Abstract
BackgroundThe deregulation of microRNAs has been reported to play a pivotal role in hepatocellular carcinoma (HCC). MiR-126-3p has been reported to be associated with poor prognosis in HCC. However the underlying mechanism of miR-126-3p in HCC remains unclear.MethodsThe expression levels of miR-126-3p in HCC tissues and cells were detected by RT-PCR. Transwell assay and capillary tube formation assay were applied to assess the metastasis and angiogenesis in vitro. Nude mice subcutaneous tumor model was used to perform in vivo study. Dual- luciferase reporter assay was conducted to confirm the direct binding of miR-126-3p and target genes. The changes of biomarker protein levels were examined by western blot and Immunohistochemistry.ResultsWe observed that the miR-126-3p expression levels in HCC tissues and cells were significantly down-regulated. Through gain- and loss- of function studies, we showed that miR-126-3p dramatically inhibited HCC cells from migrating and invading extracellular matrix gel and suppressed capillary tube formation of endothelial cells in vitro. Furthermore, overexpression of miR-126-3p significantly reduced the volume of tumor and microvessel density in vivo. LRP6 and PIK3R2 were identified as targets of miR-126-3p. Silencing LRP6 and PIK3R2 had similar effects of miR-126-3p restoration on metastasis and angiogenesis individually in HCC cells. Furthermore, the miR-126-3p level was inversely correlated with LRP6 and PIK3R2 in HCC tissues. In addition, the rescue experiments indicated that the metastasis and angiogenesis functions of miR-126-3p were mediated by LRP6 and PIK3R2.ConclusionOur results demonstrates that deregulation of miR-126-3p contributes to metastasis and angiogenesis in HCC. The restoration of miR-126-3p expression may be a promising strategy for HCC therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-014-0259-1) contains supplementary material, which is available to authorized users.
Highlights
The deregulation of microRNAs has been reported to play a pivotal role in hepatocellular carcinoma (HCC)
In 70 pairs of Hepatocellular carcinoma (HCC) tissues, the expression of miR-126-3p was significantly down-regulated in tumors tissues versus adjacent non-tumor liver tissues (Figure 1A)
Among these 70 cases, 62 cases revealed a relative lower level in HCC, which suggested that reduction of miR-126-3p was a frequent event in human HCC
Summary
The deregulation of microRNAs has been reported to play a pivotal role in hepatocellular carcinoma (HCC). MiR-126-3p has been reported to be associated with poor prognosis in HCC. Increasing numbers of studies have suggested that miRNAs. MiR-126-3p has been reported to act as a tumor suppressor by targeting CRK, SOX2, IRS-1 in several cancer types [13,14,15]. The potential role of miR-126-3p in HCC angiogenesis remains unclear. A previous study indicated that miR-126-3p associates with the recurrence rate after liver transplantation and suppresses metastasis in HCC [19]. We examined the expression patterns of miR-126-3p in HCC comparing to normal tissue. Both gain and loss of function indicated miR-126-3p suppressed metastasis and angiogenesis in HCC cells. Our findings demonstrate the importance of deregulation of miR-126-3p in promoting HCC progression and indicate that miR-126-3p might serves as a therapeutic target for HCC
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