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

The INK4alpha/ARF locus encodes p14(ARF) and p16(INK4alpha) , that function to arrest the cell cycle through the p53 and RB pathways, respectively. Genetic alterations of p14ARF and their relationship with p16(INK4a) or p53 inactivation have not been characterized in hepatocellular carcinoma (HCC). We examined 40 pairs of HCCs/noncancerous liver tissues for homozygous deletions (HD), methylation and mutations of the INK4a/ARF locus and for mutations of p53, and analyzed their clinicopathological correlation. p16(INK4a), p53 and p14(ARF) were inactivated in 62.5% (25 out of 40), 42.5% (17 out of 40) and 20% (8 out of 40) of HCCs, respectively. Inactivation of p14(ARF) was always associated with the concomitant inactivation of p16(INK4a) and occurred more frequently in hepatitis C virus (HCV)-associated HCC (p=0.042). Inactivation of p16INK4a) occurred more frequently in older patients (p=0.0027. The predominant mechanism of inactivation of p14(ARF) was homozygous deletion (7 out of 8), while that of p16(INK4a) was methylation (21 out of 25). Although statistically insignificant, genetic alterations of p14(ARF) tended to occur in tumors with wild-type p53. Genetic alterations of the INK4alpha/ARF locus could occur in small HCCs. In contrast, p53 mutations occurred more frequently in advanced HCCs (p=0.041). Inactivation of either p14(ARF)/p53 or p16(INK4a) occurred in 80% (32 out of 40) and concomitant disruption of both pathways occurred in 40% (16 out of 40) of HCCs, respectively. These results suggest that p14(ARF), p16(INK4a) and p53 are differentially disrupted through distinct molecular mechanisms at different stages in HCC and that p14(ARF) and p53 appear to function in the same tumor suppression pathway in HCC
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PMID:Genetic alterations of INK4alpha/ARF locus and p53 in human hepatocellular carcinoma. 1216 36

Epigenetic changes in gene expression due to extensive CpG island methylation is now accepted as the main cause of inactivation of the p16 gene. More recently, it has been suggested that the human ras association domain family (RASSF) 1 gene, cloned from the lung tumor-suppressor locus 3p21.3, also may be inactivated by methylation. It consists of two major alternative transcripts, RASSF1A and RASSF1C. Epigenetic inactivation of isoform A was observed in several carcinomas and tumor cell lines. In this study, promoter hypermethylation of RASSF1A and p16 was investigated in 83 hepatocellular carcinoma (HCC) tissue samples from Taiwan and in two HCC cell lines (Hep3B and HepG2). High frequencies (85% and 47%, respectively) of methylation of the CpG island promoters of RASSF1A and p16 were found in the HCC tissues. The methylation of RASSF1A also was detected in Hep3B cells but not in HepG2 cells; p16 was not methylated in either cell line. Methylation status was determined in 12 normal control liver tissues and 10 adjacent nontumor tissues. No methylation was found in normal liver control tissues for both RASSF1A and p16; methylation was detected in one of 10 and seven of 10 adjacent nontumor tissue sampless for p16 and RASSF1A, respectively, in subjects with positive tumors. These data indicate that aberrant methylation of the CpG island promoters of both genes is a frequent occurrence in hepatocarcinogenesis. The high frequency of RASSF1A methylation in adjacent tissues suggests that this may be an early event. The relationship between methylation status and clinical parameters and tumor markers, including DNA damage resulting from aflatoxin B(1) (AFB(1)), an environmental carcinogen, and p53 status, also was analyzed. A statistically significant association was found between RASSF1A methylation status and the level of AFB(1)-DNA adducts in tumor tissues. No association was found between methylation status and p53 status. These results suggest the hypothesis that exposure to environmental carcinogens may be involved in altered methylation of genes involved in cancer development.
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PMID:High frequency of promoter hypermethylation of RASSF1A and p16 and its relationship to aflatoxin B1-DNA adduct levels in human hepatocellular carcinoma. 1232 38

Four cases of brain metastasis from hepatocellular carcinoma (HCC) associated with hepatitis B virus (HBV) are reported in an area not endemic for HBV infection. Two cases are unusual, since cerebral metastases were the only secondary localization. In these cases, no other sites of metastasization were detected either before or immediately following neurosurgical treatment. In all cases the expression of pRB, p53 and p16 tumor suppressor protein was studied with immunohistochemistry, both, in the primary and metastatic lesions. The pRB expression was as follows: in two cases, lack and moderate expression were observed both, in the primary and in the metastases; in the other two, pRB was not detected. In all cases p53 expression was negative both, in the primary and the metastases. P16 expression was moderately expressed in three cases, both in the primary and the metastases. In one case it was absent. Hepatocarcinogenesis is a multistep process, in which several oncogenes and oncosuppressor genes are involved. In four unusual cases of spread to the brain, we evidenced that tumor suppressor protein expression of p16, p53, and particularly pRB (its aberrated expression is usually associated with metastasis) were altered. We also suggest that HBV and its X protein (HBX) might play an important role in such aggressive behavior of the neoplasia.
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PMID:Brain metastasis from hepatocellular carcinoma associated with hepatitis B virus. 1238 72

The aim of the present study was to determine whether p16 gene is involved in the genesis of primary hepatocellular carcinoma (HCC). Twenty-five primary HCC tumor and corresponding non-tumor liver tissue specimens were examined for P16 gene alterations. The identification of deletion of p16 gene exon 1 and exon 2 was performed using comparative multiplex polymerase chain reaction (PCR) analysis. The point mutation of p16 gene exon 2 was investigated by single strand conformational polymorphism(SSCP) analysis, and the status of p16 gene methylation was screened using PCR-based methylation analysis. Moreover, 35 parafin specimens of primary HCCs with corresponding non-tumor liver tissues, including the 25 cases described above for screening of p16 gene alterations, were investigated also for P16 protein expression by using immunohistochemical analysis. The results of comparative multiplex PCR analysis showed that 12% (3/25) p16 gene deletions, including homozygous deletions in 2 tumors and hemizygous deletion in 1 tumor, were found in the primary HCCs samples. No point mutation was identified in the remaining 22 tumor samples without p16 gene deletions by using SSCP analysis. Hypermethylation was detected in 24% (6/25) of tumor samples by PCR-based analysis. However the corresponding non-tumor liver tissue specimens were always unmethylated at p16 locus. Loss of P16 protein expression, detected by immunohistochemistry, occurred in 16 of 35 (45.7%) tumor samples, whereas all the non-tumor liver tissue specimens showed positive p16 staining. These results indicate that inactivation of p16 gene is relevant to the genesis of HCC.
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PMID:[A study on the inactivation of p16 genes and the expression of P16 protein in primary hepatocellular carcinomas]. 1254 16

Abnormality of the p16 expression is involved in the pathogenesis of hepatocellular carcinoma (HCC), and hypermethylation of p16 gene is known as a major p16 inactivation mechanism. Cirrhotic nodule (CN) is now regarded as a preneoplastic lesion that is frequently associated with microscopic foci of HCC through dysplastic nodules (DNs). This observation clearly supports a multistep hepatocarcinogenesis from CNs through DNs. We thus examined the methylation status of p16 gene in HCCs surrounded by DNs and CNs to define the significance of p16 hypermethylation in the early stage of hepatocarcinogenesis. We tested 24 hepatitis B virus (HBV)-associated CNs, 37 DNs, and 18 HCCs within DNs that were microdissected from paraffin-embedded tissue sections. Frequency of p16 hypermethylation was significantly high in HCCs within DNs (15/18. 83.3%) and it increased from CNs (15/24. 62.5%) through DNs (26/37, 70.3%). Interestingly, 11 out of 12 (91.7%) HCC associated with methylation-positive DNs revealed hypermethylation of p16, and 18 out of 23 (78.2%) DNs associated with methylation-positive CNs showed p16 hypermethylation. These data suggest that p16 hypermethylation in the early stages, CNs and DNs may predispose to HCC. In addition, p16 methylation status of five cell lines with or without HBV infection was examined to test whether the high frequency of hypermethylation is related to HBV infection. HBV-infected cell lines were exclusively methylation-positive. These data suggest that high frequency of hypermethylation may be associated with hepatitis B virus infection.
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PMID:p16 Hypermethylation in the early stage of hepatitis B virus-associated hepatocarcinogenesis. 1256 76

Aberrant promoter methylation is a fundamental mechanism of inactivation of tumor suppressor genes in cancer. The Ras association domain family 1A gene (RASSF1A) is frequently epigenetically silenced in several types of human solid tumors. In this study, we have investigated the expression and methylation status of the RASSF1A gene in hepatocellular carcinoma (HCC). In two HCC cell lines (HepG2 and Hep3B) RASSF1A was inactivated and treatment of these cell lines with a DNA methylation inhibitor reactivated the transcription of RASSF1A. The methylation status of the RASSF1A promoter region was analysed in 26 primary liver tissues including HCC, hepatocellular adenoma (HCA), liver fibrosis, hepatocirrhosis. Out of 15, 14 (93%) HCC were methylated at the RASSF1A CpG island and hypermethylation was independent of hepatitis virus infection. RASSF1A was also methylated in two out of two fibrosis and in three (75%) out of four cirrhosis; the latter carries an increased risk of developing HCC. Additionally, we analysed the methylation status of p16(INK4a) and other cancer-related genes in the same liver tumors. Aberrant methylation in the HCC samples was detected in 71% of samples for p16, 25% for TIMP3, 17% for PTEN, 13% for CDH1, and 7% for RARbeta2. In conclusion, our results demonstrate that RASSF1A and p16(INK4a) inactivation by methylation are frequent events in hepatocellular carcinoma, but not in HCA, which is in contrast to HCC without cirrhosis, viral hepatitis, storage diseases, or genetic background. Therefore, this study gives additional evidence against a progression of adenoma to carcinoma in the liver. Thus, RASSF1A hypermethylation could be useful as a marker of malignancy and to distinguish between the distinct forms of highly differentiated liver neoplasm.
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PMID:Frequent epigenetic inactivation of the RASSF1A gene in hepatocellular carcinoma. 1266 Aug 22

A comparison was made between two K vitamin analogs. Growth in vitro of Hep G2 hepatoma cells was inhibited both by Compound 5 (Cpd 5), a recently synthesized thioalkyl analog of vitamin K or 2-(2-mercaptoethanol)-3-methyl-1, 4-naphthoquinone, as well as by synthetic vitamin K3 (menadione). Using synchronized Hep G2 hepatoma cells, the actions of both Cpd 5 and vitamin K3 on cell cycle regulating proteins were examined. Cpd 5 decreased the levels of cyclin D1, Cdk4, p16, p21 and cyclin B1. By contrast, VK3 only decreased the level of cyclin D1, but had no effect on the levels of Cdk4, p16 or p21. Interestingly, both VK3 and VK2 increased the levels of p21. The naturally occurring K vitamins had little effect on cell growth and none on the cyclins or Cdks. Amounts and activity of the G1/S phase controlling Cdc25A were measured. We found that Cpd 5 directly inhibited both Cdc25A activity and its protein expression, whereas VK3 did not. Thus, the main effects of Cpd 5 were on G1 and S phase proteins, especially Cdk4 and Cdc25A amounts in contrast to VK3. Computer docking studies of Cpd 5 and VK3 to Cdc25A phosphatase showed three binding sites. In the best conformation, Cpd 5 was found to be closer to the enzyme active site than VK3. These findings show that Cpd 5 represents a new class of anticancer agent, being a protein tyrosine phosphatase (PTP) antagonist, that binds to Cdc25A with suppression of its activity. Tumors expressing high levels of oncogenic Cdc25A phosphatase may thus be susceptible to the growth inhibitory activities of this class of compound.
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PMID:Differential effects of two growth inhibitory K vitamin analogs on cell cycle regulating proteins in human hepatoma cells. 1267 93

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

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