Alterations of RB1, p53 and Wnt pathways in hepatocellular carcinomas associated with hepatitis C,hepatitis B and alcoholic liver cirrhosis

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.     

Genetic Basis of Pituitary Adenoma Invasiveness: A Review

Compatible with contemporary paradigms of the role of genetic aberrations in the progression of human tumors, the growth of pituitary tumors into a state of invasiveness appears to be due to genetic alterations. Amplification of H-ras and c-myc oncogenes and mutations of p53, nm23 and Rb genes have been identified disproportionately more in aggressive tumors and, in the case of Rb gene, in pituitary carcinomas, providing evidence that amplification of these oncogenes (H-ras and c-myc) and inactivation of tumor suppressor genes (p53, nm23 and Rb) seem to be at least one mechanism by which pituitary tumors progress. The current level of management of invasive pituitary adenomas should become more comprehensive as the advances in our understanding of genetic basis of pituitary adenoma invasiveness becomes translated into development of novel chemotherapy or gene transferbreak technique.     

beta-catenin mutations are absent in hepatocellular carcinomas of SV40 T-antigen transgenic mice

beta-catenin mutations have been found not only in melanoma and prostatic carcinoma but also in hepatocellular carcinomas in human, c-myc, H-ras genes transgenic mice and chemically-induced models. We investigated beta-catenin mutations in human hepatocellular carcinomas (HCCs), Hep G2 cell line and HCCs in SV40 T-antigen transgenic mice, in order to examine whether beta-catenin mutations are frequently observed in HCC in general. We found a point mutation of beta-catenin in one of nine HCCs in human and a deletion of it in Hep G2 cell line. However, we found no mutation in HCC in SV40 TG mice liver.     

Analysis of the c-myc, K-ras and p53 Genes in Methylcholanthrene induced Mouse Sarcomas

We have examined 63 methylcholanthrene (MCA)-induced mouse sarcomas for possible correlations of mutations involving the c-myc, ras and p53 genes. The c-myc gene was found to be amplified in 18 of these sarcomas (29%). Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and subsequent direct sequencing identified 18 cases carrying K-ras mutation at codons 12, 13 and 61 (29%). No mutation was detected in the H-ras and N-ras genes. Mutations of the p53 gene in exons 5 to 8 were found in 45 cases (71%). Comparison of these mutations revealed that out of 18 cases with c-myc gene amplifications, 10 carried K- ras mutations (56%) and 14 carried p53 mutations (78%). In contrast, among 45 cases of sarcomas without c-myc gene amplification, 8 were found to have K- ras mutations (18%). The same 45 cases were found to have 31 p53 mutations (69%). The present study suggests a strong correlation between c-myc gene amplification and K- ras gene mutation ( P < 0.01). p53 gene mutation was frequently found among MCA-induced mouse sarcomas, indicating the importance of this mutation in the etiology of these tumors. However, p53 mutations were present in sarcomas regardless of the state of c-myc amplification and K- ras mutation. Therefore, a defect in the p53 gene is independent of amplification of the c-myc gene or point mutation of the K- ras gene.     

Analysis of the c-myc, K-ras and p53 genes in methylcholanthrene-induced mouse sarcomas.

We have examined 63 methylcholanthrene (MCA)-induced mouse sarcomas for possible correlations of mutations involving the c-myc, ras and p53 genes. The c-myc gene was found to be amplified in 18 of these sarcomas (29%). Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and subsequent direct sequencing identified 18 cases carrying K-ras mutation at codons 12, 13 and 61 (29%). No mutation was detected in the H-ras and N-ras genes. Mutations of the p53 gene in exons 5 to 8 were found in 45 cases (71%). Comparison of these mutations revealed that out of 18 cases with c-myc gene amplifications, 10 carried K-ras mutations (56%) and 14 carried p53 mutations (78%). In contrast, among 45 cases of sarcomas without c-myc gene amplification, 8 were found to have K-ras mutations (18%). The same 45 cases were found to have 31 p53 mutations (69%). The present study suggests a strong correlation between c-myc gene amplification and K-ras gene mutation (P < 0.01). p53 gene mutation was frequently found among MCA-induced mouse sarcomas, indicating the importance of this mutation in the etiology of these tumors. However, p53 mutations were present in sarcomas regardless of the state of c-myc amplification and K-ras mutation. Therefore, a defect in the p53 gene is independent of amplification of the c-myc gene or point mutation of the K-ras gene.     

Activation of beta-catenin provides proliferative and invasive advantages in c-myc/TGF-alpha hepatocarcinogenesis promoted by phenobarbital

Previously, we have found that phenobarbital (PB) enhanced cell survival and facilitated tumor growth in our c-myc/transforming growth factor (TGF)-alpha transgenic mouse model of liver cancer. Given that PB selectively promoted initiated cells harboring beta-catenin mutations during chemically induced hepatocarcinogenesis and that Wnt/beta-catenin signaling is involved in both anti-apoptotic and proliferative processes, we now have extended our analysis to investigate whether promotion by PB affects the occurrence of beta-catenin mutations in c-myc/TGF-alpha-driven tumors. The frequency of beta-catenin activation as judged by somatic mutations and/or nuclear localization was significantly increased in hepatocellular carcinomas (HCCs) from c-myc/TGF-alpha mice treated with PB (15/28; 53.6%) as compared with that in control HCCs (2/28; 7.1%). Furthermore, an intact beta-catenin locus was detected in all neoplasms following PB treatment, whereas 57.1% (16/28) of malignant tumors from c-myc/TGF-alpha untreated mice displayed loss of heterozygosity at the beta-catenin locus. Strikingly, in the majority of PB-treated HCCs beta-catenin nuclear localization was limited to small cells with high nuclear/cytoplasmic ratio forming an invasion front (NAinv). beta-Catenin NAinv cells showed cytoplasmic redistribution of E-cadherin associated with intense mucin 1 and matrilysin immunostaining, suggesting their invasive phenotype. All beta-catenin-positive HCCs displayed increased proliferation and tumor size, but no difference in the apoptotic rate when compared with beta-catenin negative tumors. These findings show that PB treatment positively selects for a cell population displaying activation of beta-catenin in c-myc/TGF-alpha HCCs. beta-Catenin activation confers additional growth and invasive advantages in a model of liver cancer already accelerated by synergistic activity of the c-myc and TGF-alpha transgenes.     

Extensive methylation is associated with beta-catenin mutations in hepatocellular carcinoma: evidence for two distinct pathways of human hepatocarcinogenesis

Hepatocellular carcinoma (HCC) with p53 mutations is usually characterized by extensive chromosomal instability (CIN), whereas those with beta-catenin mutations have relatively less CIN and the molecular pathogenesis of these tumors is unknown. Methylation of CpG dinucleotides in the promoters of cancer-related genes is another characteristic feature of HCCs. The aim of this study was to determine the contribution of the methylator phenotype to HCC and its relationship to genomic instability. Fractional allelic loss (FAL) was determined using 400 microsatellite markers in 81 HCCs and 77 corresponding noncancerous livers as a measure of CIN. Methylation of 21 genetic loci was quantitated using combined bisulfite restriction analysis. Using hierarchical clustering analysis based upon the quantification of methylation levels, all HCCs were segregated into two groups characterized by either limited or extensive methylation. Mutations in the beta-catenin and p53 genes were determined by DNA sequencing. We found that the methylation levels were significantly higher in the HCCs than in noncancerous livers in 18 of the 21 loci (P values ranged from 0.035 to <0.0001). Among 18 loci, elevated levels of methylation at nine loci were significantly associated with beta-catenin mutations (P values ranged from 0.02 to <0.0001). In addition, the presence of beta-catenin mutations was associated with HCCs in the extensive methylation group (P < 0.0001), whereas p53 mutations correlated with high FAL scores (P = 0.0036). These data suggest that HCCs can be classified into two distinct categories based upon promoter methylation, CIN, and mutations of cancer-related genes. HCCs with extensive methylation harbor frequent beta-catenin mutations, whereas HCCs with high levels of CIN are associated with p53 mutations, suggesting the presence of two independent pathways for the pathogenesis of HCC.     

Epigenetic and genetic alterations of APC and CDH1 genes in lobular breast cancer: relationships with abnormal E-cadherin and catenin expression and microsatellite instability

The causes and functional consequences of E-cadherin (E-CD) loss in breast cancer are poorly understood. E-CD loss might act in concert with alterations in the APC/beta-catenin pathway to permit oncogenic beta-catenin signaling. To test this hypothesis, we have analyzed the presence of genetic and epigenetic alterations affecting E-CD (CDH1), APC and beta-catenin (CTNNB1) genes and the immunohistochemical expression of E-CD, beta- and gamma-catenin in a series of 46 infiltrating lobular breast carcinomas (ILCs). Since 80% of ILCs featured complete loss of E-CD expression, we analyzed the molecular alterations responsible for E-CD inactivation in these tumors. We found that 10 of 46 (22%) cases harbored mutations in CDH1, including 1 case with 2 different mutations (1 of which was germline). CDH1 was also inactivated by loss of heterozygosity (LOH; 30/41, 73%) and promoter hypermethylation (19/46, 41%). Interestingly, LOH and mutations were also detected in the corresponding in situ lesions of the ILCs, implying that these alterations are early events in lobular cancer tumorogenesis. Additionally, the presence of a polymorphism in the CDH1 promoter was found to be inversely correlated with CDH1 mutations, but not with E-CD levels. We next examined whether alterations in the APC/beta-catenin pathway also occurred in the same series of ILCs. Although no CTNNB1 or APC mutations were detected, promoter methylation (25/46, 52%) and LOH (7/30, 23%) of APC were found. Moreover, methylation of APC and CDH1 occurred concordantly. However, beta- and gamma-catenin were severely reduced or absent in 90% of these tumors, implying that alterations in CDH1 and APC genes do not promote beta-catenin accumulation in ILC. These molecular alterations were not associated with microsatellite instability. In summary, several different mechanisms (mutations, LOH, methylation) are involved in the frequent CDH1 inactivation in invasive and in situ lobular breast cancer. The same tumors also show genetic and epigenetic alterations of APC gene. However, altered CDH1 and APC genes do not promote beta-catenin accumulation in this tumor type.     

Different genetic alterations in rat forestomach tumors induced by genotoxic and non-genotoxic carcinogens

Human beings are exposed to a multitude of carcinogens in their environment, and most cancers are considered to be chemically induced. Here we examined differences in genetic alterations in rat forestomach tumors induced by repeated exposure to a genotoxic carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or N-methylnitrosourethane (MNUR), and chronic treatment with a non-genotoxic carcinogen, butylated hydroxyanisole (BHA) or caffeic acid (CA). A total of 132, 6-week-old male F344 rats were employed. Forty rats were treated with MNNG by intragastric administration at a dose of 20 mg/kg body wt once a week for 32 weeks, and 20 rats received 20 p.p.m. MNUR in their drinking water for 48 weeks. Further groups of 20 animals were administered 2% BHA or 2% CA in the diet for 104 weeks. The remaining rats were maintained without any supplement as controls. Multiple forestomach tumors were observed in all rats of the MNNG-, MNUR-, BHA- and CA-treated groups. Histopathologically, MNUR- and CA-treated groups showed almost the same pattern. On polymerase chain reaction-single strand conformation polymorphism analysis, H-ras and p53 gene mutations were observed at high and relatively low frequencies, respectively, in forestomach tumors induced by MNNG and MNUR. Most H-ras gene mutations were G-->A transitions in codons 7 and 12 of exon 1. On the other hand, forestomach tumors due to the non-genotoxic carcinogens, BHA and CA, had almost no mutations of the H-ras and p53 genes. Moreover, relative overexpression of cyclin D1 and p53 was detected in forestomach tumors induced by the genotoxic carcinogens, while their non-genotoxic counterparts had a tendency to show low expression of those molecules. Mutations of the beta-catenin gene were not detected in any group. The present study demonstrates that rat forestomach tumors induced by genotoxic and non-genotoxic carcinogens have different underlying genetic alterations, even if their pathological features are similar.     

Combined subcarcinogenic benzo[a]pyrene and UVA synergistically caused high tumor incidence and mutations in H-ras gene, but not p53, in SKH-1 hairless mouse skin

Combined subcarcinogenic doses of benzo[a]pyrene (BaP) and UVA induced H-ras, but not p53, gene mutations 8 weeks before tumor emergence in SKH-1 mice. Neither UVA (40 kJ/m2) nor BaP (8 nmol) induced any tumors after mice were topically treated 3 times/week for 25 weeks. However, combined BaP-UVA treatment synergistically increased tumor incidence and multiplicity. All tumors induced by BaP-UVA were malignant. The epidermis was collected from mice treated for 2, 6 and 10 weeks. DNA from UVB- (0.3 kJ/m2) or BaP-UVA-(8 nmol and 40 kJ/m2-induced tumors was isolated and screened for H-ras and p53 mutations. Four types of point mutation, GGC-->GAC, GCC, GTC and CGC, occurred in UVB-induced tumors at H-ras codon 13; and one type of point mutation, GGA-->GAA, at codon 12. Treatment with either BaP alone or BaP-UVA for 10 weeks caused GGA-->GAA mutation at codon 12 or GGC-->GAC mutation at codon 13 in nontumor skin, respectively, as well as in tumors induced by BaP-UVA. All of the 10-week samples treated with either BaP or BaP-UVA showed detectable mutations at codons 12 and 13, but the genetic load was significantly higher in BaP-UVA-treated mice than in those exposed only to BaP. UVA alone induced mutations at codon 12 in only one-third of samples. G-->A mutations induced by BaP or BaP-UVA at position 38 of codon 13 have not been reported previously. C-->T transitions were detected in p53 hot spots of exon 8 in 2 of 19 BaP-UVA-induced tumors but were not found in nontumor skin.     

Hepatocellular carcinoma in WHV/N-myc2 transgenic mice: oncogenic mutations of beta-catenin and synergistic effect of p53 null alleles

The intronless N-myc2 gene was originally identified as the major target of hepatitis virus insertion in woodchuck liver tumors. Here we report that transgenic mice carrying the N-myc2 gene controlled by woodchuck hepatitis virus (WHV) regulatory sequences are highly predisposed to liver cancer. In a WHV/N-myc2 transgenic line, hepatocellular carcinomas or adenomas arose in over 70% of mice, despite barely detectable expression of the methylated transgene in liver cells. Furthermore, a transgenic founder carrying unmethylated transgene sequences succumbed to a large liver tumor by the age of two months, demonstrating the high oncogenicity of the woodchuck N-myc2 retroposon. Stabilizing mutations or deletions of beta-catenin were found in 25% of liver tumors and correlated with reduced tumor latency (P<0.05), confirming the important role of beta-catenin activation in Myc-induced tumorigenesis. The ability of the tumor suppressor gene p53 to cooperate with N-myc2 in liver cell transformation was tested by introducing a p53-null allele into WHV/N-myc2 transgenic mice. The loss of one p53 allele in transgenic animals markedly accelerated the onset of liver cancer (P=0.0001), and most tumors of WHV/N-myc2 p53+/Delta mice harbored either a deletion of the wt p53 allele or a beta-catenin mutation. These findings provide direct evidence that activation of N-myc2 and reduction of p53 levels act synergistically during multistage carcinogenesis in vivo and suggest that different genetic pathways may underlie liver carcinogenesis initiated by a myc transgene. Oncogene (2000).     

Agreement of mutational characteristics of heterocyclic amines in lacI of the Big Blue mouse with those in tumor related genes in rodents

The mutational spectra of carcinogenic heterocyclic amines (HCAs), 2- amino-3,4-dimethylimidazo[4,5-b]quinoline (MeIQ), 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-9H-pyrido[2,3-b]indole (A alphaC) were studied in the colon of Big Blue mice. In 90, 115 and 105 lacI mutants from mice fed 300 p.p.m. MeIQ, 400 p.p.m. PhIP and 800 p.p.m. A alphaC, respectively, 92, 115 and 105 mutations were identified. G:C-->T:A transversions predominated with these HCAs. Mutational hot spots for base-substitution mutations caused by MeIQ, PhIP and A alphaC were in distinct sequence contexts; at 5'-GC-3', in runs of guanine and in 5'-CGT-3', respectively. Further, 30 of 115 (26%) PhIP-induced mutations were G:C base pair deletions, and eight of these deletions were in 5'-GGGA-3'. The mutational characteristics of MeIQ in the lacI gene coincided well with those in the Ha-ras gene of MeIQ-induced mouse forestomach tumors and rat Zymbal gland tumors. The characteristic single-base deletion induced by PhIP in the lacI gene also coincided well with those in the Apc gene of PhIP-induced rat colon tumors. These results suggest that the mutational characteristics of each chemical are conserved across different genes in different species.      

Activation of beta-catenin during hepatocarcinogenesis in transgenic mouse models: relationship to phenotype and tumor grade

Mutations affecting phosphorylation sites in the beta-catenin gene have been implicated in the development of human and rodent hepatocellular carcinomas (HCCs). To further investigate the involvement of this gene in hepatocarcinogenesis, we used several transgenic mouse models of hepatic tumors induced by overexpression of c-myc in the liver either alone or in combination with transforming growth factor (TGF) alpha or TGF-beta1. Activation of beta-catenin, as judged by the presence of mutations and/or nuclear translocation of the protein, was most frequent in liver tumors from c-myc (4/17; 23.5%) and c-myc/TGF-beta1 (6/18; 33.3%) transgenic mice. However, it was very rare in faster growing and histologically more aggressive HCCs developed in c-myc/TGF-alpha mice (1/20; 5%). Administration of diethylnitrosamine, phenobarbital, or 2-amino-3,8-diethylimidazo[4,5-f]quinoxaline did not significantly affect the occurrence of beta-catenin mutations. Notably, nuclear accumulation of beta-catenin was observed only in adenomas and highly differentiated carcinomas with eosinophilic phenotype. Furthermore, preneoplastic lesions with eosinophilic phenotype frequently displayed focal nuclear positivity, colocalized with areas of high proliferation. In contrast, basophilic and clear-cell foci, as well as pseudo-glandular and poorly differentiated HCCs, exhibited a normal or reduced membranous immunoreactivity for beta-catenin. These studies suggest that nuclear translocation of beta-catenin and activation of Wingless/Wnt signaling may represent an early event in liver carcinogenesis, providing a growth advantage in a subset of hepatic tumors with a more differentiated phenotype.     

Decreased E-cadherin augments beta-catenin nuclear localization: studies in breast cancer cell lines

We showed that the YMB-1-derived breast cancer cell line YMB-S, which proliferates in suspension without aggregation, exhibits complete loss of cell-cell adhesion despite the presence of E-cadherin-catenin complex and expression of free beta-catenin in the cytoplasm. Here, we describe beta-catenin gene regulation, interaction with E-cadherin, immunocytochemical localization, and their relation to growth rate in the YMB-1-derived cell line YMB-A, which forms tight junctions and displays anchorage-dependent growth. YMB-A cells proliferated more slowly than YMB-S cells. E-cadherin and APC gene product expression in YMB-A cells was significantly higher than that in YMB-S cells, whereas expression of beta-catenin, MUC1, and c-myc was lower in YMB-A cells than in YMB-S cells. According to immunocytochemical analysis, beta-catenin in YMB-A cells displayed membranous or submembranous localization, indicating that beta-catenin is mostly tethered to E-cadherin. Inhibition of E-cadherin expression in YMB-A cells by an antisense oligonucleotide did not change expression of whole cell beta-catenin protein, but increased nuclear beta-catenin protein level, c-myc expression, and cell growth rate. These results suggest that decreased expression of E-cadherin and APC and increased amount of beta-catenin in YMB-S cells lead to accumulation of beta-catenin in the nucleus, activate beta-catenin-LEF/TCF signaling pathway, and trigger c-myc proto-oncogene expression. c-Myc overexpression in breast cancer may be related to activated Wnt independent beta-catenin-LEF/TCF signaling.     

Amplification of c-myc in hepatocellular carcinoma: correlation with clinicopathologic features, proliferative activity and p53 overexpression.

Expression of the proto-oncogene c-myc has been implicated in liver regeneration and hepatocarcinogenesis. The biologic significance of c-myc gene amplification in human hepatocellular carcinoma, however, is unconfirmed. We correlated c-myc gene amplification with clinicopathologic features, proliferative activity, and p53 expression in 42 resected tumors. c-myc amplification in tumor tissue was determined using a differential polymerase chain reaction, a useful procedure for the evaluation of gene amplification in archival formalin-fixed paraffin-embedded tissues, in comparison with a dopamine D2 receptor gene. Proliferative activity was estimated by numbers of argyrophilic nucleolar organizer regions and immunohistochemical nuclear labeling rates using a monoclonal antibody against Ki-67. The c-myc gene was amplified in 14 of 42 tumors (33.3%). Amplification of c-myc was more frequent in younger patients and in larger tumors, and less differentiated tumors. No correlation was noted with alpha-fetoprotein level or viral hepatitis state. The amplification showed positive correlation with both proliferative activity and p53 overexpression. Disease-free survival in patients showing c-myc amplification was significantly shorter than in those without amplification. These results suggest that c-myc amplification is an indicator of malignant potential and poor prognosis in hepatocellular carcinoma. c-myc amplification and p53 alteration may be coparticipating events in the progression of these tumors.     

Abnormalities of chromosome 8, APC and beta-catenin genes in aggressive fibromatosis

OBJECTIVE: To explore the role of abnormalities of chromosome 8, APC and beta-catenin genes in tumorigenesis of aggressive fibromatosis. METHODS: Trisomy 8 was detected by interphase fluorescence in situ hybridization (FISH). The APC gene and beta-catenin gene mutations were detected by denaturing high performance liquid chromatography (DHPLC) and direct sequence analysis after the PCR transition. RESULTS: The rate of trisomy 8 in recurrent tumors (62.5%, 5/8) was significantly higher than that in the primary tumors (8.3%, 1/12). Somatic substitution of APC gene was found in 18 of 69 (26.1%) aggressive fibrometases. Somatic transition of beta-catenin gene was detected in 13 of 69 (18.8%) and mutation at codon 41 in exon 3 involving threonine residues implicated in the degradation of beta-catenin. The abnormal expression of beta-catenin had no significant correlation with the mutation of APC or beta-catenin gene. The group with positively expressed beta-catenin protein showed a significant higher c-myc protein expression than those without (P = 0.001). The Ki-67 index was extremely low in all the lesions. The apoptosis index (AI) of the groups with positively expressed c-myc and cyclin D1 showed significantly lower AI than those without. CONCLUSION: Trisomy 8 may serve as a useful predictor of recurrence in aggressive fibromatosis. There are somatic mutations of the APC and beta-catenin genes in the aggressive fibromatosis, and there are abnormalities in the Wnt signaling pathway. These abnormalities may result in the aberrances of cell proliferation and apoptosis, which are likely to be import factors in the tumorigenesis.     

Comparison of the expression of beta-catenin in hepatocellular carcinoma in areas with high and low levels of exposure to aflatoxin B1

BACKGROUND AND OBJECTIVES: Previous studies showed that the frequency of beta-catenin mutation was different in mice when induced by different chemicals. The aim of this study is to compare the expression of beta-catenin and p53 in hepatocellular carcinoma (HCC) from areas with exposure to high and low levels of aflatoxin B1 (AFB1). METHODS: Thirty-five and twenty HCC samples from Guangxi and Malaysia, respectively, were studied. The expression of beta-catenin and p53 was determined by immunohistochemistry. RESULTS: The overexpression of beta-catenin was detected in 65.7% of HCC tissues and 37.1% in adjacent liver tissues samples from Guangxi, China. Similarly, overexpression of beta-catenin was also detected in 60.0% of HCC tissues and in 35.0% of adjacent liver tissues samples from Malaysia. The overexpression of p53 was detected in 42.9% of HCC specimens from Guangxi and in 25.0% of HCC specimens from Malaysia. There was a relationship between the expression of beta-catenin and hepatitis B virus (HBV) infection in the adjacent liver tissues in Guangxi, and between the expression of beta-catenin and p53 in HCC tissues in Malaysia. CONCLUSIONS: The differences in the exposure to AFB1 did not affect the overexpression of beta-catenin in the development of HBV-associated HCC.