Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Biochemical studies revealed that nonstructural proteins of hepatitis C virus (HCV) interacted with each other and were associated with intracellular membranes. The goals of this study were to determine whether nonstructural viral proteins are colocalized at specific intracellular sites where HCV RNA is replicated and to identify the virus components of the HCV replication complex (RC). Immunofluorescence and subcellular fractionation studies were performed to determine the intracellular colocalization of nonstructural HCV proteins and the replicating RNA in a human hepatoma cell line, Huh7, in which a subgenomic HCV RNA was replicated persistently. The replicating HCV RNA was labelled with 5-bromouridine 5'-triphosphate (BrUTP). Results show that each of the nonstructural HCV proteins was colocalized predominantly with the newly synthesized HCV RNA labelled with BrUTP and an endoplasmic reticulum (ER) protein, calnexin. Consistent with these findings, subcellular fractionation and Western blot analyses revealed that the nonstructural HCV proteins were colocalized with HCV RNA mainly in the membrane fractions. Conversely, the viral nonstructural proteins and RNA remained in the soluble fractions upon treatment with detergent, confirming the membrane association of the HCV RC. HCV RNA in the membrane-bound RC was resistant to RNase treatment, whereas it became sensitive to RNases once the membranes were disrupted by treatment with detergent, suggesting that the HCV RC is assembled within membrane structures. Collectively, these findings demonstrate that HCV RNA replication occurs in the perinuclear ER membrane-bound HCV RC, containing nonstructural viral proteins and RNA.
J Gen Virol 2003 Oct
PMID:Replication of hepatitis C virus RNA occurs in a membrane-bound replication complex containing nonstructural viral proteins and RNA. 1367 11

The induction of apoptotic cell death is a prominent cytopathic effect of dengue (DEN) viruses. One of the key questions to be addressed is which viral components induce apoptosis in DEN virus-infected cells. This study investigated whether the small membrane (M) protein was involved in the induction of apoptosis by DEN virus. This was addressed by using a series of enhanced green fluorescent protein-fused DEN proteins. Evidence is provided that intracellular production of the M ectodomains (residues M-1 to M-40) of all four DEN serotypes triggered apoptosis in host cells such as mouse neuroblastoma Neuro 2a and human hepatoma HepG2 cells. The M ectodomains of the wild-type strains of Japanese encephalitis, West Nile and yellow fever viruses also had proapoptotic properties. The export of the M ectodomain from the Golgi apparatus to the plasma membrane appeared to be essential for the initiation of apoptosis. The study found that anti-apoptosis protein Bcl-2 protected HepG2 cells against the death-promoting activity of the DEN M ectodomain. This suggests that the M ectodomain exerts its cytotoxic effects by activating a mitochondrial apoptotic pathway. The cytotoxicity of the DEN M ectodomain reflected the intrinsic proapoptotic properties of the nine carboxy-terminal amino acids (residues M-32 to M-40) designated ApoptoM: Residue M-36 was unique in that it modulated the death-promoting activity of the M ectodomain. Defining the ApoptoM-activated signalling pathways leading to apoptosis will provide the basis for studying how the M protein might play a key role in the fate of the flavivirus-infected cells.
J Gen Virol 2003 Oct
PMID:Dengue virus M protein contains a proapoptotic sequence referred to as ApoptoM. 1367 13

Hepatitis B virus (HBV) X antigen (HBxAg) may contribute to the development of hepatocellular carcinoma (HCC) by activation of signalling pathways such as NF-kappaB. To identify NF-kappaB target genes differentially expressed in HBxAg-positive compared to -negative cells, HepG2 cells consistently expressing HBxAg (HepG2X cells) were stably transfected with pZeoSV2 or pZeoSV2-IkappaBalpha. mRNA from each culture was isolated and compared by PCR select cDNA subtraction. The results showed lower levels of alpha(2)-macroglobulin (alpha(2)-M) in HepG2X-pZeoSV2 compared to HepG2X-pZeoSV2-IkappaBalpha cells. This was confirmed by Northern and Western blotting, and by measurement of extracellular alpha(2)-M levels. Elevated transforming growth factor-beta1 (TGF-beta1) levels were also seen in HepG2X compared to control cells. Serum-free conditioned medium (SFCM) from HepG2X cells suppressed DNA synthesis in a TGF-beta-sensitive cell line, Mv1Lu. The latter was reversed when the SFCM was pretreated with exogenous, activated alpha(2)-M or with anti-TGF-beta. Since elevated TGF-beta1 promotes the development of many tumour types, these observations suggest that the HBxAg-mediated alteration in TGF-beta1 and alpha(2)-M production may contribute importantly to the pathogenesis of HCC.
J Gen Virol 2004 Feb
PMID:Hepatitis B virus X antigen promotes transforming growth factor-beta1 (TGF-beta1) activity by up-regulation of TGF-beta1 and down-regulation of alpha2-macroglobulin. 1476 85

A variant of the serpin squamous cell carcinoma antigen (SCCA) has been identified as a hepatitis B virus binding protein and high expression of SCCA has recently been found in hepatocarcinoma. Since HBV is involved in liver carcinogenesis, experiments were carried out to examine the effect of HBV preS1 envelope protein on SCCA expression. Surface and intracellular staining for SCCA was assessed by FACS analysis. Preincubation of HepG2 cells and primary human hepatocytes with preS1 protein or with preS1(21-47) tetrameric peptide significantly increased the surface expression of SCCA, without modification of its overall cellular burden, suggesting a surface redistribution of the serpin. An increase in HBV binding and internalization was observed after pre-incubation of the cells with preS1 preparations, compared to cells preincubated with medium alone. Pretreatment of cells with DMSO, while not influencing SCCA basal expression, was responsible for an increase in the efficiency of HBV internalization and this effect was additive to that obtained after incubation with preS1 preparations. In conclusion, the HBV preS1(21-47) sequence is able to induce overexpression of SCCA at the cell surface facilitating virus internalization, while the increased efficiency of HBV entry following DMSO addition is not mediated by SCCA.
J Gen Virol 2004 Mar
PMID:Surface expression of squamous cell carcinoma antigen (SCCA) can be increased by the preS1(21-47) sequence of hepatitis B virus. 1499 46

Complete nucleotide sequences of 19 hepatitis B virus (HBV) isolates of genotype A (HBV/A) were determined and analysed along with those of 20 previously reported HBV/A isolates. Of the 19 HBV/A isolates, six including three from Japan and three from the USA clustered with the 14 HBV/A isolates from Western countries. The remaining 13 isolates including four from The Philippines, two from India, three from Nepal and four from Bangladesh clustered with the six HBV/A isolates reported from The Philippines, South Africa and Malawi. Due to distinct epidemiological distributions, genotype A in the 20 HBV isolates was classified into subtype Ae (e for Europe), and that in the other 19 into subtype Aa (a for Asia and Africa) provisionally. The 19 HBV/Aa isolates had a sequence variation significantly greater than that of the 20 HBV/Ae isolates (2.5+/-0.3 % vs 1.1+/-0.6 %, P<0.0001); they differed by 5.0+/-0.4 % (4.1-6.4 %). The double mutation (T1762/A1764) in the core promoter was significantly more frequent in HBV/Aa isolates than in HBV/Ae isolates (11/19 or 58 % vs 5/20 or 25 %, P<0.01). In the pregenome encapsidation (epsilon) signal, a point mutation from G to A or T at nt 1862 was detected in 16 of the 19 (84 %) HBV/Aa isolates but not in any of the 20 HBV/Ae isolates, which may affect virus replication and translation of hepatitis B e antigen. Subtypes Aa and Ae of genotype A deserve evaluation for any clinical differences between them, with a special reference to hepatocellular carcinoma prevalent in Africa.
J Gen Virol 2004 Apr
PMID:Epidemiological and sequence differences between two subtypes (Ae and Aa) of hepatitis B virus genotype A. 1503 24

The ideal treatment of localized cancer should directly cause an irreversible and complete death of tumor cells without damage to surrounding normal tissue. High intensity focused ultrasound (HIFU) is such a potential treatment, which induces a complete coagulative necrosis of a tumor at depth through the intact skin. The idea that using an extracorporeal source of therapeutic ultrasound was introduced more than 50 years ago [J. Gen. Physiol. 26 (1942) 179]. However, up to now, most of the studies on HIFU have been dealing with animal experiments because this extracorporeal technique is very complicated in clinical applications. The purpose of this study is to introduce Chinese clinical experience of using extracorporeal HIFU for the treatment of patients with various kinds of solid tumor. From December 1997 to October 2001, a total of 1038 patients with solid tumors underwent HIFU ablation in China. Among them, 313 patients were treated at the Chongqing University of Medical Sciences, China. Pathological examination showed that the target region presented clear evidence of cellular destruction. Small blood vessels less than 2 mm in diameter were severely damaged. Follow-up diagnostic imaging revealed that there was no, or reduced, blood supply, and no uptake of radioisotope in the treated tumor after HIFU, both indicating a positive therapeutic response and an absence of viable tumor. Imaging at 6-12 months showed obvious regression of the lesion. Four-year follow-up data were significantly observed in patients with hepatocellular carcinoma, osteosarcoma, and breast cancer. An extremely low major complication rate was noted. It is concluded that HIFU ablation is a safe, effective, and feasible modality for the ablation of carcinomas.
 ...
PMID:Extracorporeal high intensity focused ultrasound ablation in the treatment of 1038 patients with solid carcinomas in China: an overview. 1508 72

TT virus (TTV) is widespread among the global population. Its pathogenic nature is still unclear but TTV seems to be more prevalent in cases of hepatitis than in healthy individuals. TTV harbours similarities to chicken anaemia virus (CAV). Here, the apoptotic potential of a putative TTV-derived 105 aa protein and of the main apoptosis-inducing agent of CAV, Apoptin, is compared. As the putative protein induced apoptosis in various human hepatocellular carcinoma (HCC) cell lines, it was named TTV-derived apoptosis-inducing protein (TAIP). The apoptotic activity of TAIP in HCC lines was comparable with that of Apoptin. Conversely, unlike Apoptin, TAIP induced only low-level apoptosis in several non-HCC human cancer cell lines. The data suggest that TAIP acts in a different way to Apoptin as it is selective to a certain degree for HCC lines. This activity of TAIP, coupled with the heterogeneity of TTV isolates, may help to explain the variable reports of TTV pathogenicity.
J Gen Virol 2004 Jun
PMID:TT virus-derived apoptosis-inducing protein induces apoptosis preferentially in hepatocellular carcinoma-derived cells. 1516 27

Quasispecies shifts are essential for the development of persistent hepatitis C virus (HCV) infection. Naturally occurring sequence variations in the 5' non-translated region (NTR) of the virus could lead to changes in protein expression levels, reflecting selective forces on the virus. The extreme 5' end of the virus' genome, containing signals essential for replication, is followed by an internal ribosomal entry site (IRES) essential for protein translation as well as replication. The 5' NTR is highly conserved and has a complex RNA secondary structure consisting of several stem-loops. This report analyses the quasispecies distribution of the 5' NTR of an HCV genotype 1b clinical isolate and found a number of sequences differing from the consensus sequence. The consensus sequence, as well as a major variant located in stem-loop IIIa of the IRES, was investigated using self-replicating HCV RNA molecules in human hepatoma cells. The stem-loop IIIa mutation, which is predicted to disrupt the stem structure, showed slightly lower translation efficiency but was severely impaired in the colony formation of selectable HCV replicons. Interestingly, during selection of colonies supporting autonomous replication, mutations emerged that restored the base pairing in the stem-loop. Recloning of these altered IRESs confirmed that these second site revertants were more efficient in colony formation. In conclusion, naturally occurring variants in the HCV 5' NTR can lead to changes in their replication ability. Furthermore, IRES quasispecies evolution was observed in vitro under the selective pressure of the replicon system.
J Gen Virol 2004 Jul
PMID:Evolution of naturally occurring 5' non-translated region variants of hepatitis C virus genotype 1b in selectable replicons. 1521 70

An efficient model is currently used to study hepatitis C virus (HCV) replication in cell culture. It involves transfection in Huh7, a hepatoma-derived cell line, of an antibiotic (neomycin) selectable HCV subgenomic replicon encoding the non-structural (NS) proteins from NS3 to NS5B. However, strong and sustained replication is achieved only on the appearance of adaptive mutations in viral proteins. The most effective of these adaptive mutations are concentrated mainly in NS5A, not only into the original Con1 but also in the recently established HCV-BK and HCV-H77 isolate-derived replicons. This suggests that the expression of wild-type (wt) NS5A may not allow efficient HCV RNA replication in cell culture. With the use of a beta-lactamase reporter gene as a marker for HCV replication and TaqMan RNA analysis, the replication of different HCV replicons in cotransfection experiments was investigated. Comparing wt with NS5A-adapted replicons, the strong evidence accumulated showed that the expression of wt NS5A was actually able to inhibit the replication of NS5A-adapted replicons. This feature was characterized as a dominant negative effect. Interestingly, an NS5B (R2884G)-adapted replicon, containing a wt NS5A, was dominant negative on an NS5A-adapted replicon but was not inhibited by the original Con1 replicon. In conclusion, these studies revealed that the original wt Con1 replicon is not only incompetent for replication in cell culture, but is also able to interfere with NS5A-adapted replicons.
J Gen Virol 2004 Jul
PMID:Dominant negative effect of wild-type NS5A on NS5A-adapted subgenomic hepatitis C virus RNA replicon. 1521 71

Growth hormone (GH) is a key factor controlling postnatal growth and development. Despite growth-promoting effects in mammals, GH is not associated with muscle growth in the chicken. Janus kinase 2 (JAK2) has been identified as the first intracellular step in GH receptor (GHR) signaling in many species, however, there is limited knowledge regarding the GH signaling pathway in the chicken. In this study, GH-responsive, JAK2 immunoreactive proteins were first assessed in an avian hepatoma cell line (LMH). Tyrosine phosphorylation of a 120-122 kDa JAK2 immunoreactive protein was GH dose-dependent. In addition to in vitro studies, the timecourse of JAK2 activation in liver and skeletal muscle (Pectoralis superficialis) in response to a single intravenous (i.v.) injection of chicken GH (cGH), and the effect of chronic exposure to GH in a physiologically relevant pattern on JAK2 protein expression and tyrosine phosphorylation in vivo were assessed. At a dose of GH that was previously demonstrated to elicit a maximal metabolic response (6.25 microg/kg BW), maximum tyrosine phosphorylation of JAK2 appeared at 10 min post-GH administration in the pectoralis muscle, but was not detectable in liver. To assess whether chronic enhancement of GH would alter expression of JAK2, we utilized a dynamic model of pulsatile GH infusion that mimicked the early pattern of circulating GH expressed in younger, rapidly growing birds (high amplitude peaks with an inter-peak interval of 90 min). A 120-122 kDa protein in liver and muscle, and a dominant 130-136 kDa protein in the muscle, that was phosphorylated in response to GH, were specifically recognized by the JAK2 antibody. Chronic, pulsatile infusion of cGH into 8-week-old chickens was associated with increased abundance and tyrosine phosphorylation of JAK2 protein in both liver and muscle (P < 0.05), which were GH dose-dependent, and mirrored previously reported biological responses for the same birds [Vasilatos-Younken, R., Zhou, Y., Wang, X., McMurtry, J.P., Rosebrough, R.W., Decuypere, E., Buys, N., Darras, V.M., Van Der Geyten, S., Tomas, F., 2000. Altered chicken thyroid hormone metabolism with chronic GH enhancement in vivo: Consequences for skeletal muscle growth. Journal of Endocrinology 166, 609-620.]. In summary (1) JAK2 immunoreactive proteins that associate with the GHR and are tyrosine phosphorylated in response to GH were identified in an avian hepatoma cell line and expressed in both GH responsive (liver) and "non-responsive" (skeletal muscle) tissues; (2) tyrosine phosphorylation of JAK2 occurred within minutes of exposure to a single i.v. injection of GH in vivo in muscle but not liver of 8-week-old birds; and 3) there were GH dose-dependent increases in abundance of JAK2 protein and tyrosine phosphorylation in both tissues when chronically exposed to GH in a physiologically relevant pattern, that mirrored dose-dependent biological responses, including alterations in the pathway of thyroid hormone metabolism, previously reported. Enhanced JAK2 suggests one possible mechanism whereby chronic, physiologically appropriate exposure to the ligand enhances GH biological action via increased abundance of a key upstream component of the signal transduction pathway.
Gen Comp Endocrinol 2005 Nov
PMID:Regulation of JAK2 protein expression by chronic, pulsatile GH administration in vivo: a possible mechanism for ligand enhancement of signal transduction. 1599 10


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