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)

The oncogene c-myc and transforming growth factor (TGF) alpha are frequently coexpressed in human cancers, suggesting that their interaction may be a critical step in malignant growth. Consistent with this idea, we recently demonstrated in a transgenic mouse model that TGF-alpha dramatically enhances c-myc-induced hepatocarcinogenesis. To elucidate this synergistic effect, we have now investigated regulation of cell cycle and apoptosis during neoplastic development in the liver of c-myc and c-myc/TGFalpha transgenic mice. Both lines displayed dramatic increases of mitotic and apoptotic rates before the onset of hepatocellular carcinoma (HCC), but only c-myc/TGF-alpha livers showed significant levels of net proliferation (mitosis minus apoptosis). Subsequently, mitosis declined in peritumorous tissues, concomitant with the previously reported induction of TGF-beta1, whereas c-myc and c-myc/TGFalpha HCCs maintained mitotic hyperactivity. The c-myc/TGF-alpha HCCs were also characterized by a particularly strong expression of TGF-alpha and very low apoptotic index in contrast to high levels of apoptosis in peritumorous tissues and c-myc HCCs. The differential levels of cell proliferation in noncancerous and cancerous tissues correlated with a stronger induction of cyclin D1 mRNA and protein in c-myc/TGF-alpha and c-myc HCCs associated with intense pRb hyperphosphorylation. Severe deregulation of G1-S transition was also indicated by the dramatic up-regulation, particularly in the HCCs, of pRb-free E2F1-DP1 and E2F2-DP1 transcription factor heterodimers, as assessed by immunoprecipitation and immunohistochemistry. The existence of increased E2F activity during hepatocarcinogenesis was further indicated by the transcriptional induction of putative E2F target genes involved in cell cycle progression, such as endogenous c-myc, cyclin A, Cdc2, and E2F itself. Cdc2 overexpression and the elevated mitotic indices in the HCCs correlated also with induction of cyclin B steady-state levels. The data suggest that coexpression of c-myc and TGF-alpha leads to a selective growth advantage for hepatic (pre)neoplastic cells by disrupting the pRb/E2F pathway and by TGF-alpha-mediated reduction of apoptosis.
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PMID:Disruption of the pRb/E2F pathway and inhibition of apoptosis are major oncogenic events in liver constitutively expressing c-myc and transforming growth factor alpha. 942 68

Hepatitis B virus X (HBx) protein is known as an oncogenic transactivator, E2F1 as a positive regulator of the cell cycle, and pRb as a tumor suppressor. Here, we investigated the functional interactions of these proteins on the human Rb promoter. Interestingly, HBx transactivated the Rb promoter cooperatively with E2F1 in HepG2 cells but not in HeLa cells, in which the functions of p53 and pRb are inactive. Combinatorial cotransfection analyses in HepG2 cells showed that HBx overcame the inhibition of E2F1 activity by pRb but not that by p53. Domain analysis showed that aa 47-70 and aa 117-133 of HBx are important for this effect. These results suggest that HBx could inhibit the pRb tumor suppressor and increase E2F1 activity. Our data support the oncogenic potential of HBx, which may cause HBV-infected cells to grow continuously in the development of hepatocellular carcinoma.
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PMID:Hepatitis B viral X protein overcomes inhibition of E2F1 activity by pRb on the human Rb gene promoter. 1124 64

p53 and p73 proteins activate similar target genes and induce apoptosis and cell cycle arrest. However, p53, but not p73 is considered a tumour-suppressor gene. Unlike p53, p73 deficiency in mice does not lead to a cancer-prone phenotype, and p73 gene is not mutated in human cancers, including hepatocellular carcinoma. Here we report that normal liver cells express only DeltaN-p73 transcript forms giving rise to the synthesis of N-terminally truncated, transcriptionally inactive and dominant negative p73 proteins. In contrast, most hepatocellular carcinoma cells express TA-p73 transcript forms encoding full-length and transcriptionally active p73 proteins, in addition to DeltaN-p73. We also show that together with the acquired expression of TA-p73, the 'retinoblastoma pathway' is inactivated, and E2F1-target genes including cyclin E and p14(ARF) are activated in hepatocellular carcinoma. However, there was no full correlation between 'retinoblastoma pathway' inactivation and TA-p73 expression. Most TA-p73-expressing hepatocellular carcinoma cells have also lost p53 function either by lack of expression or missense mutations. The p73 gene, encoding only DeltaN-p73 protein, may function as a tumour promoter rather than a tumour suppressor in liver tissue. This may be one reason why p73 is not a mutation target in hepatocellular carcinoma.
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PMID:Acquired expression of transcriptionally active p73 in hepatocellular carcinoma cells. 1152 99

Previously, we have shown that over-expression of either E2F1 or c-Myc promotes hepatocarcinogenesis and that E2F1 mice acquire HCC more rapidly than c-Myc transgenic mice. We also found that co-expression of E2F1/c-Myc further accelerates liver cancer development. Here we describe that the deregulated expression of these two transcription factors also affects hepatic ploidy during post-natal liver growth and before the onset of tumors. Oncogenic activity of E2F1 and/or c-Myc was associated with a persistent increase in hepatocyte proliferation. However, E2F1-mediated cell proliferation favored the predominance of diploid cells characteristic of pre-neoplastic type of liver growth whereas c-Myc functioned to accelerate age-related hepatocyte polyploidization. Similarly, proliferative advantage conferred by co-expression of E2F1 and c-Myc increased the frequency of diploid cells at a young age. Thus, the opposing effects of E2F1 and c-Myc on hepatocyte ploidy suggest that these two transcription factors have different mechanisms by which they control liver proliferation/maturation and ultimately, carcinogenesis.
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PMID:E2F1 blocks and c-Myc accelerates hepatic ploidy in transgenic mouse models. 1259 56

Hepatitis B virus (HBV) is a causative agent of chronic and acute hepatitis, and is associated with the development of hepatocellular carcinoma (HCC). We demonstrate here that the Hepatitis B viral core protein (HBc) functions as a repressor on the promoter activity of the human p53 gene. The functional analyses of the promoter of the p53 gene by serial deletion, site-directed mutagenesis, and the heterologous promoter system revealed that the promoter activity was repressed through the E2F1-binding site (nucleotides -28 to -8) by HBc. An electrophoretic mobility shift assay (EMSA) showed that the HBc reduced the DNA-binding ability of E2F1 to the binding site of the p53 promoter. The interaction of HBc with E2F1 was also observed by glutathione S-transferase (GST) fusion protein binding assay. Furthermore, HBc represses the expression of the p53 gene in the human liver cell line HepG2. Finally, HBc and HBx synergistically repress both the promoter activity and the expression of the p53 gene in HepG2 cells. These results, together with our previous study, strongly suggest that HBc, like HBx, represses the expression of the human p53 tumor suppressor gene.
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PMID:Transcriptional repression of the human p53 gene by hepatitis B viral core protein (HBc) in human liver cells. 1267 12

A number of genetic interactions are involved in the control of cell cycle, but their role and nature have not been completely clarified. The knowledge of the behavior of these interactions in hepatocellular carcinoma, could optimize preventive and therapeutic strategies based on cell cycle restraint. We studied downstream events following c-MYC and CYCLIN D1 gene inhibition, by lipoplex-delivered MYC and CYCLIN D1 antisense oligodeoxy nucleotides (aODNM, aODND1), in in vitro cultured human HepG2 and rat Morris 5123 hepatoma cells. 0.5-20 micro M aODN(M) and aODND1 inhibited in vitro growth of both cell types. Scramble oligomer (SCR) and sense ODNs had no or relatively poor effect. Ten micromolar aODNM and aODND1, but not SCR, also induced a significant increase in the apoptotic index of HepG2 and 5123 cells, and inhibited colony formation in soft agar by HepG2 cells. Treatment of the cells with aODNM plus aODND1 had no additive effect on growth and apoptosis. aODNM and aODND1 induced >50% decrease in c-MYC and CYCLIN D1 gene expression, respectively, at both mRNA and protein level. The inhibition of gene expression by aODNs was highly specific, and SCR was without effect. The reduction in c-MYC and CYCLIN D1 expression by aODNs, was associated with a >50% decrease in E2F1 mRNA and protein production, without changes in CYCLIN A and CYCLIN E expression. These results suggest the involvement of both c-MYC and CYCLIN D1 on E2F1 gene function, and indicate that aODNM and aODND1 may inhibit hepatoma cell growth through down-regulation of the E2F1 gene. The inhibition of E2F1 gene expression by E2F1 aODN, was associated with strong growth restraint of HepG2 cells. Thus, interactions of c-MYC and CYCLIN D1 with E2F1 gene are essential for cell cycle activity in hepatoma cells, and their inhibition may have a therapeutic effect.
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PMID:Down-regulation of c-myc and Cyclin D1 genes by antisense oligodeoxy nucleotides inhibits the expression of E2F1 and in vitro growth of HepG2 and Morris 5123 liver cancer cells. 1460 89

E-cadherin is a cell-cell adhesion molecule that plays a pivotal role in the development and maintenance of cell polarity. Disruption of E-cadherin-mediated adhesion represents a key step toward the invasive phenotype in a variety of solid tumors, including hepatocellular carcinoma (HCC). Here, we investigate whether deregulation of E-cadherin occurs along the multistep process of hepatocarcinogenesis in transgenic mouse models, including c-Myc, E2F1, c-Myc/TGF-alpha and c-Myc/E2F1 mice. Liver tumors from the transgenic mouse lines could be divided into two categories based on E-cadherin levels. Of 28, 20 (71.4%) c-Myc HCCs showed marked reduction of E-cadherin expression when compared with wild-type livers. In contrast, all of c-Myc/TGF-alpha and the majority of E2F1 and c-myc/E2F1 preneoplastic and neoplastic lesions exhibited overexpression of E-cadherin. Downregulation of E-cadherin was associated with promoter hypermethylation in seven of 20 c-Myc HCCs (35%), while no loss of heterozygosity at the E-cadherin locus was detected. Nuclear accumulation of beta-catenin did not correlate with E-cadherin downregulation. Furthermore, c-Myc HCCs with reduced E-cadherin displayed upregulation of hypoxia-inducible factor-1alpha and vascular endothelial growth factor proteins. Importantly, loss of E-cadherin was associated with increased cell proliferation and higher microvessel density in c-Myc tumors. Taken together, these data suggest that loss of E-cadherin might favor tumor progression in relatively more benign HCC from c-Myc transgenic mice by stimulating neoplastic proliferation and angiogenesis under hypoxic conditions.
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PMID:Disregulation of E-cadherin in transgenic mouse models of liver cancer. 1522 Sep 35

Human hepatocellular carcinoma is one of the most common cancers in the world. We previously showed that dbpA, a member of the Y box family of proteins, could accelerate the process of inflammation-induced hepatocarcinogenesis, and that dbpA is more abundantly expressed in hepatocellular carcinoma than in non-tumorous tissue. In this study, to clarify the mechanism by which expression of dbpA is enhanced in the proliferative state, we examined the transcriptional activity of the dbpA promoter region. We focused on the sequence 5'-TTTGGGGC-3' (-8 to -1 in the promoter region) resembling the E2F binding site (one base mismatch, TFSEARCH score 86.2). By overexpressing E2F1 in Huh-7 cells, transcriptional activity of dbpA was significantly increased, and this increase was abolished by mutating or deleting this sequence. Thus, expression of dbpA was positively regulated by E2F1, suggesting that one of the effects of E2F1 on cell proliferation might be mediated by dbpA at the carcinogenesis step.
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PMID:Transcription of dbpA, a Y box binding protein, is positively regulated by E2F1: implications in hepatocarcinogenesis. 1531 6

We recently reported that the expression of dbpA (DNA binding protein A) is associated with advanced stages of human hepatocellular carcinoma (HCC) and that its transcription is positively regulated by E2F1, which is also implicated in hepatocarcinogenesis. To study the in vivo effect of dbpA on hepatocarcinogenesis, we generated the dbpA-transgenic mouse that specifically expressed a transgene in hepatocytes. Here, we studied the effect of dbpA on the expression of other cellular genes by using microarray analyses. The expression profiles from livers of 31- and 32-week-old male transgenic mice [Tg(+)] that did not show any morphological changes and from livers of their male wild-type littermates [Tg(-)] were compared. Expression differences detected by microarray analyses were validated by reverse transcription-polymerase chain reaction (RT-PCR) using total RNA samples from livers of 3 pairs of Tg(+) and (-) mice. The 11 up-regulated genes included 7 carcinogenesis-related genes (Igfbp1, Tff3, Hpx, Orm2, Ctsl, Plg, Jdp1), and the 9 down-regulated genes included Car3 that is associated with the protection of cells from attack by oxygen radicals. We confirmed that the expression of Igfbp1 (insulin like growth factor binding protein 1) was reduced by siRNA targeting dbpA in the human HCC cell line. In conclusion, our present data suggested that dbpA could be positively involved in carcinogenesis by changing the expression profiles of cellular genes.
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PMID:Gene expression profile of DNA binding protein A transgenic mice. 1686 84

DNA methyltransferase 1 (DNMT1) is responsible for copying DNA methylation patterns to the daughter strands during DNA replication. Its expression is frequently up-regulated in human tumors, including hepatocellular carcinoma, but the mechanism of overexpression and its biological significance remain unclear. Here, we show that hepatitis B virus X protein (HBx) activates DNMT1 expression via a regulatory circuit involving the p16(INK4a)-cyclin D1-cyclin-dependent kinase (CDK) 4/6-retinoblastoma protein (pRb)-E2F1 pathway. HBx induced DNA hypermethylation of p16(INK4a) promoter to repress its expression, which subsequently led to activation of G1-CDKs, phosphorylation of pRb, activation of E2F1, and finally transcriptional activation of DNMT1. Inhibition of DNMT1 activity by either treatment with 5'-Aza-2'dC or introduction of DNMT1 small interfering RNA not only abolished the DNA methylation-mediated p16(INK4a) repression but also impaired DNMT1 expression itself, suggesting a cross-talk between DNMT1 and p16(INK4a). The up-regulation of cyclin D1 by HBx is likely to serve as an initiative impulse for the circuit because it was absolutely required for the activation of DNMT1 expression. We also observed that accumulated DNMT1 via this pathway inactivates E-cadherin expression through promoter hypermethylation. Considering that the pRb-E2F1 pathway is commonly activated in human tumors, activation of this circuit might be widespread and a potential therapeutic target.
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PMID:Expression of DNA methyltransferase 1 is activated by hepatitis B virus X protein via a regulatory circuit involving the p16INK4a-cyclin D1-CDK 4/6-pRb-E2F1 pathway. 1757 44


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