Viral hijacking of the TENT4-ZCCHC14 complex protects viral RNAs via mixed tailing.

TENT4 enzymes generate 'mixed tails' of diverse nucleotides at 3' ends of RNAs via nontemplated nucleotide addition to protect messenger RNAs from deadenylation. Here we discover extensive mixed tailing in transcripts of hepatitis B virus (HBV) and human cytomegalovirus (HCMV), generated via a similar mechanism exploiting the TENT4-ZCCHC14 complex. TAIL-seq on HBV and HCMV RNAs revealed that TENT4A and TENT4B are responsible for mixed tailing and protection of viral poly(A) tails.

SERPINA3 is a key modulator of HNRNP-K transcriptional activity against oxidative stress in HCC.

Most studies about serpin peptidase inhibitor, clade A member 3 (SERPINA3) has been limited to its inhibitory functions and mechanisms. Herein, we report a novel role of SERPINA3 in transcriptional regulation of HCC progression-related genes. Among 19 selected genes through HCC cell isolation system based on telomere length, microarray analyses, and cell-based studies, SERPINA3 was the strongest determinant of increases in telomere length, HCC cell proliferation, survival, migration, and invasion.

Cetylpyridinium chloride interaction with the hepatitis B virus core protein inhibits capsid assembly.

Hepatitis B virus (HBV) infection is a major risk factor for chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC) worldwide. While multiple hepatitis B drugs have been developed, build up of drug resistance during treatment or weak efficacies observed in some cases have limited their application. Therefore, there is an urgent need to develop substitutional pharmacological agents for HBV-infected individuals.

PI3Kδ Is a Therapeutic Target in Hepatocellular Carcinoma.

Class I phosphoinositide 3-kinase (PI3K) signaling is a major pathway in human cancer development and progression. Among the four PI3K isoforms, PI3Kα and PI3Kβ are ubiquitously expressed, whereas PI3Kγ and PI3Kδ are found primarily in leukocytes. Until now, PI3K targeting in solid tumors has focused on inhibiting PI3Kα-mediated and PI3Kβ-mediated cancer cell-intrinsic PI3K activity.

Heat shock protein 70 and heat shock protein 90 synergistically increase hepatitis B viral capsid assembly.

Hepatitis B virus (HBV) infection can cause chronic liver diseases, cirrhosis, and hepatocellular carcinoma (HCC). Heat shock proteins (Hsps) are important factors in the formation of the HBV capsid and in genome replication during the viral life cycle. Hsp90 is known to promote capsid assembly.

Oxidatively Modified Protein-Disulfide Isomerase-Associated 3 Promotes Dyskerin Pseudouridine Synthase 1-Mediated Malignancy and Survival of Hepatocellular Carcinoma Cells.

Dyskerin pseudouridine synthase 1 (DKC1) is a conserved gene encoding the RNA-binding protein dyskerin, which is an essential component of the telomerase holoenzyme. DKC1 up-regulation is frequently observed in many different human cancers including hepatocellular carcinoma (HCC); however, its regulatory mechanisms remain unclear. Thus, we investigated the regulatory mechanism of DKC1 in HCC progression.

WITHDRAWN: Cetylpyridinium chloride as a novel inhibitor of hepatitis B viral capsid assembly.

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Telomere length and reactive oxygen species levels are positively associated with a high risk of mortality and recurrence in hepatocellular carcinoma.

Unlabelled: Telomeres protect chromosomal ends from deterioration and have been shown to be susceptible to shortening by reactive oxygen species (ROS)-induced damage. ROS levels increase during the progression from early to advanced hepatocellular carcinoma (HCC). An independent study found that the telomeres in most HCC tissues lengthened during carcinogenic advancement.

Epigenetic regulation of Kcna3-encoding Kv1.3 potassium channel by cereblon contributes to regulation of CD4+ T-cell activation.

The role of cereblon (CRBN) in T cells is not well understood. We generated mice with a deletion in Crbn and found cereblon to be an important antagonist of T-cell activation. In mice lacking CRBN, CD4(+) T cells show increased activation and IL-2 production on T-cell receptor stimulation, ultimately resulting in increased potassium flux and calcium-mediated signaling.

The TERT promoter SNP rs2853669 decreases E2F1 transcription factor binding and increases mortality and recurrence risks in liver cancer.

A common single-nucleotide polymorphism in the telomerase reverse transcriptase (TERT) promoter, rs2853669 influences patient survival rates and the risk of developing cancer. Recently, several lines of evidence suggest that the rs2853669 suppresses TERT promoter mutation-mediated TERT expression levels and cancer mortality as well as recurrence rates. However, no reports are available on the impact of rs2853669 on TERT expression in hepatocellular carcinoma (HCC) and its association with patient survival.

Reactive oxygen species promote heat shock protein 90-mediated HBV capsid assembly.

Hepatitis B virus (HBV) infection induces reactive oxygen species (ROS) production and has been associated with the development of hepatocellular carcinoma (HCC). ROS are also an important factor in HCC because the accumulated ROS leads to abnormal cell proliferation and chromosome mutation. In oxidative stress, heat shock protein 90 (Hsp90) and glutathione (GSH) function as part of the defense mechanism.

Reactive oxygen species increase HEPN1 expression via activation of the XBP1 transcription factor.

Hepatocellular carcinoma downregulated 1 (HEPN1), a cell growth arrest- and apoptosis-related gene, is suppressed in hepatocellular carcinoma (HCC). However, transcriptional control of HEPN1 has not been characterized. Here, we show that exposure to reactive oxygen species (ROS) leads to upregulation of the mRNA expression of HEPN1 in HCC cell lines.

Positive association of long telomeres with the invasive capacity of hepatocellular carcinoma cells.

Invasion, the representative feature of malignant tumors, leads to an increase in mortality. The malignant liver tumor - hepatocellular carcinoma (HCC) - has an enhanced invasive capacity that results in increased patient mortality. Moreover, this enhanced invasive capacity is due to the up-regulation of invasion promoters such as zinc finger protein SNAI1 (Snail) and matrix metalloproteinases (MMPs), and the down-regulation of invasion suppressor molecules such as E-cadherin.

Interaction between nucleophosmin and HBV core protein increases HBV capsid assembly.

Host factors are involved in Hepatitis B virus (HBV) genome replication and capsid formation during the viral life cycle. A host factor, nucleophosmin (B23), was found to bind to HBV core protein dimers, but its functional role has not been studied. This interaction promoted HBV capsid assembly and decreased the degree of capsid dissociation when subjected to denaturant treatments in vitro.

Snail inhibits Notch1 intracellular domain mediated transcriptional activation via competing with MAML1.

Notch1 intracellular domain (NICD) is the transcription factor which controls cell fate and differentiation in embryonic and tumor cells. Snail has a critical role which increases invasion and metastasis of cancer cell as a transcription factor and epigenetic regulator. Recently, we discovered NICD induced Snail degradation by direct binding interaction with Snail.

Structure-based design and biochemical evaluation of sulfanilamide derivatives as hepatitis B virus capsid assembly inhibitors.

Virus capsid structure is essential in virion maturation and durability, so disrupting capsid assembly could be an effective way to reduce virion count and cure viral diseases. However, currently there is no known antiviral which affects capsid inhibition, and only a small number of assembly inhibitors were experimentally successful. In this present study, we aimed to find hepatitis B virus (HBV) capsid assembly inhibitor which binds to the HBV core protein and changes protein conformation.

Co-expression patterns of Notch1, Snail, and p53 in grade III hepatocellular carcinoma with postoperative recurrence: a preliminary study.

Background/aims: We aimed to determine the association between the co-expression patterns of Notch1, Snail, and p53 proteins (NSP) and the postoperative prognosis of hepatocellular carcinoma (HCC).

Methods: The immunoblot data for molecular expression (147 HCC/corresponding non-HCC tissues and 15 dysplastic nodules) and the sequencing data for p53 mutations (110 HCCs) were obtained from our previous study. Data analyses were restricted to cases with HCC differentiation grade III (n=47), due to its high p53 mutation rate.

Notch1 binds and induces degradation of Snail in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is a common, highly invasive malignant tumor associated with a high mortality rate. We previously reported that the aberrant expression of Snail via activation of reactive oxygen species contributes to the invasive property of HCC, in part by downregulation of E-cadherin through both transcriptional repression and epigenetic modification of the E-cadherin promoter. Having demonstrated the ability of Snail to bind and recruit histone deacetylase 1 and DNA methyltransferase 1 in this context, we set out to look for other interactions that could affect its ability to promote oncogenic transformation and cancer cell invasion.

Reactive oxygen species downregulate catalase expression via methylation of a CpG island in the Oct-1 promoter.

Reactive oxygen species (ROS) caused oxidative stress plays a key role in carcinogenesis. The POU domain transcription factor Oct-1 and catalase is closely associated with ROS. However, a correlation between these two key proteins has not been demonstrated before.

Combination treatment with intrahepatic arterial infusion and intratumoral injection chemotherapy in patients with far-advanced hepatocellular carcinoma and arterioportal or arteriovenous shunts: preliminary results.

Background/aims: Combination treatment consisting of hepatic arterial infusion chemotherapy with epirubicin and cisplatin (HAIC-EC) and systemic infusion of low-dose 5-fluorouracil (5-FU) are sometimes effective against advanced hepatocellular carcinoma (HCC). However, there is no effective treatment for advanced HCCs with arterioportal shunts (APS) or arteriovenous shunts (AVS).

Methods: We investigated a response and adverse events of a new combination protocol of repeated HAIC-EC and percutaneous intratumoral injection chemotherapy with a mixture of recombinant interferon-gamma (IFN-γ) and 5-FU (PIC-IF) in patients with far-advanced HCCs with large APSs or AVSs.

Notch1 differentially regulates oncogenesis by wildtype p53 overexpression and p53 mutation in grade III hepatocellular carcinoma.

Unlabelled: The tumor suppressor p53 is a key prognostic factor in hepatocellular carcinoma (HCC), yet only 35% of grade III tumors exhibit mutation of p53. Several other pathways have been implicated in HCC and, among these, the role of the Notch1/Snail pathway remains unclear. Therefore, we investigated the expression of p53, Notch1, and Snail proteins in HCC with regard to both clinical grade and p53 mutational status.

Aberrant CpG island hypermethylation in dysplastic nodules and early HCC of hepatitis B virus-related human multistep hepatocarcinogenesis.

Background & Aims: The concept of multistep hepatocarcinogenesis has been well-established, and an accumulation of methylating events has recently been demonstrated; however, the methylation status of low-grade dysplastic nodules (LGDN), high-grade dysplastic nodules (HGDN), and the recently introduced early hepatocellular carcinoma (eHCC) in hepatitis B virus (HBV)-related hepatocarcinogenesis has not yet been studied.

Methods: One hundred thirty-three DNA samples (45 cirrhotic nodules, 29 LGDNs, 13 HGDNs, 14 eHCCs, and 32 progressed HCCs (pHCCs)) from HBV-infected resected livers were subjected to MethyLight analysis for nine CpG island loci (APC, RASSF1A, SOCS1, P16, COX2, SPRY2, PTEN, GNMT, and ERK), and COX2, RASSF1A, and SOCS1 protein expression status was analyzed by immunohistochemistry. The methylation status of each sample was correlated with the clinicopathological features.

Heat shock protein 90 facilitates formation of the HBV capsid via interacting with the HBV core protein dimers.

The mechanism by which host factors contribute to hepatitis B virus (HBV) capsid formation during the viral life cycle remains unclear. This study analyzed the interaction between heat shock protein 90 (Hsp90), a host factor, and the HBV core protein. Hsp90 was found to bind to HBV core protein dimers, which was then encapsidated into the HBV capsid.

Hepatitis B viral X protein interacts with tumor suppressor adenomatous polyposis coli to activate Wnt/β-catenin signaling.

HBV X protein is a transactivator of several cellular signaling pathways including Wnt which contributes to HBV associated neoplasia. The Wnt/β-catenin pathway is associated with HCC-initiating cells. Here we perform a functional screen for host factors involved in the transactivational properties of HBx.