Genetic heterogeneity of hepatocellular carcinoma.

Ünsal, Hilal; Yakıcıer, Cengiz; Marçais, Christophe; Kew, Michael C.; Volkmann, Martin; Zentgraf, H.; Isselbacher, Kurt J.; Öztürk, Mehmet

doi:10.1073/pnas.91.2.822

Cited by 148 publications

(61 citation statements)

References 23 publications

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“…[65][66][67][68] HBx variants expressed from the chromosomally integrated mutants may also contribute to different HBx distribution patterns and expression levels, particularly in the neoplastic lesions. Combined use of several antibodies recognizing different epitopes, as in this study, should greatly increase the possibility to detect HBx in the tissue.…”

Section: Discussionmentioning

confidence: 99%

“…78,80,81 In this study, we observed a close statistical correlation between expression of HBx and existence of HBsAg in HCC-bearing liver, which may reflect the frequent preservation of the X gene together with the PreS2/S1 region during the integration of HBV DNA into cellular genomic DNA and the following rearrangements. [65][66][67][68] However, their distribution patterns were differ- ent. Our results demonstrated that the expression of HBx, among the three HBV antigens examined, was preferentially maintained through the multistage process from foci and nodules of altered hepatocytes, for which a preneoplastic nature has been demonstrated, 54,57 to HCC.…”

Section: Discussionmentioning

confidence: 99%

“…Expression of the X gene in HBV-infected livers has been inferred from the preferential conservation of the X sequence within integrated HBV DNA in HCC and cirrhotic livers with HBV infection, [65][66][67][68] the frequent occurrence of X sequence components containing RNA in HCC specimens, 33,34 the emergence of circulating antibodies, [35][36][37][38][39][40][41][42] and the demonstration of a frequent cellular immune response 43 specific to HBx. The detection of HBx has, however, proved to be very difficult, and the reported data are contradictory.…”

Section: Discussionmentioning

confidence: 99%

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Expression of hepatitis B virus X protein in HBV-infected human livers and hepatocellular carcinomas

et al. 1998

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. The X gene-encoded protein (HBx), consisting of 154 amino acid residues with a molecular weight of 17 kd, is detected after overexpression in some eukaryotic expression systems 3-6 and localized mainly within the cytoplasm. 3,6 The function of HBx is largely obscure, but it has been shown to transactivate many viral and cellular genes, including some transcriptional factors (reviewed by Caselmann, 1 Hildt et al., 2 and Rossner 7 ) and growth-regulating genes such as ras, 8,9 c-myc, 10 c-fos, 10,11 c-jun, 12 and the gene coding for the epidermal growth factor receptor. 13 Recent studies indicate that HBx is also associated with elevated expression of insulin-like growth factor II 14 and insulin-like growth factor I receptor 15 in hepatocytes and hepatocellular carcinoma (HCC). HBx has been reported to be capable of binding p53, 16-22 the TATA-binding protein 23 and a cellular protein associated with DNA repair. 24 These findings indicate a possible role of HBx in HBV replication, in accordance with the well-established mechanism of replication of the woodchuck hepatitis virus, 25 as well as the potential to disturb growth control and DNA repair in the host cells. Malignant transformation has been observed in some X gene-transfected cell lines 1,26,27 and in an X gene-transgenic mouse model. 28,29 The X gene is, therefore, considered to play a decisive role in neoplastic transformation of hepatocytes in HBV-infected liver. 29,30 Transactivation of the growthregulating genes and functional inactivation of p53 by HBx have been proposed as alternative mechanisms. 1,2,7,16,21,30 Expression of the X gene in liver tissue has been established in woodchucks carrying the woodchuck hepatitis virus. 31,32 However, only indirect evidence for the expression of X gene in HBV-infected human liver has so far been obtained. RNA, containing components of the X region, has been demonstrated by reverse-transcription polymerase chain reaction. 33,34 Circulating antibodies reactive to recombinant HBx, [35][36][37][38][39][40][41][42] and HBx-specific cellular immune response, 43 may be detected in patients with chronic hepatitis B. By means of antibodies against recombinant HBx or its fragments, some immunoreactivity has been demonstrated in HBV-infected livers, 14,39,[44][45][46][47][48][49][50][51] with three polypeptides identified as the HBx antigen in HCC-bearing livers of HBV-infected Chinese patients. 16 While interactions between HBx and the p53 protein are documented, 17-22,52 a dissenting view was expressed recently by Henkler et al., 53 who did not show either HBx expression in, or coprecipitation of HBx and p53 protein from, HCC specimens of 31 Chinese patients with chronic HBV infection. These conflicting results may at least partly be caused by the application of different anti-HBx antibodies. In the present study, 11 anti-HBx antibodies prepared in five laboratories were therefore characterized comparatively. With Abbreviations: HBV, hepatitis B virus; HBx, hepatitis B virus X protein; HCC, hepatocellular carcinoma; PB...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Expression of hepatitis B virus X protein in HBV-infected human livers and hepatocellular carcinomas

et al. 1998

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“…Characteristics of these tumors and methods for DNA isolation have been described previously [13,14]. SNP309 (T/G) of MDM2 were genotyped using PCR amplification of the first intron of the MDM2, followed by MspA1I (Promega) digestion as described elsewhere [15].…”

Section: Methodsmentioning

confidence: 99%

Mdm2 Snp309 G allele displays high frequency and inverse correlation with somatic P53 mutations in hepatocellular carcinoma

Acun

Terzioğlu-Kara

Konu

et al. 2010

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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a b s t r a c tLoss of function of the p53 protein, which may occur through a range of molecular events, is critical in hepatocellular carcinoma (HCC) evolution. MDM2, an oncogene, acts as a major regulator of the p53 protein. A polymorphism in the MDM2 promoter, SNP309 (T/G), has been shown to alter protein expression and may thus play a role in carcinogenesis. MDM2 SNP309 is also associated with HCC. However, the role of SNP309 in hepatocarcinogenesis with respect to TP53 mutations is unknown. In this study, we investigated the distribution of the MDM2 SNP309 genotype and somatic TP53 (the p53 tumor suppressor gene) mutations in 99 human HCC samples from Africa, Europe, China and Japan. Samples exhibited striking geographical differences in their distribution of SNP309 genotypes. The frequency and spectrum of p53 mutations also varied geographically; TP53 mutations were frequent in Africa, where the SNP309 T/T genotype predominated but were rare in Europe and Japan, where the SNP309 G allele was present more frequently.TP53 mutations were detected in 18% (4/22) of SNP309 T/G and G/G and 82% (18/22) of SNP309 T/T genotype holders; this difference was statistically highly significant (P-value = 0.0006).Our results indicated that the presence of the SNP309 G allele is inversely associated with the presence of somatic TP53 mutations because they only coincided in 4% of HCC cases. This finding suggests that the SNP309 G allele may functionally replace p53 mutations, and in addition to known etiological factors, may be partly responsible for differential HCC prevalence.

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“…[2][3][4] Only a few tumor suppressor genes have been implicated in liver carcinogenesis. P53 mutations [5][6][7][8] and Rb-encoding gene rearrangements 9,10 have indeed been shown in HCC tumor tissues. More recently, deletions and mutations have been identified in around 61%, and in up to 26% of HCCs, in the genes encoding the mannose 6-phosphate/insulin-like growth factor II receptor 11,12 and in the ␤-catenin encoding gene, 13 respectively.…”

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confidence: 99%

Structure and expression of Tg737, a putative tumor suppressor gene, in human hepatocellular carcinomas

1999

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Deletions of the Tg737 gene, whose product is involved in liver oval cell proliferation, differentiation, and ploidy control, have been recently shown in chemically induced rat liver tumors and in a limited series of patients with hepatocellular carcinoma (HCC). Thus, Tg737 has been proposed as a candidate new liver‐specific tumor suppressor gene. To investigate this important issue, we analyzed the structure and expression pattern of the Tg737 gene in a group of 23 tumorous and adjacent nontumorous liver tissues, by combining polymerase chain reaction (PCR) and Southern and Northern blot–based analyses. We failed to identify deletions or gross alterations of the Tg737 gene by both PCR and Southern blot analyses. Northern blots showed comparable accumulation of normal Tg737 transcripts in both tumorous and nontumorous tissues. Collectively, therefore, our results do not support the hypothesis of frequent Tg737 genetic alterations in human HCC.

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Genetic heterogeneity of hepatocellular carcinoma.

Cited by 148 publications

References 23 publications

Expression of hepatitis B virus X protein in HBV-infected human livers and hepatocellular carcinomas

Expression of hepatitis B virus X protein in HBV-infected human livers and hepatocellular carcinomas

Mdm2 Snp309 G allele displays high frequency and inverse correlation with somatic P53 mutations in hepatocellular carcinoma

Structure and expression of Tg737, a putative tumor suppressor gene, in human hepatocellular carcinomas

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