miR-1301 inhibits hepatocellular carcinoma cell migration, invasion, and angiogenesis by decreasing Wnt/β-catenin signaling through targeting BCL9.
miR-1301 inhibits hepatocellular carcinoma cell migration, invasion, and angiogenesis by decreasing Wnt/β-catenin signaling through targeting BCL9.
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miR-1301 通过靶向 BCL9 减少 Wnt/β-catenin 信号传导来抑制肝细胞癌细胞迁移、侵袭和血管生成
DOI：
10.1038/cddis.2017.356
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发表时间：
2017-08-17
影响因子：
9
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Yang C;Xu Y;Cheng F;Hu Y;Yang S;Rao J;Wang X
转移是肝细胞癌（HCC）预后不良的主要原因，越来越多的证据支持miRNAs在肿瘤进展中的作用。然而，miR-1301表达水平与HCC细胞迁移、侵袭和血管生成之间的确切关系在很大程度上仍然未知。使用定量PCR来评估肝癌组织和细胞系中miR-1301的表达水平。Transwell和管形成试验分别用于测量miR-1301对HCC细胞迁移和侵袭以及血管生成的影响。使用荧光素酶报告基因测定和蛋白质印迹法来确认miR-1301靶基因。我们发现miR-1301在HCC组织和细胞系中显著下调。miR-1301低表达与肿瘤血管浸润和Edmondson分级相关。功能获得和功能丧失分析表明，miR-1301在体外和体内抑制HCC细胞的迁移、侵袭、上皮-间质转化和血管生成。与匹配的邻近正常组织相比，在HCC组织中上调的BCL 9与HCC组织中的miR-1301水平呈负相关。通过报告基因和蛋白质印迹分析，显示BCL 9是miR-1301的直接靶标。BCL 9过表达可部分逆转miR-1301对HCC细胞迁移和侵袭的影响。最重要的是，miR-1301过表达通过下调肿瘤细胞中的BCL 9、β-连环蛋白和血管内皮生长因子表达来降低肿瘤负荷、转移和宿主血管生成，从而显著抑制癌症异种移植小鼠模型的死亡。我们的观察表明，miR-1301通过靶向BCL 9减少Wnt/β-catenin信号传导来抑制肝癌的迁移、侵袭和血管生成，并且可能成为肝癌的治疗靶点。
Metastasis is the major cause of the poor prognosis of hepatocellular carcinoma (HCC), and increasing evidence supports the contribution of miRNAs to cancer progression. However, the exact relationship between the level of miR-1301 expression and HCC cell migration, invasion, and angiogenesis remains largely unknown. Quantitative PCR was used to evaluate the level of miR-1301 expression in HCC tissues and cell lines. Transwell and tube-formation assays were used to measure the effects of miR-1301 on HCC cell migration and invasion, and angiogenesis, respectively. Luciferase reporter assays and western blotting were used to confirm the miR-1301 target genes. We found that miR-1301 was significantly downregulated in HCC tissues and cell lines. Low miR-1301 expression was associated with tumor vascular invasion and Edmondson grade. Gain- and loss-of-function assays demonstrated that miR-1301 inhibited the migration, invasion, epithelial–mesenchymal transition, and angiogenesis of HCC cells in vitro and in vivo. BCL9, upregulated in HCC tissues compared with matched adjacent normal tissues, was inversely correlated to miR-1301 levels in HCC tissues. Through reporter gene and western blot assays, BCL9 was shown to be a direct miR-1301 target. BCL9 overexpression could partially reverse the effects of miR-1301 on HCC cell migration and invasion. Most importantly, miR-1301 overexpression markedly suppressed the death of xenograft mouse models of cancer by reducing tumor load, metastasis, and host angiogenesis by downregulating BCL9, β-catenin, and vascular endothelial growth factor expression in tumor cells. Our observations suggested that miR-1301 inhibits HCC migration, invasion, and angiogenesis via decreasing Wnt/β-catenin signaling through targeting BCL9, and might be a therapeutic target for HCC.
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