Purpose: To investigate Tip30 promoter methylation status in human hepatocellular carcinoma (HCC) and the correlation with clinicopathologic features and prognosis. Experimental Design: The methylation status of CpG islands inTip30 promoter was examined in 15 HCC cell lines as well as 59 paired HCC and adjacent nontumor tissues. The associations betweenTip30 methylation status and the survival of patients were analyzed. Results: Tip30 promoter was hypermethylated in 6 of 10 HCC cell lines with reduced Tip30 mRNA. DNA methyltransferase inhibitor, 5-aza-2 ¶-deoxycytidine, greatly enhanced TIP30 expression and sensitized HCC cells to cytotoxic drug-induced cell death. The promoter region of Tip30 was identified and the main promoter activity was located in the -135 to -45 region sited within a CpG island. The minimal promoter element contained four Sp1binding sites, which were hypermethylated in HCC cell-derived promoters. Moreover, analyses of Tip30 promoter methylation status in 59 paired HCC tissues showed that 47% of the cases were hypermethylated. Recurrence rate (95% versus 67%; P = 0.011) and mortality (82% versus 53%; P = 0.033) were significantly higher in patients with methylated Tip30. Disease-free survival was significantly higher in patients with unmethylated Tip30 (33.3% versus 4.5%; P = 0.036). Conclusions: Our results show that epigenetic silencing ofTip30 gene expression by CpG island DNA hypermethylation is associated with poor prognosis in patients with HCC.
Duck Hepatitis A Virus (DHAV) belongs to the Avihepatovirus, which is also classified into Picornaviridae with Hepatovirus, Hepatitis A Virus (HAV). In humans, the pathogenesis of HAV is not well understood because of limited work with animal models. Here, we investigated the progress of duck viral hepatitis caused by DHAV and their potential for dissecting the pathogenesis of HAV. During the course of infection, the duck model had undergone hepatocellular lesions (vacuolation, acidophilic degeneration and steatosis), lymphocytes recruitment (neutrophil granulocytes, heterophilic granulocytes and T cells or plasm cells) and repair (activation of hepatic stellate cells, fibrosis and regeneration). Coincident with liver injury, the serum biomarkers, aspartate aminotransferase and alanine transaminase were significantly increased. Moreover, comparatively lower CD4+ and CD8+ T-cells were recruited to the liver, which might lead to a persistent infection (40 wk). Because DHAV and HAV have similar genomic structure, biological phenotypes and can easily replicate in liver. And half of fibrosis-related genes had high homology between humans and ducks. Considering these similarity in pathological and virological phenotypes, we proposed that the ducks might be an alternatively small animal model that would provide insight into the pathogenesis of viral hepatitis, fibrosis and liver regeneration.
Duck hepatitis A virus type 1 (DHAV-1) is one of the most common and lethal pathogens in young ducklings. Live-attenuated DHAV vaccine (CH60 strain) developed by passaging in chicken embryos provided effective immune protection for ducklings. However, the accurate mechanism for such adaption in chicken embryos is not fully revealed. Here, we utilize RNA-sequencing to perform global transcriptional analysis of DHAV-1-innoculated embryonated livers along with histopathological and ultrastructural analysis. This study revealed that infection with DHAV-1 strain CH60 is associated with enhanced type I and II interferon responses, activated innate immune responses, elevated levels of suppressor of cytokine signaling 1 and 3 (SOCS1 and SOCS3) accompanied with abnormalities in multiple metabolic pathways. Excessive inflammatory and innate immune responses induced by the CH60 strain are related to severe liver damage. Our study presents a comprehensive characterization of the transcriptome of chicken embryos infected with DHAV-CH60 and provides insight for in-depth exploration of viral adaption and virus–host interactions.
To investigate the function of the duck enteritis virus (DEV) tegument protein US10, we generated US10 deletion and revertant mutants (ΔUS10 and US10FRT) via two-step RED recombination based on an infectious BAC clone of DEV CHv-BAC-G (BAC-G). In multistep growth kinetic analyses, ΔUS10 showed an approximately 100-fold reduction in viral titer, while the genome copies decreased only 4-fold compared to those of BAC-G. In one-step growth kinetic analyses, there were no significant differences in genome copies among BAC-G, ΔUS10 and US10FRT, but ΔUS10 still showed a 5- to 20-fold reduction in viral titer, and the replication defect of ΔUS10 was partially reversed by infection of US10-expressing cells. The transcription levels of Mx, OASL, IL-4, IL-6 and IL-10 in ΔUS10-infected duck embryo fibroblasts (DEFs) were significantly upregulated, while TLR3 was downregulated compared with those in BAC-G-infected DEFs. Taken together, these data indicated that US10 is vital for DEV replication and is associated with transcription of some immunity genes.
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