UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One of the main regulatory pathways reported to be altered in hepatocellular carcinoma (HCC) is that of cell cycle control involving RB1 gene-related cell inhibitors. We investigated p14(ARF), p15(INK4B), p16(INK4A), p18(INK4C), and RB1 genes in a series of HCCs and associated cirrhosis with the goal of ascertaining their pattern of inactivation by gene methylation. Thirty-three HCCs, adjacent nonneoplastic cirrhotic tissues, and 6 HCC cell lines were studied. Cirrhoses (25 of 33, 76%), HCCs (31 of 33, 94%), and 3 of 6 (50%) cell lines showed 1 or more methylated genes. Cirrhoses (17 of 33, 51%) had more frequently than HCCs (11 of 33, 33%, P =.01) only 1 methylated gene. With the exception of p18(INK4C) the genes under study showed promoter methylation with frequency ranging from 82% (p16(INK4A) in HCC) to 33% and 39% (p15(INK4B) and p16(INK4A) in cirrhoses). In cases with only 1 methylated gene, p15(INK4B) in cirrhosis (8 of 17, 47%) and p16(INK4A) in HCC (10 of 11, 91%) were the more frequently altered. An optimal correlation was found between p15 and p16 gene methylation and complete protein loss in HCC detected by immunocytochemistry, whereas a partial loss of the same proteins was a feature of methylated cirrhoses. Inactivation by DNA methylation of several genes of the RB1 pathway is common to cirrhosis and HCC. An early pattern of methylatory events (1 methylated gene) is a feature of cirrhosis rather than HCC, whereas an advanced one (> or = 3 methylated genes) is characteristic of malignancy. Early methylation changes seem to involve p15(INK4B) and p16(INK4A) in cirrhosis and p16(INK4A) in HCC. In conclusion, a stepwise progression of methylating events is a feature of the sequence cirrhosis-HCC and contributes to the process of hepatic carcinogenesis with potential clinical implications.
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PMID:Methylation framework of cell cycle gene inhibitors in cirrhosis and associated hepatocellular carcinoma. 1214 52

Major etiologic factors associated with human hepatocellular carcinomas (HCCs) include infection with hepatitis C (HCV) and hepatitis B virus (HBV), excess alcohol intake and aflatoxin B(1) exposure. While the G-->T p53 mutation at codon 249 has been identified as a genetic hallmark of HCC caused by aflatoxin B(1), the genetic profile associated with other etiologic factors appears to be less distinctive. In our study, we screened HCCs resulting from HCV infection (51 cases), HBV infection (26 cases) or excess alcohol intake (23 cases) for alterations in genes involved in the RB1 pathway (p16(INK4a), p15(INK4b), RB1, CDK4 and cyclin D1), the p53 pathway (p53, p14(ARF) and MDM2) and the Wnt pathway (beta-catenin, APC). Alterations of the RB1 pathway, mainly p16(INK4a) methylation, loss of RB1 expression and cyclin D1 amplification, were most common (69-100% of cases). There was a significant correlation between loss of RB1 expression and RB1 methylation. All 24 HCCs with RB1 promoter methylation lacked RB1 expression, while none of the 67 cases with RB1 expression exhibited RB1 methylation (p < 0.0001), suggesting that promoter methylation is a major mechanism of loss of RB1 expression in HCCs. Alterations of the p53 pathway consisted mostly of p53 mutations or p14(ARF) promoter methylation (20-48%). Mutations of the p53 gene were found at a similar frequency (13-15%) in all etiologic groups, without any consistent base change or hot spot. Mutations of beta-catenin were found in 13-31% of cases, while no APC mutations were detected in any of the HCCs analyzed. With the exception of only 3 of 39 cases (8%), cyclin D1 amplification and beta-catenin mutations were mutually exclusive, supporting the view that cyclin D1 is a target of the Wnt signaling pathway. Overall, the RB1, p53 and Wnt pathways were commonly affected in HCCs of different etiology, probably reflecting common pathogenetic mechanisms, i.e., chronic liver injury and cirrhosis, but tumors associated with alcoholism had more frequent alterations in the RB1 and p53 pathways than those caused by HCV infection.
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PMID:Alterations of RB1, p53 and Wnt pathways in hepatocellular carcinomas associated with hepatitis C, hepatitis B and alcoholic liver cirrhosis. 1284 70

Hepatocellular carcinoma (HCC) is one of the most fatal human malignancies, but the molecular mechanisms of hepatocarcinogenesis remain unclear. Although p53 mutations are frequently observed in Asian HCC, it is not a common event in Western HCC. Recent studies suggest that tumor suppressor genes (TSGs) can also be silenced through epigenetic disruption, such as promoter CpG island methylation, during carcinogenesis. To further understand the molecular mechanism of hepatocarcinogenesis, we have investigated the promoter methylation status of nine TSGs (SOCS-1, GSTP, APC, E-cadherin, RAR-beta, p14, p15, p16, and p73) in 51 cases of HCC using methylation-specific polymerase chain reaction. We found that 82% of HCCs had methylation of at least one TSG promoter. The most frequently methylated TSGs in HCC were: SOCS-1 (65%), GSTP (54%), APC (53%), E-cadherin (49%), and p15 (49%). Methylation of SOCS-1, GSTP, APC, E-cadherin, and p15 was more frequent in HCC than in nontumor liver (P < 0.05). Methylation of SOCS-1, GSTP, and p15 was also significantly more frequent in HCC than cirrhotic liver (P < 0.05). Although methylation of one or two genes could be seen in both nontumor and cirrhotic livers, 53% of the HCC cases had three or more TSG promoters methylated, in comparison to 0% in nontumor liver and 13% in cirrhosis (P = 0.001). Methylation of SOCS-1, APC, and p15 was more frequently seen in hepatitis C virus-positive HCC than hepatitis C virus/hepatitis B virus-negative HCC. Our data suggest that promoter hypermethylation of TSGs is a common event in HCC and may play an important role in hepatocarcinogenesis.
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PMID:Aberrant promoter methylation profiles of tumor suppressor genes in hepatocellular carcinoma. 1293 51

Hepatocarcinogenesis may involve multiple mutations with distinctive pathogenetic and clinicopathologic significance. To test this hypothesis, 68 cases of hepatocellular carcinoma (HCC) were studied prospectively for genetic-clinicopathologic correlation. Ten pathologic characteristics were evaluated. TP53 (alias p53) gene mutation was studied by a polymerase chain reaction (PCR)-single-strand conformation polymorphism-sequencing; CDKN2B (alias p15) and CDKN2A (alias p16) gene methylation by methylation-specific PCR; and genetic imbalances by comparative genomic hybridization (CGH). TP53 gene mutations occurred in 25% of cases, more than half being codon 249 G to T transversion. Methylation of CDKN2A was frequent (61.7%); of CDKN2B, rare (5.9%). The CGH analysis showed a median of nine aberrations per case, with amplifications more frequent than deletions. Isochromosomes might be involved in about 25% of cases. Amplifications of 1q and 8q were most frequent. Clinicopathologic correlations showed that CDKN2A methylation was significantly associated with tumors arising in cirrhotic livers; amplifications of 17q was significant in multiple parameters of tumor invasiveness (size, venous invasion, poor cellular differentiation, microsatellite formation); other amplifications (1q, 6p, 10p, and 20p) were also significant in tumor invasion; and deletions (at 1p, 11q, 4q, and 14q) were significant in tumor growth. Consistent patterns of genetic alterations were defined in HCC, which might represent distinctive pathways in hepatocarcinogenesis.
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PMID:Clinicopathologic significance of genetic alterations in hepatocellular carcinoma. 1449 90

Survivors of allogeneic hematopoietic stem cell transplantation (HSCT) are at a life-long increased risk of secondary nonhematologic malignancies. In 615 adult Chinese allogeneic HSCT patients, nine developed nonhematologic malignancies. The 5-year cumulative incidence was 6.1%, 4.5 times the background cancer incidence. Early-onset (within first 6 months) and late-onset (>3 years) subtypes were observed. Secondary cancers included hepatocellular carcinoma, oral and esophageal squamous cell tumors and lung adenocarcinoma in a female nonsmoker. The spectrum reflected local cancer epidemiology, which was different from Western populations. The pathogenesis might be related to acceleration of pre-existing cancers (early-onset type), or prolonged immunosuppression (late-onset type). DNA chimerism studies showed that all tumors were recipient-derived. In the plasma, DNA in all cases was apparently donor-derived, although aberrantly methylated p15 was detectable in a patient with a p15-methylated secondary cancer, implying that minute quantities of tumor (and therefore recipient) derived DNA might be present.
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PMID:Nonhematologic malignancies after allogeneic hematopoietic stem cell transplantation: incidence and molecular monitoring. 1550 54

The signaling mechanisms for most of the antiproliferative processes are not fully understood. We have demonstrated that ERK(MAPK) signaling was involved in the induction of both p15(INK4b)and p16(INK4a) CDK inhibitors and growth inhibition of hepatoma cell HepG2 triggered by the tumor promoter tetradecanoyl phorbol acetate (TPA). In this study, the upstream signal mechanism for TPA-induced ERK(MAPK) activation was investigated. In HepG2 cells only one of the cPKC isozymes, PKCalpha, but not cPKCbetaII, nPKCepsilon or aPKCzeta was activated by TPA as demonstrated by its membrane translocation within 10-30 min and down-regulation at 24 h after TPA treatment. Pretreatment of 0.2-2.0 microM Bisindolylmaleimides, an inhibitor of PKC, attenuated the TPA-induced phosphorylation of ERK, gene expressions of p15(INK4b) and p16(INK4a), and growth inhibition of HepG2 cell in a dose-dependent manner. Consistently, transfection of HepG2 with 1.0-3.0 microM antisense (AS) PKCalpha, but not (AS) PKCbetaII, or nPKCepsilon oligonucleotides (ODN), for 36 h prior to TPA treatment also prevented the TPA-induced molecular and cellular effects described above. Taken together, we concluded that PKCalpha is specifically required for TPA-induced ERK(MAPK) signaling to trigger gene expressions of p15(INK4b) and p16(INK4a) leading to HepG2 growth inhibition.
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PMID:Activation of protein kinase C alpha is required for TPA-triggered ERK (MAPK) signaling and growth inhibition of human hepatoma cell HepG2. 1591 95

The methylthioadenosine phosphorylase (MTAP) gene is localized in the chromosomal region 9p21. Here, frequently homozygous deletions occur in several kinds of cancer associated with the loss of tumour suppressor genes as p16 and p15. The aim of this study was to analyse MTAP expression in hepatocellular carcinoma (HCC) and to get an insight into the regulation and functional role of MTAP in hepatocancerogenesis. Compared with primary human hepatocytes MTAP expression was markedly downregulated in three different HCC cell lines as determined by real-time PCR and western blotting. This was not due to genomic losses or mutations but to promoter-hypermethylation. Reduced MTAP-expression was confirmed in vivo in HCC compared with non-cancerous liver tissue on both mRNA and protein levels. To study the functional relevance of the downregulated MTAP expression in HCC, MTAP expression was re-induced in HCC cell lines by stable transfection. In these MTAP re-expressing cell clones the invasive potential was strongly reduced, whereas no effects on cell proliferation were observed in comparison with mock transfected cell clones. Furthermore, in MTAP re-expressing cells interferon (IFN)-alpha and IFN-gamma induced a significantly stronger inhibition of cell proliferation than in mock transfected cells. In conclusion, our results suggest a functional role of MTAP inactivation in HCC development and invasiveness. Furthermore, in the light of a recent report revealing an association between MTAP activity and IFN sensitivity, our findings may have clinical significance for therapeutic strategies.
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PMID:Promoter-hypermethylation is causing functional relevant downregulation of methylthioadenosine phosphorylase (MTAP) expression in hepatocellular carcinoma. 1608 15

The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) is a well-known activator of both protein kinase C (PKC) and mitogen activated protein kinase (MAPK) signal cascade triggering a lot of effects in many non-tumor and tumor cells. We have reported activation of PKCalpha isozyme was specifically required for TPA-induced ERK (MAPK) signaling that mediated gene expressions of the CDK inhibitors p15(INK4b) and p16 (INK4a) leading to growth inhibition of hepatoma cell HepG2. We further investigated the upstream signal molecule linking PKCalpha to ERK. In the Ras activation assay, HepG2 cell exhibited substantial amount of Ras activity. Treatment of the cell with 50nM TPA for 10min slightly inhibited Ras activity by about 10-20%. Pretreatment of the cell with 10microM manumycin A, which abolish basal Ras activity, did not prevent TPA-triggered ERK phosphorylation. Immunoprecipitation coupled with kinase assay demonstrated that MEK-1 activity was strongly induced by treatment of TPA for 5-30min in HepG2. In contrast, c-Raf activity was not significantly induced by TPA within 5-15min. Consistently, Western blot of Phospho(ser-218/222)-MEK demonstrated that phosphorylation of MEK-1 was greatly induced by 50nM TPA, which can be prevented by the PKC inhibitor Bisindolylmaleimides II. Moreover, pretreatment of the MEK1/2 inhibitor, but not c-Raf inhibitor prevented the TPA-induced ERK phosphorylation, gene expression of p15(INK4b) and p16 (INK4a) and growth inhibition of HepG2. In addition, transient expression of a dominant negative Raf mutant in HepG2 did not prevent these effects of TPA. Constitutive expression of an active PKCalpha mutant in HepG2 enhanced phosphorylation of both MEK and ERK accompanied with induction of gene expression of p16(INK4a) and growth inhibition of HepG2. In contrast, Ras and Raf activity were not increased by expression of active PKCalpha. Taken together, we conclude that PKCalpha may activate MEK, independently of Raf and Ras, to trigger sustained ERK (MAPK) signaling and cell cycle arrest of HepG2 induced by TPA.
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PMID:Protein kinase C alpha trigger Ras and Raf-independent MEK/ERK activation for TPA-induced growth inhibition of human hepatoma cell HepG2. 1616 61

Hepatocellular carcinoma (HCC) ranks fifth in frequency of cancers worldwide. The main aetiological factor is hepatitis B virus (HBV) although the importance of hepatitis C virus (HCV) is growing. The most important tumour marker for HCC is alpha-fetoprotein (AFP). The common method of screening high risk patients by AFP and ultrasonography has been shown to result in earlier detection and consequently more easily treatable tumours and longer survival. Proposed screening interval varies from once every 3 months to annually to "as indicated' but, most commonly, is once every 6 months. AFP is a fairly specific but insensitive marker for HCC. Sensitivity of HCC detection by blood markers is improved by combining various other markers with AFP. Of the other markers, the newer high sensitivity des-gamma-carboxy-prothrombin (DCP) has been found to be useful. In addition the AFP fractions L3, P4/5 and the +II band are highly specific for HCC. Among routinely assayed tumour markers in the laboratory, CA 125 is more sensitive for HCC than AFP but far less specific. Various other enzymes, isoenzymes, growth factors, adhesion molecules, other proteins such as interleukin-2 receptor (IL-2R), human cervical cancer oncogene protein (HCCR) and glypican-3 (GPC3), p15 and p16 hypermethylation and nitrite/nitrate ratio have been tested; some of these show promise but none is presently in routine use. The value of other newer markers such as the HBx protein that is produced by HBV, and what are thought to be specific proteins and signatures identified by proteomics remain to be determined.
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PMID:Recent developments in the first detection of hepatocellular carcinoma. 1645 14

Hepatocellular carcinoma (HCC) is associated with multiple risk factors and is believed to arise from pre-neoplastic lesions, usually in the background of cirrhosis. However, the genetic and epigenetic events of hepatocarcinogenesis are relatively poorly understood. HCC display gross genomic alterations, including chromosomal instability (CIN), CpG island methylation, DNA rearrangements associated with hepatitis B virus (HBV) DNA integration, DNA hypomethylation and, to a lesser degree, microsatellite instability. Various studies have reported CIN at chromosomal regions, 1p, 4q, 5q, 6q, 8p, 10q, 11p, 16p, 16q, 17p and 22q. Frequent promoter hypermethylation and subsequent loss of protein expression has also been demonstrated in HCC at tumor suppressor gene (TSG), p16, p14, p15, SOCS1, RIZ1, E-cadherin and 14-3-3 sigma. An interesting observation emerging from these studies is the presence of a methylator phenotype in hepatocarcinogenesis, although it does not seem advantageous to have high levels of microsatellite instability. Methylation also appears to be an early event, suggesting that this may precede cirrhosis. However, these genes have been studied in isolation and global studies of methylator phenotype are required to assess the significance of epigenetic silencing in hepatocarcinogenesis. Based on previous data there are obvious fundamental differences in the mechanisms of hepatic carcinogenesis, with at least two distinct mechanisms of malignant transformation in the liver, related to CIN and CpG island methylation. The reason for these differences and the relative importance of these mechanisms are not clear but likely relate to the etiopathogenesis of HCC. Defining these broad mechanisms is a necessary prelude to determine the timing of events in malignant transformation of the liver and to investigate the role of known risk factors for HCC.
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PMID:Review of genetic and epigenetic alterations in hepatocarcinogenesis. 1670 6

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