Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1864663 (HCC)
 2,985 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have demonstrated that sodium butyrate induces differentiation in human hepatoma cells; however, recent studies have shown that this agent causes apoptosis in some types of cancer cells. In this study, we examined whether sodium butyrate causes apoptosis in the human hepatoma cell lines, HCC-M and HCC-T. The growth of human hepatoma cells was dose-dependently reduced by sodium butyrate. Flow cytometric analysis showed cell-cycle arrest at the G1 phase in the sodium butyrate-treated cells. Apoptotic change was never found in treated cells at concentration levels of less than 5 mmol/L. Sodium butyrate decreased p53 expression and increased p21WAF-1 expression in HCC-T and HCC-M cells having the wild-type p53 gene. Western blot analysis showed that Bcl-2 was expressed in the HCC-T and HCC-M cells, and its expression was increased after exposure to sodium butyrate. Antisense oligodeoxynucleotide against bcl-2 easily caused apoptosis. These results indicate that sodium butyrate hardly induces apoptotic change in the human hepatoma cell lines, HCC-T and HCC-M, with the increase of Bcl-2 expression. Cell-cycle arrest in the G1 phase caused by sodium butyrate was suggested to be induced by the increase in p21WAF-1 expression, but this change did not link with the p53 increase.
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PMID:Loss of butyrate-induced apoptosis in human hepatoma cell lines HCC-M and HCC-T having substantial Bcl-2 expression. 958 76

TP53 gene mutations occur in 30 to 55% hepatocellular carcinomas. Both the frequency and the type of p53 mutations in HCC vary according to geographical location of tumors. A specific mutation at codon 249 (AGG-->AGT) was found at high frequency in tumors from high aflatoxin-areas. TP53 mutations in other geographic locations are less frequent and scattered on the exons encoding the central region of the protein. TP53 mutations observed in hepatocellular carcinoma are accompanied by a loss of wild-type p53 function. Moreover, the p53-249ser mutant appears to display a gain of function at some degree. In addition to p53 inactivation by gene mutation, there is growing evidence that the wild-type p53 functions can be inactivated by the HBx protein of Hepatitis B Virus. The hepatocellular functions of wild-type p53 protein are not entirely known. The present data suggest that the DNA damaging agents induce p53-dependent cell cycle arrest or apoptosis in cell lines derived from normal liver or hepatocellular carcinoma. In contrast, the exposure of mice to genotoxic agents does not induce p53-dependent changes in normal adult liver. This could be due to the fact that the hepatocytes of the adult liver are quiescent cells.
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PMID:TP53 and hepatocellular carcinoma. 976 50

Chronic infection by HBV is the leading cause of hepatocellular carcinoma in man. Several lines of evidence suggest that the viral transactivator HBx plays a critical role in the molecular pathogenesis of HBV-related HCC. To study the actual impact of HBx and the mechanism of its action, we have recently cloned and characterized a set of X-sequences from HCC in patients with chronic infection by HBV. In the present study, we have compared the effects of HBx and its naturally arising mutants on cell growth and viability. We report that HBx inhibits clonal outgrowth of cells and induces apoptosis by a p53-independent pathway. Furthermore, HBx expression induced a late G1 cell cycle block prior to their counterselection by apoptosis. Importantly, mutations in the HBx-gene evolving in hepatocellular carcinoma abolished both HBx-induced growth arrest and apoptosis. Using a panel of engineered mutants we have mapped the growth suppressive effect of HBx to domains shown to be required for its transactivating function. Based on these results, we propose that abrogation of the anti-proliferative and apoptotic effects of HBx by naturally occurring mutations might render the hepatocytes susceptible to uncontrolled growth and contribute to multistep hepatocarcinogenesis associated with HBV-infection.
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PMID:Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx. 1049 Aug 18

Fibrolamellar hepatocellular carcinoma (FHCC) is a unique histologic variant of HCC that occurs in a younger subset of patients than classical HCC, and is associated with a better prognosis. Wilms tumor (WT) is a malignant embryonal neoplasm of the kidney and is one of the most common solid tumors of childhood, occurring at an estimated frequency of 1 in 8000 to 10,000 births. Although second malignant neoplasms (SMNs) following therapy for WTs have been reported in the liver, the coexistence of HCC and WT is extremely rare. We present the first report of a synchronous anaplastic WT and FHCC in a previously healthy 4-year-old girl. Despite the presence of focal immunohistochemical positivity for p53 in the WT, molecular analysis failed to reveal a germline or somatic p53 mutation, and was inconclusive in establishing a clonal relation between the two tumors.
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PMID:Synchronous wilms tumor and fibrolamellar hepatocellular carcinoma: report of a case. 1089 Sep 35

Relationship between p53 protein overexpression and clinicopathological findings and the proliferative activity was studied in 50 cases of hepatocellular carcinoma (34 biopsy and 16 surgically resected cases) using immunohistochemistry. Overexpression of p53 was observed in 26.5% of biopsy cases and 31. 3% of surgically resected cases. Investigation of the relationship between the p53-positive rate and the clinical stage of HCC showed that it was significantly higher in Stage IV (the most advanced cancer; 54.5%) than in Stage I/II/III (13.0%) (p<0.05). Examination of the relationship between the p53-positive rate and tumor differentiation in the biopsy cases showed that p53 was positive in 9.1% of well differentiated carcinomas, 21.4% of moderately differentiated carcinomas, and 55.6% of poorly differentiated carcinomas, indicating that p53 positivity increased as tumors became less differentiated. The p53-positive rate of poorly differentiated carcinoma (55.6%) was significantly higher than that of well and moderately differentiated carcinoma (16.0%) (p<0.05). In the surgically resected cases, p53 overexpression tended to be more frequent in the less differentiated parts of each tumor nodule. In cases with nodule in nodule pattern of HCC, the p53-positive rate was different among nodules with the same level of differentiation. Examination of tumor cell proliferative activity using the proliferating cell nuclear antigen L.I. showed that this indicator was significantly higher in the p53-positive tumors than in the p53-negative tumors (52.7+/-32.4% vs. 32.4+/-15.3%: p<0.05). These results suggest that p53 overexpression may be involved in determining the dedifferentiation and the proliferative activity of HCC. Examination of the surgically resected cases confirmed that p53 overexpression became heterogeneous during the multistep carcinogenesis and growth process of HCC, which is considered to develop from a single cell. This finding suggests that p53 overexpression may be involved in tumor progression.
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PMID:Relationship between p53 overexpression and the proliferative activity in hepatocellular carcinoma. 1089 56

AIM:To study hepatocarcinogenesis of hepatitis C virus (HCV).METHODS: Expression of HCV antigens (CP10, NS3 and NS5) and several cancer-associated gene products (ras p21, c-myc, c-erbB-2, mutated p53 and p16 protein) in the tissues of hepatocellular carcinoma (HCC, n = 46) and its surrounding liver tissue were studied by the ABC(avidin-biotin complex) immunohistochemical method. The effect of HCV infection on expression of those gene products in HCC was analyzed by comparing HCV antigen positive group with HCV antigen negative group.RESULTS:Positive immunostaining with one, two or three HCV antigens was found in 20 (43.5%) cases,with either of two or three HCV antigens in 16 (34.8%) cases, and with three HCV antigens in 9 (19.6%) cases.Deletion rate of p16 protein expression in HCC with positive HCV antigen (80%, 16/20)was significantly higher than that in HCC with negative HCV antigen. Whereas no significant difference of the other gene product expression was observed between the two groups.CONCLUSION:HCV appears related to about one third of cases of HCC in Chongqing, the southwest of China, and it may be involved in hepatocarcinogenesis by inhibi ting the function of p16 gene, which acts as a negative regulator of cell cycle.
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PMID:Effect of HCV infection on expression of several cancer-associated gene products in HCC. 1181 78

It is still unclear as to whether the gene expression profile in HCV- or HBV-related HCC exhibits a degree of specificity and whether the development of HCC in a context of cirrhosis influences this gene profile. To address these issues, the expression profiles of 15 cases of HCC were analysed using cDNA macroarray. A global analysis and hierarchical clustering, demonstrated the heterogeneity of HCC patterns, with a majority of down-regulated genes. Statistical analysis clearly showed a distinction between the gene expression profiles of HCV- and HBV-related HCC. HBV-associated HCC exhibited involvement of different cellular pathways, those controlling apoptosis, p53 signalling and G1/S transition. In HCV-related HCC we identified a more heterogenous pattern with an over-expression of the TGF-beta induced gene. In HCC developing on non-cirrhotic tissues, beta-catenin encoding gene and genes implicated in the PKC pathway were specifically up-regulated. In addition, our investigation highlighted a distinct profiles of TGF-beta superfamily encoding genes in well, moderately or poorly differentiated HCC. Overall, our study supports the hypothesis that despite the heterogeneity of the HCC pattern, the large-scale screening of gene expression may provide data significant to our understanding of the mechanism of liver carcinogenesis.
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PMID:Identification, using cDNA macroarray analysis, of distinct gene expression profiles associated with pathological and virological features of hepatocellular carcinoma. 1197 55

DNA structure and expression of p53 gene in human hepatoma cell lines SMMC-7721, YY-8103 and a spontaneously transformed liver cell line L-02 were analysed using the following method: analysis of allelic losses on chromosome 17p, PCR/SSCP, Northern blot and immunoprecipitation. There was no point mutation found in the exons 4-9 of the p53 gene, and a low level of expression of p53 gene was detected in the three cell lines. These observations were in agreement to the reported results of the relevant experiment using the human hepatoma cell line QGY-7703. Sensitivities of these cell lines and other eight human hepatoma cell lines (QGY-7703, PLC/PRF/5, Tong/HCC, Huh-7, FOCUS, Hep3B, SK-Hep-1, HepG2) with known p53 backgrounds to parvovirus H-1 was assayed using MTT method. Abnormality in the structure and/or function was observed in all of the cell lines examined except HepG2. The cell line HepG2 with normal structure and function of the p53 gene was found to be the least sensitive to H-1 in comparison to all the cell lines which have defeated structure and/or function of the p53 gene. The present study serves as a preliminary evidence that enhancement of the sensitivity of human hepatoma cell lines to H-1 is correlated to the abnormality of the structure and/or function of the p53 gene.
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PMID:[p53 gene expression of human hepatoma cell lines and their sensitivities to parvovirus H-1]. 1254 91

Epidemiological data collected after the atomic-bomb blasts of Hiroshima and Nagasaki have established a link between radiation exposure and human cancer development and are the major source of information for current radiation-induced cancer risk assessment. To determine the mechanistic basis for radiation carcinogenesis, retrospective molecular analyses of archival hepatocellular carcinoma tissues from the atomic-bomb survivors were conducted. The tumor suppressor genes p53 and M6P/IGF2r were examined. HCC cases had either p53 mutations or M6P/IGF2r mutations, but rarely both. Moreover, the frequency of cases with M6P/ IGF2r mutations actually decreased with dose, while those for p53 increased. This implies two independent selection processes leading to liver cancer and that in radiation-induced HCC tumors the spectrum of molecular changes is different from that in "background" tumors.
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PMID:Tracking the errant cell after the atomic bombings: what went wrong? 1285 74

Although the overview above provides a partial molecular picture of the early stages of stepwise hepatocarcinogenesis. it should be emphasized that tumor and nontumor liver contain multiple changes, and that there is variability in their profile among different patients even within single studies. Variability in the number and types of genetic changes has also been observed geographically, and may be dependent upon the etiology of the tumor (viral, chemical or both). Interestingly, HBxAg inactivates tumor suppressors (such as p53 [by direct binding] and Rb [by stimulating its phosphorylation]) early in carcinogenesis that are mutated later during tumor progression. HBxAg also constitutively activates signal transduction pathways, such as those involving c-jun and ras, and activates oncogenes,such as c-nloc, that are otherwise activated by 3-catenin mutations. These findings suggest common molecular targets in hepatocarcinogenesis, despite different mechanisms of activation or inactivation. These observations need to be exploited in future drug discovery and in the development of new therapeutics. Heterogeneity in the mechanisms of tumor development, evidenced by the differences in the up- and down regulated genes reported in micro array analyses, as well as in the genetic loci that undergo mutation or LOH indifferent reports, has now been well documented. This suggests that there are multiple pathways to HCC, and that there is redundancy in the pathways that regulate cell growth and survival. These findings also reflect that,although hepatocarcinogenesis is multistep, the molecular changes that underpin histopathological changes in tumor development are likely to be different or only partially overlapping in individual tumors. Overall, the consequences of these changes suggest that the pathogenesis of HCC is accompanied by a progressive loss of differentiation, loss of normal cell adhesion, loss of the ECM, and constitutive activation of selected signal transduction pathways that promote cell growth and survival. Although mechanisms are important, attention also has to be paid to the target genes whose altered expression actually mediate the neoplastic phenotype. Other key avenues of work need to be explored. For example, it will be important to try to identify germline mutations in HBV-infected patients that are passed on to their children, resulting in the development of HCC in childhood. Clinical materials will also be important for the validation of new markers with diagnostic or prognostic potential. In this context, there is an urgent need to establish simple and low-cost tests based upon molecular changes that are hallmarks of HCC development. Identification of patients with early HCC will also significantly increase survival through its impact upon treatment. The discovery and validation of HCC markers may permit accurate staging of lesions, determine the proximity of such lesions to malignancy, and determine whether lesions with a particular genetic profile are still capable of remodeling through appropriate therapeutic intervention. The efficient reintroduction of the relevant tumor suppressors, or the inhibition of oncogene expression by siRNA, provide just some of the additional opportunities that will ultimately be useful in patient treatment. Together, these approaches will go far in reducing the very high morbidity and mortality associated with HCC.
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PMID:Early molecular and genetic determinants of primary liver malignancy. 1506 49


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