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

Accumulation of mutations in oncogenes and tumor suppressor genes transforms a normal cell to a malignant cell by allowing it to escape from normal control of growth. In order to learn (a) how many tumor suppressor genes are involved in the tumor progression of hepatocellular carcinoma, (b) whether there is any association among allelic losses of chromosomes, or (c) whether integration of hepatitis B virus into host DNA influences any particular chromosomal losses, we have examined loss of heterozygosity with 44 restriction fragment length polymorphism markers in 46 cases of hepatocellular carcinoma. The markers represented all chromosomal arms except 5p, 8p, 9p, 18p, and acrocentric chromosomes. Allelic losses in tumors indicated that five tumor suppressor genes, located on chromosomes 5q, 10q, 11p, 16q, and 17p, may be involved in this cancer. However, no significant associations were observed among the various allelic losses or between the integration of hepatitis B virus and chromosomal losses. Furthermore, a deletion map for chromosome 16q indicated the localization of a tumor suppressor gene between q22 and q24 and that for chromosome 17p suggested the existence of a second tumor suppressor gene in addition to the p53 gene.
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PMID:Allelotype study of primary hepatocellular carcinoma. 167 Sep 95

Hepatocellular carcinoma (HCC) is a prevalent cancer in sub-Saharan Africa and eastern Asia. Hepatitis B virus and aflatoxins are risk factors for HCC, but the molecular mechanism of human hepatocellular carcinogenesis is largely unknown. Abnormalities in the structure and expression of the tumour-suppressor gene p53 are frequent in HCC cell lines, and allelic losses from chromosome 17p have been found in HCCs from China and Japan. Here we report on allelic deletions from chromosome 17p and mutations of the p53 gene found in 50% of primary HCCs from southern Africa. Four of five mutations detected were G----T substitutions, with clustering at codon 249. This mutation specificity could reflect exposure to a specific carcinogen, one candidate being aflatoxin B1 (ref. 7), a food contaminant in Africa, which is both a mutagen that induces G to T substitution and a liver-specific carcinogen.
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PMID:Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. 201 Nov 86

Mutations of the p53 gene are found in hepatocellular carcinoma (HCC), the most common form of primary liver cancer. Specific mutations might reflect exposure to specific carcinogens and we have screened HCC samples from patients in 14 different countries to determine the frequency of a hotspot mutation at codon 249 of the tumour suppressor p53 gene. We detected mutations in 17% of tumours (12/72) from four countries in south Africa and the southeast coast of Asia. There was no codon 249 mutation in 95 specimens of HCC from other geographical locations including North America, Europe, Middle East, and Japan. Worldwide, the presence of the codon 249 mutation in HCCs correlated with high risk of exposure to aflatoxins and the hepatitis B virus (HBV). Further studies were completed in two groups of HBV-infected patients at different risks of exposure to aflatoxins. 53% of patients (8/15) from Mozambique at high risk of aflatoxin exposure had a tumour with a codon 249 mutation, in contrast with 8% of patients from Transkei (1/12) who were at low risk. HCC is an endemic disease in Mozambique and accounts for up to two thirds of all tumours in men. A codon 249 mutation of the p53 gene identifies an endemic form of HCC strongly associated with dietary aflatoxin intake.
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PMID:p53 mutation in hepatocellular carcinoma after aflatoxin exposure. 168 37

Recent fundamental research has disclosed the presence of multiple genetic alterations including activation of oncogenes and inactivation of tumor suppressor genes in various human cancers. These multiple genetic alterations are thought to be correlated with multiple stages of carcinogenesis and further progression. Hepatocellular carcinoma (HCC) is a typical example. The majority of HCCs are associated with infection by hepatitis virus B or C. In the damaged liver, small nodular lesions develop due to clonal expansion of hepatocytes. Some of these nodules are diagnosed as early HCC of the well differentiated type and correspond to in situ or microinvasive carcinoma. Within these nodules, moderately or poorly differentiated HCCs often emerge as nodule-in-nodule lesions when the diameter of the nodules exceeds 1.5 cm. Ordinary HCCs formed by progression show highly increased cell proliferation, neovascularization, production of high-molecular-mass forms of basic fibroblast growth factor and aneuploidy in some tumors. Corresponding to this stage of malignant progression, HCCs show loss of heterozygosity for multiple chromosomes including chromosomes 4, 16q and 17p. Tumor suppressor gene p53, located on 17p, is frequently mutated in high-grade, but not in early, HCCs. Thus, it is strongly suggested that inactivation of multiple tumor suppressor genes plays an important role in progression, and probably directly or indirectly causes chromosome instability, enhanced cell proliferation and neovascularization.
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PMID:Pathology and molecular mechanisms of multistage human hepatocarcinogenesis. 172 34

We have examined p53 oncogene/anti-oncogene alleles in 10 different human hepatoma cell lines and 18 primary hepatocellular carcinomas. The p53 allele in these hepatoma cell lines appears to be a frequent target of mutation as demonstrated by Southern and Northern blotting, immunoprecipitation and Western blot analysis. In general, the steady state level of p53 specific RNA or protein in these hepatoma cell lines is higher than in normal liver. However, in three out of ten cell lines, normal-sized p53 mRNA cannot be detected. In contrast, the involvement of the p53 allele in primary hepatocellular carcinoma appears to be an exceedingly rare event. Steady state levels of p53 specific RNA in primary hepatomas are practically indistinguishable from those in normal adult liver. Using the polymerase chain reaction technique, we have amplified and subcloned exons 5, 6, 7 and 8 of p53 from 10 different hepatoma samples. DNA sequence analysis of these exon subclones reveals no apparent structural alterations. Finally, synthesis of p53 specific mRNA or protein in a HepG2 human hepatoblastoma cell line does not appear to be affected by gene expression and replication of human hepatitus B virus. Surprisingly, unlike many other kinds of human solid tumors, point mutations in p53 do not appear to be important in primary tumors of hepatocellular carcinomas.
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PMID:Molecular analysis of the p53 alleles in primary hepatocellular carcinomas and cell lines. 184 99

We have studied the expressions of nine proto-oncogenes (c-myc, N-myc, c-fos, C-jun, p53, H-ras, N-ras, c-raf, hst) and two other genes (PCNA, GST-P) during the spontaneous development of hepatocellular carcinomas (HCCs) in LEC rats. Expression of c-myc, H-ras, N-ras, C-raf, p53 and PCNA genes was detected, but this did not significantly change during the development of HCCs in LEC rats. Expression of N-myc and hst genes was not detectable. Expression of c-fos gene was detected in one HCC case out of four. Significantly increased expression of c-jun gene was observed in the liver tissues of LEC rats aged 8 months. This high expression was decreased with the development of HCCs. On the other hand, the expression of GST-P gene increased in parallel with the clinical course of the development of HCCs in LEC rats. The pattern of c-jun mRNA augmentation was different from that of GST-P mRNA. These observations suggest that c-jun gene may play a role in the spontaneous development of HCCs in LEC rats.
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PMID:Increased expression of c-jun gene during spontaneous hepatocarcinogenesis in LEC rats. 197 34

There is little information regarding the molecular mechanisms of hepatocarcinogenesis. We studied the p53 gene at the DNA, RNA, and protein level in seven human hepatocellular carcinoma (HCC)-derived cell lines; six of seven showed p53 abnormalities. By Southern blotting, the p53 gene was found to be partially deleted in Hep 3B and rearranged in SK-HEP-1 cells. Transcripts of the p53 gene were undetectable in Hep 3B as well as in FOCUS cells that had no apparent deletion or rearrangement of the p53 gene. Immunoprecipitation after [35S]methionine labeling of HCC cells demonstrated that p53 protein was absent in Hep 3B and FOCUS and reduced in concentration in PLC/PRF/5 cells. p53 synthesized by Mahlavu cells showed a slower migration on SDS/polyacrylamide gels suggesting it was an abnormal protein. In Huh7 cells, p53 protein had a prolonged half-life leading to its accumulation in the nuclei; increased levels of p53 protein were also found by immunoblotting. The p53 gene and its expression appeared to be unaltered in the hepatoblastoma-derived Hep G2 cell line. We found that the loss of p53 expression did not occur as a late in vitro event in the FOCUS cell line because p53 protein was also nondetectable at an early passage. We conclude that the loss of p53 expression or the presence of abnormal forms of the protein are frequently associated with HCC cell lines. These observations suggest that alterations in p53 may be important events in the transformation of hepatocytes to the malignant phenotype.
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PMID:Abnormal structure and expression of p53 gene in human hepatocellular carcinoma. 215 27

The development of chemically induced hepatocellular carcinoma in the rat proceeds through a series of premalignant changes that may ultimately progress to a primary malignant tumor. Using the selection technique based on diminished binding of preneoplastic hepatocytes to tissue culture plates precoated with asialofetuin, we have isolated poly(A+)RNA from early preneoplastic foci as well as preneoplastic persistent nodules and primary hepatocellular carcinoma induced by the Solt-Farber protocol in the Fischer rat. The steady-state poly(A+)RNA levels of genes traditionally associated with growth, differentiation and/or transformation were then determined to address the question of their temporal expression in the multistep nature of cancer development. Ornithine decarboxylase- and P53-specific transcripts did not significantly change in preneoplastic foci but were increased in later-stage preneoplastic nodules and hepatocellular carcinoma. Albumin-specific transcripts were decreased in all hepatocellular carcinoma but there was no consistent coordinated increase in alpha-fetoprotein-specific transcripts. c-myc and raf transcripts increased at the very early preneoplastic foci stage and continued to increase throughout the neoplastic process. No L-myc or N-myc transcripts could be detected in any RNA sample. c-Ha-ras-specific transcripts were essentially unaltered in all RNA samples whereas no c-Ki-ras or N-ras transcripts could be detected throughout the neoplastic process. In addition, no dominant-acting transforming mutations in the ras gene family were detected by DNA transfection experiments using NIH/3T3 cells.
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PMID:Poly(A+)RNA levels of growth-, differentiation- and transformation-associated genes in the progressive development of hepatocellular carcinoma in the rat. 246 94

A hybrid clone was developed by the fusion of a pluripotent mouse teratocarcinoma cell line PCC-4 AzaR to the Zajdela ascitic hepatoma (ZAH) of rat origin. This hybrid cell line, F2231A, possessed a predominantly teratocarcinoma morphology with a large nucleus and prominent nucleoli, and grew in nests. F2231A cells formed undifferentiated tumours in irradiated Sv/129 mice. It formed aggregates when subcultured at high densities in bacteriological Petri dishes. The hybrid cell line differentiated in response to retinoic acid and also underwent spontaneous differentiation upon overgrowth. Karyological analysis showed the presence of several rat chromosomes in the hybrid and upon isozyme analysis it was found that only the rat variant of the X-linked enzyme HGPRT was expressed. Analysis of the genomic DNA with a cloned probe, specific for rat repetitive sequences, gave strong positive signals in the hepatoma parent and F2231A cells while the parental embryonal carcinoma (EC) cells were negative. The hybrid cell line, like the PCC-4 cells, expressed the SSEA-1 surface marker but not SSEA-3, intercellular fibronectin and EGF receptors. Upon differentiation of F2231A cells there was a loss of expression of SSEA-1. The mRNA for alpha-fetoprotein was expressed by the hybrid cell line and in this respect it resembled the hepatoma parent. Albumin mRNA was not detectable in the hybrid cell line. The mRNA for the transformation-related protein, p53, was expressed at a high level in F2231A cells. The hybrid cell line F2231A retained several of the biochemical and immunological properties of the teratocarcinoma cells.
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PMID:A malignant, stem cell-like somatic hybrid between a mouse teratocarcinoma and a rat ascitic hepatoma is differentiation competent. 247 69

In rats maintained on a carcinogenic diet (choline deficient containing 0.1% ethionine), the levels of c-myc and p53 mRNAs increased by 4 wk after animals were placed on the diet. Cell isolation studies showed that the change in c-myc takes place in oval cells, while p53 increases predominantly in oval cells but also in hepatocytes. To determine whether this increase is a consequence of cell proliferation or is associated with transformation, we have developed an in vitro model of hepatocarcinogenesis using epithelial cells isolated from the livers of rats fed the carcinogenic diet. When maintained in vitro with infrequent subculture, this cell line (LE/6) undergoes spontaneous transformation. Inoculation s.c. of the transformed cells into nude mice yields tumors histologically identified as hepatocellular carcinoma. We have used these cell lines to compare the cell cycle expression of c-myc and p53 mRNAs in untransformed, partially transformed, and tumorigenic LE/6 cells. We find that the expression of both genes is under cell cycle control in untransformed and partially transformed cells. However, complete transformation of this cell line is associated with constitutive expression of myc but not p53 transcripts. On the basis of this work we suggest that constitutive expression of c-myc may be a late event in hepatocarcinogenesis.
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PMID:Production of hepatocellular carcinoma by oval cells: cell cycle expression of c-myc and p53 at different stages of oval cell transformation. 264 88


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