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)

Hepatocellular carcinoma (HCC) is one of the most common malignancies in Southeast Asia. Hyperphosphorylation of retinoblastoma (pRB) by cyclin/CDKs in G1/S transition is required for its inactivation and cell cycle progression. In the present study, we report that phosphorylation of pRB at Ser780 and Ser795 was detected in 71% (33 of 46) and 63% (29 of 46) of HCCs examined respectively. pRB protein was undetectable in 13% (6 of 46) of HCCs examined. Phosphorylated pRB was localized in the nuclei of hepatocarcinoma cells. Benign hepatocytes exhibited very weakly or no nuclear staining for phosphorylated pRB. Over-expression of E2F-1, cyclin D1, Cdk-2, Cdk-4 and cyclin A was found in 64% (30 of 46), 43% (26 of 46), 28% (11 of 46), 71% (33 of 46) and 63% (29 of 46) of HCCs examined respectively and this was correlated with elevation of ERK. Treatment of HepG2 cells with MEK1/2 inhibitor U0126 resulted in cell cycle arrest, downregulation of cyclin D1 and Cdk-2 expression and inhibition of pRB phosphorylation at Ser780 and Ser795. Ectopic expression of activated MEK1 in HepG2 cells increased cyclin D1 and Cdk-2 expression, phosphorylation of pRB at Ser780 and Ser795, and percentage of cells in S phase. Our data indicate that activated ERK plays an important role in cyclin D1 and Cdk-2 expression and phosphorylation of pRB at Ser780 and Ser795 in liver cancer cells.
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PMID:Extracellular signal-regulated kinase induces cyclin D1 and Cdk-2 expression and phosphorylation of retinoblastoma in hepatocellular carcinoma. 1554 25

Hepatocyte growth factor (HGF) induces growth stimulation of a variety of cell types, but it also induces growth inhibition of several types of tumor cell lines. We previously investigated the intracellular signaling pathway involved in the antiproliferative effect of HGF on the human hepatocellular carcinoma cell line HepG2. The results suggested that the HGF-induced proliferation inhibition is caused by cell cycle arrest, which results from the retinoblastoma tumor suppressor gene product pRb being maintained in its active hypophosphorylated form via a high-intensity ERK signal. In this study, we examined the molecular mechanism of the HGF-induced cell cycle arrest in HepG2 cells. Cyclin A/Cdk2 complexes phosphorylated serine residues on pRb crucial for the G1 to S phase transition in proliferating HepG2 cells, and HGF treatment inhibited the phosphorylation. The expression of cyclin A was decreased and the expression of a Cdk inhibitor p21(Cip1) was increased in HGF-treated HepG2 cells, and these changes were prevented by pretreatment with a low concentration of a MEK inhibitor. These results suggest that the decrease in cyclin A expression and increase in p21(Cip1) expression through a high-intensity ERK signal by HGF lead to suppression of the phosphorylation of pRb by Cdk2, which contributes to the cell cycle arrest at G1 in HepG2 cells by HGF. Furthermore, the expression of E2F-1, a member of the E2F transcription factor family, was decreased in HGF-treated HepG2 cells, suggesting that the decrease in E2F-1 expression may also contribute to the cell cycle arrest at G1.
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PMID:Involvement of down-regulation of Cdk2 activity in hepatocyte growth factor-induced cell cycle arrest at G1 in the human hepatocellular carcinoma cell line HepG2. 1563 11

We investigated hepatitis B virus (HBV) DNA integration and expression of several proteins involved in the cell cycle and apoptosis, including cyclin A, retinoblastoma protein (pRB), Fas-associated death domain protein (FADD), tumor necrosis factor receptor-associated death domain protein (TRADD), and nuclear factor kappaB (NF-kappaB) in HBV-associated hepatocellular carcinoma (HCC) and liver cirrhosis (LC). Archival HCC and LC specimens were obtained from 35 patients each with HBV infection; 5 normal liver specimens used as controls were also obtained. Polymerase chain reaction and Southern blot hybridization were used to detect the integration of HBV DNA in the HCC and LC specimens. The protein levels were determined by Western blot assay. The difference in HBV DNA integration between HCC and LC and correlation between HBV-encoded X protein (Hbx) integration and protein expression were analyzed statistically. HBV DNA was detected in 33 (94%) of the HCC and LC specimens. HBx integration differed in the HCC [24 (69%)] and LC [14 (40%)] specimens (p=0.015). Sixty percent of the HCC specimens and 6% of the LC specimens had increased cyclin A expression. Also, 34, 37, 69, and 77% of the HCC specimens were positive for pRB, FADD, TRADD, and NF-kappaB expression, whereas 80, 60, 100, and 100% of the LC specimens were positive for pRB, FADD, TRADD, and NF-kappaB expression. Significant correlations between HBx integration and the level of expression of cyclin A (r=0.452; p=0.006), pRB (r=-0.419; p=0.012), and TRADD (r=0.470; p=0.004) were discovered. Therefore, integration of HBV DNA occurred frequently in HCC and LC cases with chronic HBV infection, whereas HBx integration occurred more often in HCC than in LC cases (p=0.015). HBx integration and altered expression of genes is a key to apoptosis and may play important roles in HBV-induced hepatocarcinogenesis.
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PMID:Integration of the hepatitis B virus X fragment in hepatocellular carcinoma and its effects on the expression of multiple molecules: a key to the cell cycle and apoptosis. 1564 32

In Huh-7 hepatoma cells, low dose (LD) doxorubicin treatment induces cell death through mitotic catastrophe accompanying the formation of large cells with multiple micronuclei, whereas high dose (HD) doxorubicin induces apoptosis. In this study, we investigated the role of Cdc2 and Cdk2 kinase in the regulation of the two modes of cell death induced by doxorubicin. During HD doxorubicin-induced apoptosis, the histone H1-associated activities of Cdc2 and Cdk2 both progressively declined in parallel with reductions in cyclin A and cyclin B protein levels. In contrast, during LD doxorubicin-induced cell death through mitotic catastrophe, the Cdc2 and Cdk2 kinases were transiently activated 1 day post-treatment, with similar changes seen in the protein levels of cyclin A, cyclin B, and Cdc2. Treatment with roscovitine, a specific inhibitor of Cdc2 and Cdk2, significantly blocked LD doxorubicin-induced mitotic catastrophe and cell death, but did not affect HD doxorubicin-induced apoptosis in Huh-7, SNU-398, and SNU-449 hepatoma cell lines. Our results demonstrate that differential regulation of Cdc2 and Cdk2 activity by different doses of doxorubicin may contribute to the induction of two distinct modes of cell death in hepatoma cells, either apoptosis or cell death through mitotic catastrophe.
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PMID:Cdc2 and Cdk2 play critical roles in low dose doxorubicin-induced cell death through mitotic catastrophe but not in high dose doxorubicin-induced apoptosis. 1603 17

Tyrosine phosphatase PRL-1 is one of the immediate-early genes up-regulated during liver regeneration and is apparently involved in cell proliferation. Previously, we have demonstrated that halofuginone, an inhibitor of collagen type I synthesis, prevents liver fibrosis and improves cirrhotic liver regeneration. In this study, we evaluated the effect of halofuginone on PRL-1 expression, its cellular localization in vitro and during liver regeneration, and fibrosis progression in vivo. In culture, halofuginone increased PRL-1 expression in primary rat hepatocytes and in hepatocellular carcinoma (HCC) cell lines, the former being more sensitive to halofuginone. The halofuginone-dependent increase in PRL-1 gene expression was correlated with an increase in the transcription factor early growth response-1 (Egr-1) and inversely correlated with the inhibition of cell proliferation. Halofuginone arrested HepG2 and Huh7 cell lines at the G1 phase, whereas Hep3B cells were arrested at G2/M, probably because of a reduction in the synthesis of cyclins D1 and B1 in all HCC cells and increased cyclin A in Hep3B cells. Halofuginone also affected the PRL-1 sub-cellular localization that was cell-cycle-dependent. In addition, halofuginone augmented PRL-1 expression in the remnant liver after partial hepatectomy and in chemically induced fibrosis in rats; this was accompanied by increased expression of insulin-like growth factor binding protein 1 (IGFBP-1), another immediate-early gene of regeneration. The regulation of the expression of the early genes of regeneration such as PRL-1 and IGFBP-1 is thus part of the mode of action of halofuginone and results in the prevention of liver fibrosis and improved cirrhotic liver regeneration.
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PMID:Involvement of the tyrosine phosphatase early gene of liver regeneration (PRL-1) in cell cycle and in liver regeneration and fibrosis effect of halofuginone. 1650 89

Ultra-wideband (UWB) technology has increased with the use of various civilian and military applications. In the present study, we hypothesized that low-dose UWB electromagnetic radiation (UWBR) could elicit a mitogenic effect in AML-12 mouse hepatocytes, in vitro. To test this hypothesis, we exposed AML-12 mouse hepatocytes, to UWBR in a specially constructed gigahertz transverse electromagnetic mode (GTEM) cell. Cells were exposed to UWBR for 2 h at a temperature of 23 degrees C, a pulse width of 10 ns, a repetition rate of 1 kHz, and field strength of 5-20 kV/m. UWB pulses were triggered by an external pulse generator for UWBR exposure but were not triggered for the sham exposure. We performed an MTT Assay to assess cell viability for UWBR-treated and sham-exposed hepatocytes. Data from viability studies indicated a time-related increase in hepatocytes at time intervals from 8-24 h post exposure. UWBR exerted a statistically significant (p < 0.05) dose-dependent response in cell viability in both serum-treated and serum free medium (SFM) -treated hepatocytes. Western blot analysis of hepatocyte lysates demonstrated that cyclin A protein was induced in hepatocytes, suggesting that increased MTT activity after UWBR exposure was due to cell proliferation. This study indicates that UWBR has a mitogenic effect on AML-12 mouse hepatocytes and implicates a possible role for UWBR in hepatocarcinoma.
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PMID:Induced mitogenic activity in AML-12 mouse hepatocytes exposed to low-dose ultra-wideband electromagnetic radiation. 1670 98

C75, a well-known fatty acid synthase (FAS) inhibitor, has been shown to possess potent anti-cancer activity in vitro and in vivo. In this study, we reveal that C75 is a cell cycle arrest inducer and explore the potential mechanisms for this effect in hepatocellular carcinoma (HCC) cell lines with abundant FAS expression: HepG2 and SMMC7721 cells with wt-p53, and Hep3B cells with null p53. The results showed FAS protein expression and basal activity levels were higher in HepG2 cells than in the other two HCC cell lines. Treatment with C75 inhibited FAS activity within 30 min of administration and induced G(2) phase arrest accompanied by p53 overexpression in HepG2 and SMMC7721 cells. By contrast, C75 triggered G(1) phase arrest in Hep3B cells, and RNA interference targeting p53 did not attenuate C75-induced G(2) arrest in HepG2 cells. Similarly, p53 overexpression via p53 plasmid transfection did not affect C75-induced G(1) phase arrest in Hep3B cells. However, we observed a clear correlation between p38 MAPK activation triggered by C75 and the induction of cell cycle arrest in all three HCC cells. Furthermore, treatment with the p38 MAPK inhibitor SB203580 reduced p38 MAPK activity and cell cycle arrest, and also partially restored cyclin A, cyclin B1, cyclin D1 and p21 protein levels. Collectively, it was p38 MAPK but not p53 involved in C75-mediated tumor cell growth arrest in HCC cells.
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PMID:Growth arrest induced by C75, A fatty acid synthase inhibitor, was partially modulated by p38 MAPK but not by p53 in human hepatocellular carcinoma. 1699 3

Although hepatitis B virus (HBV) has been documented to cause hepatocellular carcinoma (HCC), the exact role of HBV in the development of HCC remains enigmatic. Several hypotheses have been proposed to explain the potential mechanism, including insertional mutagenesis of HBV genomes and transcriptional activators of HBV gene products such as hepatitis B x protein (HBx) and truncated middle S mutants. In the past few years, we have identified two types of large HBV surface antigens (LHBs) with deletions at the pre-S1 (DeltaS1-LHBs) and pre-S2 (DeltaS2-LHBs) regions in ground glass hepatocytes. The pre-S mutant LHBs are retained in the endoplasmic reticulum (ER) and escape from immune attack. The pre-S mutants, particularly DeltaS2-LHBs, are increasingly prevalent in patients with hepatitis B e antigen (HBeAg)-positive chronic HBV infection, ranging from 6% before the 3rd decade to 35% in the 6th decade. In HCC patients, the two pre-S mutants were detected in 60% of HCC patients, in the serum and in HCC tissues. Pre-S mutant LHBs can initiate ER stress to induce oxidative DNA damage and genomic instability. Furthermore, pre-S mutant LHBs can upregulate cyclooxygenase-2 and cyclin A to induce cell cycle progression and proliferation of hepatocytes. In transgenic mice, the pre-S mutants can induce dysplasia of hepatocytes and development of HCC. In a nested control study, the presence of pre-S mutants carried a high risk of developing HCC in HBV carriers. In summary, the findings we describe in this review suggest a potential role for HBV pre-S mutants in HBV-related hepatocarcinogenesis, providing a model of viral carcinogenesis associated with ER stress.
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PMID:Hepatitis B virus pre-S mutants, endoplasmic reticulum stress and hepatocarcinogenesis. 1686 2

The hepatitis B virus (HBV) X protein (pX) is implicated in hepatocarcinogenesis by an unknown mechanism. pX variants encoded by HBV genomes found integrated in genomic DNA from liver tumors of patients with hepatocellular carcinoma (HCC) generally lack amino acids 134 to 154. Since deregulation of mitogenic pathways is linked to oncogenic transformation, herein we define the pX region required for mitogenic pathway activation. A series of pX deletions was used to construct tetracycline-regulated pX-expressing cell lines. The activation of the mitogenic pathways by these pX deletions expressed in the constructed cell lines was measured by transient transreporter assays, effects on endogenous cyclin A expression, and apoptosis. Conditional expression of pX51-140 in AML12 clone 4 cell line activates the mitogenic pathways, induces endogenous cyclin A expression, and sensitizes cells to apoptosis, similar to wild-type (WT) pX. By contrast, pX1-115 is inactive, supporting the idea that amino acids 116 to 140 are required for mitogenic pathway activation. Moreover, this pX deletion analysis demonstrates that WT pX function is modulated by two regions spanning amino acids 1 to 78 and 141 to 154. The N-terminal X1-78, expressed via a retroviral vector in WT pX-expressing 4pX-1 cells, coimmunoprecipitates with WT pX, indicating this pX region participates in protein-protein interactions leading to pX oligomerization. Interestingly, pX1-78 interferes with WT pX in mediating mitogenic pathway activation, endogenous gene expression, and apoptosis. The C-terminal pX region spanning amino acids 141 to 154 decreases pX stability, determined by pulse-chase studies of WT pX and pX1-140, suggesting that increased stability of naturally occurring pX variants lacking amino acids 134 to 154 may play a role in HCC development.
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PMID:The mitogenic function of hepatitis B virus X protein resides within amino acids 51 to 140 and is modulated by N- and C-terminal regulatory regions. 1692 Aug 20

It was previously reported that a methanol extract of Gloiopeltis furcata (MEGF), a kind of edible seaweed, inhibited the growth of several human cancer cell lines. In the present study, the effect of MEGF on the growth of human hepatocarcinoma HepG2 cells and its effect on the cyclooxygenases (COXs) expression were investigated. MEGF markedly reduced the viability of HepG2 cells and induced the G2/M arrest of the cell cycle in a concentration dependent manner. These effects were associated with the down-regulation of cyclin A, up-regulation of cyclin-dependent kinase (Cdk) inhibitor p21 (WAF1/CIP1) and dephosphorylation of Cdc25C. Furthermore, it was found that MEGF decreased the levels of COX-2 mRNA and protein expression without significant changes in the levels of COX-1, which was correlated with a decrease in prostaglandin E(2) (PGE(2)) synthesis. These findings indicate that MEGF may have a possible therapeutic potential in hepatoma cancer patients.
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PMID:Methanol extract of the seaweed Gloiopeltis furcata induces G2/M arrest and inhibits cyclooxygenase-2 activity in human hepatocarcinoma HepG2 cells. 1707 9


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