BackgroundDespite accumulating evidence that long noncoding RNAs (lncRNAs) are associated with cancer development in multiple types of cancer, the biological roles of many lncRNAs in human hepatocellular carcinoma (HCC) metastasis have not been well characterized.MethodsA lncRNA+ mRNA human gene expression microarray analysis was used to identify differentially expressed lncRNAs in metastatic HCC tissues compared to non-metastatic tissue.ResultsWe observed remarkable overexpression of HOXD-AS1 in metastatic cancer tissues. In vitro and in vivo gain- or loss-of-function studies re-affirmed that HOXD-AS1 is able to facilitate cancer metastasis and inhibit apoptosis. Moreover, we identified that HOXD-AS1 upregulated the Rho GTPase activating protein 11A (ARHGAP11A) by competitively binding to microRNA-19a (miR19a), resulting in induced metastasis. Interestingly, the regulator of G-protein signaling 3 (RGS3), a potential inhibitor of the MEK-ERK1/2 signaling axis, was also found to be downregulated by ectopic HOXD-AS1 overexpression, leading to a remarkably reduced apoptotic effect.ConclusionsThe present investigation strongly indicates that HOXD-AS1 is an oncogenic lncRNA that promotes HCC metastasis and that its pro-metastatic phenotype can partially be attributed to the HOXD-AS1/miR19a/ARHGAP11A signaling axis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0676-x) contains supplementary material, which is available to authorized users.

MicroRNAs are known to be involved in the pathogenesis of hepatocellular carcinoma (HCC). This study aims to explore the potential biological function of miR-376a, which was found to be inhibited after partial hepatectomy, in HCC. We discovered that miR-376a was frequently down-regulated in HCC cell lines and HCC tissues, while higher relative level of miR-376a was significantly associated with high serum AFP level. Over-expression of miR-376a not only inhibited proliferation but induced apoptosis in Huh7 cells. Additionally, p85α (PIK3R1) was identified as a direct and functional target of miR-376a in Huh7 cells. Moreover, we confirmed that p85α and miR-376a were inversely correlated in HCC. These findings suggest that down-regulation of miR-376a may contribute to the development of HCC by targeting p85α.

Edited by Veli-Pekka LehtoKeywords: MicroRNAs miR-23b Liver regeneration Transforming growth factor-b1 Smad3 a b s t r a c t MicroRNAs (miRNAs) are known to play important roles in liver regeneration, although the role of miRNAs associated with the termination of liver regeneration is not as well studied. Here we reported the down-regulation of miR-23b in the termination stage of liver regeneration in rats. In addition, Smad3 was identified as a target of miR-23b during liver regeneration. Up-regulation of miR-23b promoted BRL-3A cell proliferation and partially inhibited transforming growth factor (TGF)-b1-induced apoptosis. Furthermore, TGF-b1 transcriptionally inhibited miR-23b expression. We conclude that down-regulation of miR-23b may contribute to activation of the TGF-b1/Smad3 signalling pathway during the termination stage of liver regeneration.

Hydrogen sulfide (H2S) is the third most common endogenously produced gaseous signaling molecule, but its impact on hepatic ischemia/reperfusion (I/R) injury, especially on mitochondrial function, remains unclear. In this study, rats were randomized into Sham, I/R, ischemia preconditioning (IPC) or sodium hydrosulfide (NaHS, an H2S donor) preconditioning groups. To establish a model of segmental (70%) warm hepatic ischemia, the hepatic artery, left portal vein and median liver lobes were occluded for 60 min and then unclamped to allow reperfusion. Preconditioning with 12.5, 25 or 50 μmol/kg NaHS prior to the I/R insult significantly increased serum H2S levels, and, similar to IPC, NaHS preconditioning decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the plasma and prevented hepatocytes from undergoing I/R-induced necrosis. Moreover, a sub-toxic dose of NaHS (25 μmol/kg) did not disrupt the systemic hemodynamics but dramatically inhibited mitochondrial permeability transition pore (MPTP) opening and thus prevented mitochondrial-related cell death and apoptosis. Mechanistic studies revealed that NaHS preconditioning markedly increased the expression of phosphorylated protein kinase B (p-Akt), phosphorylated glycogen synthase kinase-3 beta (p-GSK-3β) and B-cell lymphoma-2 (Bcl-2) and decreased the release of mitochondrial cytochrome c and cleaved caspase-3/9 levels. Therefore, NaHS administration prior to hepatic I/R ameliorates mitochondrial and hepatocellular damage through the inhibition of MPTP opening and the activation of Akt-GSK-3β signaling. Furthermore, this study provides experimental evidence for the clinical use of H2S to reduce liver damage after perioperative I/R injury.

Liver regeneration (LR) after partial hepatectomy (PH) involves the proliferation and apoptosis of hepatocytes, and microRNAs have been shown to post-transcriptionally regulate genes involved in the regulation of these processes. To explore the role of miR-127 during LR, the expression patterns of miR-127 and its related proteins were investigated. MiR-127 was introduced into a rat liver cell line to examine its effects on the potential target genes Bcl6 and Setd8, and functional studies were undertaken. We discovered that miR-127 was down-regulated and inversely correlated with the expression of Bcl6 and Setd8 at 24 hours after PH, a time at which hypermethylation of the promoter region of the miR-127 gene was detected. Furthermore, in BRL-3A rat liver cells, we observed that overexpression of miR-127 significantly suppressed cell growth and directly inhibited the expression of Bcl6 and Setd8. The results suggest that down-regulation of miR-127 may be due to the rapid methylation of its promoter during the first 24 h after PH, and this event facilitates hepatocyte proliferation by releasing Bcl6 and Setd8. These findings support a miRNA-mediated negative regulation pattern in LR and implicate an anti-proliferative role for miR-127 in liver cells.