Irene Yan

Long noncoding RNA in liver diseases

The identification of the presence of large RNA transcripts that do not code for proteins but that may have biological functions has provided an important new perspective in gene regulation. These long noncoding RNAs (lncRNAs) are being increasingly recognized to contribute to many biological processes through diverse mechanisms. The roles of these emerging genes are being recognized across kingdoms. These findings are profoundly altering our understanding of disease pathobiology and leading to the emergence of new biological concepts underlying human diseases. Strategies for the discovery and characterization of lncRNAs are highlighted. Several lncRNAs have been described in liver disease, and in liver cancers in particular. Their molecular mechanisms of action, function, and contributions to disease pathophysiology are reviewed. LncRNA genes associated with liver diseases have potential roles as biomarkers of disease diagnosis, prognosis, or therapeutic response as well as direct targets for therapeutic intervention. Conclusion: The emerging knowledge in this rapidly advancing field offers promise for new fundamental knowledge and clinical applications that will be relevant for human liver diseases. (Hepatology 2014;60:744–753)

Therapeutic Potential of the Translation Inhibitor Silvestrol in Hepatocellular Cancer

Background & Aims Although hepatocellular cancers (HCC) frequently arise in the setting of fibrosis and a hepatic regenerative response requiring new cell growth, therapeutic strategies for these cancers have not targeted protein synthesis. Silvestrol, a rocaglate isolated from Aglaia foveolata , can inhibit protein synthesis by modulating the initiation of translation through the eukaryotic initiation factor 4A. In this study, we evaluated the therapeutic efficacy of silvestrol for HCC. Methods The efficacy of silvestrol was examined using human HCC cells in vitro using an orthotopic tumor cell xenograft model in a fibrotic liver. The impact of silvestrol on the liver was assessed in vivo in wild-type mice. Results Silvestrol inhibited cell growth with an IC50 of 12.5-86 nM in four different HCC cell lines. In vitro, silvestrol increased apoptosis and caspase 3/7 activity accompanied by loss of mitochondrial membrane potential and decreased expression of Mcl-1 and Bcl-xL. A synergistic effect was observed when silvestrol was combined with other therapeutic agents, with a dose-reduction index of 3.42-fold with sorafenib and 1.75-fold with rapamycin at a fractional effect of 0.5. In vivo, an antitumor effect was observed with 0.4 mg/kg silvestrol compared to controls after one week, and survival of tumor-bearing mice was improved with a median survival time of 42 and 28 days in the silvestrol and control groups, respectively. The effect on survival was not observed in orthotopic xenografts in non-fibrotic livers. Silvestrol treatment in vivo did not alter liver structure. Conclusions These data identify silvestrol as a novel, structurally unique drug with potent anticancer activity for HCC and support the potential value of targeting initiation of translation in the treatment of HCC.

Hepatic miR-29ab1 expression modulates chronic hepatic injury

MicroRNAs (miRNAs) are small, regulatory non‐coding RNAs that have potent effects on gene expression. Several miRNA are deregulated in cellular processes involved in human liver diseases and regulation of cellular processes. Recent studies have identified the involvement of miR‐29 in hepatic fibrosis and carcinogenesis. Although several targets of miR‐29 have been identified, there is limited information regarding the cell‐type specific roles of miR‐29 in the liver, and we sought to evaluate the role of this miRNA in hepatic pathobiology. We report the generation of a tissue–specific knockout mouse to evaluate the role of miR‐29 in hepatic fibrosis and carcinogenesis in response to injury. We hypothesized that miR‐29 contributes to the hepatocyte driven response to chronic cellular injury that results in fibrosis. In support of this hypothesis, fibrosis and mortality were enhanced in miR29 knockout mice in response to carbon tetrachloride. Genome‐wide gene expression analysis identified an over‐representation of genes associated with fibrosis. The oncofetal RNA H19 was modulated in a miR‐29 dependent manner following exposure to carbon tetrachloride in vivo. The impact of a hepatocyte specific miR‐29 knockout on survival following chronic hepatic injury in vivo implicates this miRNA as a potential target for intervention. These results provide evidence of the involvement of miR‐29 in chronic hepatic injury, and suggest a role for deregulated hepatocyte expression of miR‐29 in the response to hepatic injury, fibrosis and carcinogenesis.

microRNAs in liver disease: from diagnostics to therapeutics.

There is a need to identify effective biomarkers for diagnosis, prognosis and prediction of treatment efficacy for many liver diseases such as hepatocellular cancer, and chronic viral hepatitis. The identification of disease-specific alterations in microRNA expression and the ability to detect microRNAs in the circulation provide the basis for identifying novel clinically effective treatments and biomarkers. Knowledge regarding miRNA in human liver disease may eventually lead to serum or tissue biomarkers with clinical utility. A selection of relevant studies is reviewed. There are major challenges that need to be addressed prior to clinical application such as the need for careful validation of diagnostic miRNA candidates in well described clinical cohorts, and technical issues such as quantitation and standardization of assays. The rapid progress in therapeutic interventions using miRNA based strategies for chronic hepatitis C and hepatocellular cancer provides optimism for novel approaches that will build on the existing and emerging knowledge regarding miRNA in liver diseases.

Emerging insights into the role of microRNAs in the pathogenesis of cholangiocarcinoma

The microRNAs (miRNAs) are small noncoding RNAs that are potent regulators of gene expression and can regulate several diverse biological functions. This minireview provides an overview of recent studies that have examined the role and involvement of miRNAs in cholangiocarcinomas. These studies provide evidence for deregulated expression of miRNA and are providing new insights into the potential contribution of these in the pathogenesis of cholangiocarcinoma.

Mo1034 Extracellular Long Non-Coding RNA Lincrna-Vldlr Modulates Hepatocellular Cancer Responses to Chemotherapy

Background/Aims: Spontaneous bacterial peritonitis (SBP) is a frequent complication of cirrhosis, associated with a poor long-term prognosis. The risk of SBP associated with proton pump inhibitor (PPI) use has been raised in advanced cirrhotic patients. However, those studies are limited by small series and/or case-control study design. This study aimed to determine whether PPI use is associated with SBP in a cohort composed of cirrhotic patients with ascites. Methods: This retrospective cohort study included 1,965 cirrhotic patients with ascites who was first diagnosed at Samsung Medical Hospital between Jan 2005 and Dec 2009. Propensity score matching generated a matched cohort composed of 886 patients. According to the PPI use (PPI group vs. non-PPI group), the SBP incidence was calculated in the each total study population and in the propensity score matched-cohort. Results: Of the 1,965 patients, 512 (32.9%) were included in PPI group. At baseline, PPI group showed lower platelet count (91.3 ± 54.2 x 103/mm3 vs. 103.4 ± 62.7 x 103/mm3; P<0.001), more prolonged prothrombin time (1.41 ± 0.43 INR vs. 1.35 ± 0.31 INR; P=0.001), and higher Child-Pugh score (8.0 ± 1.8 vs. 7.8 ± 1.6; P=0.041) than non-PPI group. PPI group showed higher SBP incidence rate than non-PPI group (10.3%/year vs. 5.9%/year; P=0.002). In the propensity score-matched cohort, baseline characteristics did not differ between the two groups. After matching, SBP incidence rate did not differ between the two groups (PPI group vs. non-PPI group, P=0.124) during a mean follow-up of 22.8 ± 24.5 months (range: 095.3 months). Conclusion: On the contrary to the current knowledge, our data suggest that PPI use is not a significant risk factor for SBP in cirrhotic patients with ascites.