted target gene of miR-197 using a genetic report system. The role of miR-197 in HCC cell invasion and migration (wound healingand cell invasion and migrationby Transwell assays) and in an HCC xenograft modelwas analyzed. Results: Using a miRNA microarray analysis of HCC specimens and compared with non-metastatic HCC, miR-197 was identified as one of the most upregulated miRNAs in metastatic HCC. miR-197 expression was positively associated with the invasiveness of HCC cell lines. Metastatic HCC cells with high miR-197 expression had Wnt/-catenin signaling activation. High levels of miR-197 expression also promoted EMT and invasionHCC cells in vitro and in vivo. miR-197 directly targeted Axin-2, Naked cuticle 1 (NKD1), and Dickkopf-related protein 2 (DKK2), leading to inhibition of Wnt/-catenin signaling. High miR-197 expression was found in HCC specimens from patients with portal vein metastasis;high miR-197 expression correlated to the expression of Axin2, NKD1, and DKK2. Conclusion: miR-197 promotes HCC invasion and metastasis by activating Wnt/-catenin signaling. miR-197 could possibly be used as a prognostic marker and therapeutic target for HCC.