MiR-126-3p suppresses tumor metastasis and angiogenesis of hepatocellular carcinoma by targeting LRP6 and PIK3R2

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.

MicroRNA-126a Directs Lymphangiogenesis Through Interacting With Chemokine and Flt4 Signaling in Zebrafish

“…Moreover, miR-126 exhibits bidirectional function in angiogenesis. 42,43 The most optimal approach for using miR-126 as a useful target for the treatment should be determined by the context of pathological conditions. The findings reported here demonstrate that miR-126a prompts lymphangiogenesis by cooperating with Flt4 and chemokine signaling cascades and thereby provides a new basis for understanding the generation of LVs.…”

Identification of microRNA-487b as a negative regulator of liver metastasis by regulation of KRAS in colorectal cancer

“…6). LRP6 has been shown to function as an oncogene by promoting cell growth, invasion and migration, and is expected to be a target for cancer therapy (40)(41)(42)(43)(44)(45). Notably, there is evidence that ERK1/2 in the RAS/MAPK pathway could facilitate WNT/β-catenin signaling via LRP6 phosphorylation on serine-1490 (S1490) and threonine-1572 (T1572) at both mature (transmenbrane LRP6) and immature state during its Golgi network-based maturation process (46,47).…”

Evaluating normalization approaches for the better identification of aberrant microRNAs associated with hepatocellular carcinoma

“…In contrast, several previous studies found significant dysregulation of miR-30c, [21,53] miR-30b [21] and miR-126 [54,55] in HCC tumor tissue and blood samples, suggesting their potential etiologic or diagnostic roles. However, none of those previous studies used global mean of miRNAs as the normalizer and did not evaluate miRNAs expression stabilities that might lead to false positive findings.…”