RP11-40C6.2 Inactivates Hippo Signaling by Attenuating YAP1 Ubiquitylation in Hepatitis B Virus-associated Hepatocellular Carcinoma

Background and Aims:Chronic hepatitis caused by hepatitis B virus(HBV)infection is a leading cause of hepatocellular carcinoma(HCC).We investigated the roles of oncogenic HBV infection-associated long noncoding RNAs in HCC.Methods:Bioinformatics analysis of data from the Cancer Genome Atlas(TCGA)was performed to screen potential oncogenic HBV-related lncRNAs.Next,we assessed their expression in clinical samples and investigated their correlation with clinical characteristics.The detailed oncogenic effects were analyzed by performing in vitro and in vivo studies.Results:RP11-40C6.2,an HBV infection-related lncRNA,was identified by analysis of the TCGA–Liver Hepatocellular Carcinoma database.Gene Set Enrichment Analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis of differentially expressed genes revealed a strong association of RP11-40C6.2 with the Hippo signaling pathway.RP11-40C6.2 was overexpressed in HCC patients with HBV infection compared to those without HBV infection.RP11-40C6.2 transcription showed a positive association with HBV-X protein(HBx),but not HBV core protein(HBc)expression,both of which are carcinogenic proteins.Luciferase gene reporter and ChIP assays revealed that YAP1/TAZ/TEADs complex enhanced RP11-40C6.2 transcription by binding to its promoter area.RP11-40C6.2 showed oncogenic characteristics in HCC cell lines and in animal models that were mediated via activation of YAP1.In vitro ubiquitylation assay revealed that RP11-40C6.2 can promote the stabilization of YAP1 by stopping phosphorylation at its s127 residue and further stopping its degradation through binding to 14-3-3.Conclusions:RP11-40C6.2 is an HBV infection-related lncRNA that exerts its oncogenic effects by targeting the Hippo signaling pathway.

Interleukin-33 drives hepatic fibrosis through activation of hepatic stellate cells

Liver fibrosis is a consequence of chronic liver disease,causing morbidity and mortality.Interleukin-33(IL-33)is a critical mediator of inflammation,which may be involved in the development of liver fibrosis.Here,we investigated the role of IL-33 in human patients and experimental bile-duct ligation(BDL)-induced fibrosis in mice.We report increased hepatic IL-33 expression in the murine BDL model of fibrosis and in surgical samples obtained from patients with liver fibrosis.Liver injury,inflammatory cell infiltration and fibrosis were reduced in the absence of the IL-33/ST2 receptor,and the activation of hepatic stellate cells(HSCs)was decreased in ST2-deficient mice.Recombinant IL-33 activated HSCs isolated from C57BL/6 mice,leading to the expression of IL-6,TGF-β,α-SMA and collagen,which was abrogated in the absence of ST2 or by pharmacological inhibition of MAPK signaling.Finally,administration of recombinant IL-33 significantly increased hepatic inflammation in sham-operated BL6 mice but did not enhance BDL-induced hepatic inflammation and fibrosis.In conclusion,BDL-induced liver inflammation and fibrosis are dependent on ST2 signaling in HSCs,and therefore,the IL-33/ST2 pathway may be a potential therapeutic target in human patients with chronic hepatitis and liver fibrosis.

A Novel Hybrid Method to Analyze Security Vulnerabilities in Android Applications

We propose a novel hybrid method to analyze the security vulnerabilities in Android applications.Our method combines static analysis,which consists of metadata and data flow analyses with dynamic analysis,which includes dynamic executable scripts and application program interface hooks.Our hybrid method can effectively analyze nine major categories of important security vulnerabilities in Android applications.We design dynamic executable scripts that record and perform manual operations to customize the execution path of the target application.Our dynamic executable scripts can replace most manual operations,simplify the analysis process,and further verify the corresponding security vulnerabilities.We successfully statically analyze 5547 malwares in Drebin and 10 151real-world applications.The average analysis time of each application in Drebin is 4.52 s,whereas it reaches 92.02 s for real-word applications.Our system can detect all the labeled vulnerabilities among 56 labeled applications.Further dynamic verification shows that our static analysis accuracy approximates 95%for real-world applications.Experiments show that our dynamic analysis can effectively detect the vulnerability named input unverified,which is difficult to be detected by other methods.In addition,our dynamic analysis can be extended to detect more types of vulnerabilities.