Xu Feng Feng, Xie Wen Feng, Zha Guo Qing, Chen Hong Wu, Deng Liang
Department II of General Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510700, China.
Department of Intensive Care Unit, The Eastern Hospital of the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510700, China.
Oncotarget. 2017 Nov 30;8(65):109546-109558. doi: 10.18632/oncotarget.22726. eCollection 2017 Dec 12.
Cancer metastasis is a multistep cellular process, which has be confirmed one of mainly causes of cancer associated-death in hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) participate in tumorigenesis function as either tumor suppressor genes or oncogenes. In order to elaborate the critical miRNAs and their targets in HCC, we compared the differential expression of miRNA between HCC tissues and normal tissues. Microarray analysis revealed there were several significantly up-expression miRNAs in HCC, compared to normal solid tissue. Among them, the expression of miR-520f was the most over-expression in HCC cell lines than that in human normal liver cells LO2, as well as up-regulated in HCC than that in the corresponding normal tissues. Moreover, Kaplan Meier-plotter analyses revealed that higher miR-520f levels were negatively correlated with poor overall survival. By applying bioinformatics methods to identify the targeting genes of miRNA, we demonstrated that fibroblast growth factor 16 (FGF16) was the miR-520f-targeted gene. Meanwhile, FGF16 exhibited similar expression patterns to miR-520f in HCC. Forced miR-520f expression accelerated HCC cells proliferation and aggressiveness and , whereas down-regulation of miR-520f caused an opposite outcome. Moreover, over-expression of FGF16 was closely related to the metastatic potential of HCC cells. Herein, we also confirmed that ectopic expression of FGF16 in HCC cells promoted proliferation, colony formation, and increased migration, invasion of HCC cells . Collectively, our results indicated that over-expression of miR-520f and FGF16 was positively associated with aggressive phenotypes and poor survival of patients with HCC, and miR-520f promoted HCC aggressive phenotypes by regulating the expression of FGF16. MiR-520f may be employed as a prognostic factor and therapeutic target for HCC.
癌症转移是一个多步骤的细胞过程，已被确认为肝细胞癌（HCC）中与癌症相关死亡的主要原因之一。微小RNA（miRNA）作为肿瘤抑制基因或癌基因参与肿瘤发生功能。为了阐明HCC中关键的miRNA及其靶标，我们比较了HCC组织与正常组织中miRNA的差异表达。微阵列分析显示，与正常实体组织相比，HCC中有几种miRNA显著上调。其中，miR-520f在HCC细胞系中的表达比在人正常肝细胞LO2中过度表达最多，并且在HCC中比在相应的正常组织中上调。此外，Kaplan Meier绘图分析显示，较高的miR-520f水平与总体生存率差呈负相关。通过应用生物信息学方法鉴定miRNA的靶向基因，我们证明成纤维细胞生长因子16（FGF16）是miR-520f靶向的基因。同时，FGF16在HCC中的表达模式与miR-520f相似。强制表达miR-520f可加速HCC细胞增殖和侵袭，而miR-520f的下调则产生相反的结果。此外，FGF16的过表达与HCC细胞的转移潜能密切相关。在此，我们还证实HCC细胞中FGF16的异位表达促进了增殖、集落形成，并增加了HCC细胞的迁移和侵袭。总体而言，我们的结果表明，miR-520f和FGF16的过表达与HCC患者的侵袭性表型和不良生存呈正相关，并且miR-520f通过调节FGF16的表达促进HCC侵袭性表型。MiR-520f可作为HCC的预后因素和治疗靶点。
