Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The codon 249 mutation specific expression of the p53 gene was determined in 7 human hepatocellular carcinoma (HCC) cell lines. Two 20-base oligomers complementary to bases 872-891 of human p53 cDNA with a single nucleotide difference in the third position of codon 249 were end-labelled with biotin-conjugated dATP using terminal deoxynucleotidyltransferase (TdT). The hybridized oligomer was visually detected in situ using streptavidin-alkaline phosphatase (AP) conjugate and AP substrate. Expression of the codon 249 mutant p53 was steady in PLC/PRF/5 and Mahlavu cells (derived from African patients), while Huh4, Huh6, Huh7 and HCC-M cells (derived from Japanese patients) expressed only the codon 249 wild-type p53. The transcripts of the p53 gene were undetectable in Hep3B cells (derived from an American patient). Hybridizations of the codon 249 specific oligomers were specific to the p53 transcripts, since the cells that expressed p53 gene homogeneously were stained in the cytoplasm only by differential hybridization with a codon 249 specific oligomer; moreover, hybridization with a labelled oligomer non-complementary to the p53 cDNA showed nuclear stainings. Thus, detection of the codon 249 mutant p53 mRNA by differential in situ hybridization is a specific method for studying the mutation-specific expression of the p53 gene in liver cancers at the cellular level, while simultaneously visualizing the cell morphology. The results also support the notion that the p53 gene codon 249 mutation may have etiological implications involving HCC from various geographic areas.
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PMID:Differential in situ hybridization for determination of mutational specific expression of the p53 gene in human hepatoma cell lines. 756 52

Hepatocellular carcinoma is one of the most common cancers worldwide. Epidemiologic studies shows a striking correlation between areas where this tumor is prevalent and where hepatitis virus B and C are endemic, contaminations of food with mycotoxin aflatoxin B1, excessive alcohol intake, prolonged cigarette smoking, sexual hormones. Combination of chemical, physical, and genetic insults to individual hepatocytes involve changes in the genome transformed or neoplastic cell, depending to both the activation of oncogenes (e.g., ras) and the inactivation of tumor supressor genes (e.g., p53). Advances in radiologic techniques such as ultrasonography, computed tomography, angiography and dosages of tumor markers like alpha-fetoprotein offers still the best for diagnosis and screening for hepatocellular carcinoma. Then the diagnosis has become possible during the early stages, characterized to be a very well-differentiated tumour that has returned its preexisting liver structure, with a certain proportion have a multicentric origin. Hepatocellular carcinoma carries an extremely poor prognosis, with a median survival between 2-4 weeks, for those without treatment. Surgical resection are the only curative modality for this disease. In these patients two main patterns of intrahepatic recurrence after hepatectomy are defined, and depends on the growth of residual satellite tumours or synchronous and metachronous multicentric carcinogenesis. This evolution is estimated to be nearly 50%, with 5-year survival rate of nearly 30%. The presence of cirrhosis, satellite nodules, venous invasion, the absence of capsule formation and positive surgical margin (< or = 5 mm) were associated with higher intrahepatic recurrence rates.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Small hepatocellular carcinoma. New concepts on intrahepatic recurrence after hepatectomy in orthotopic liver transplantation]. 757 79

Hepatic malignancy accounts for a large number of cancer-related deaths worldwide. Radiologic evaluation of the liver is critically important in the selection of patients for surgical treatment and newer modalities including computed tomographic arterial portography and intraoperative sonography show promise in the detection of small lesions. Advances in our understanding of the segmental anatomy of the liver, studies of intraoperative hepatic ischemia, and improved care of patients following major hepatic resections have extended the limits of surgical treatment of liver lesions, especially in cirrhotic patients with limited functional reserve. Along with hepatitis B, new data suggest that hepatitis C is also important as an agent causing hepatocellular carcinoma. In addition, the tumor suppressor gene p53 is frequently mutated in aflatoxin-induced hepatoma. In endemic regions, mass screening for early hepatocellular carcinoma appears to increase the surgical cure rate. Resectional surgery remains the best treatment for primary liver cancer and, in selected cases, liver transplantation is worthwhile. Liver resection for some patients with metastases of colorectal origin is now considered standard therapy and studies of regional chemotherapy for liver cancer are beginning to show promise. It remains to be seen whether adjuvant chemotherapy after liver resection will increase cure rates.
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PMID:Primary and secondary hepatic malignancies. 758 84

The present study characterised p53 mutations in 44 hepatocellular carcinomas (HCCs) from Chinese patients residing in a high-incidence area. Twelve point mutations (27%) were detected in tumour tissues using single-strand conformation polymorphism analysis followed by direct DNA sequencing. Remarkably, no mutations were observed at codon 249. This is in contrast to HCCs from other high HCC incidence areas with endemic aflatoxin exposures, in which codon 249 is a mutational hot spot. It is therefore suggested that risk factors other than dietary exposure to aflatoxin may contribute to the high HCC incidence in Singapore.
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PMID:Codon 249 mutation of the p53 gene is a rare event in hepatocellular carcinomas from ethnic Chinese in Singapore. 759 44

A mutation in the tumor suppressor p53 gene resulting in an Arg-->Ser substitution in position 249 is found frequently in human hepatocellular carcinomas associated with hepatitis B infection and with aflatoxin exposure. To determine the significance of this mutation in an in vivo experimental model using transgenic mice, we introduced a two-nucleotide change in the mouse p53 gene at amino-acid position 246, which is equivalent to position 249 in human p53, by the recombinant polymerase chain reaction mismatched primer method. This p53 mutation resulted in the same change, an Arg-->Ser substitution, as in the human p53 gene at position 249. We now report that the protein product of this mutant mouse p53ser246 had properties similar to those of the wild-type protein when tested by binding to (i) monoclonal antibodies PAb246 and PAb240, ii) simian virus 40 large T antigen, and (iii) heat-shock protein. However, it had mutant-type transforming properties when tested for colony formation with an osteosarcoma cell line. It was not active, as is wild-type p53, in transcription activation of the muscle creatine kinase promoter. These properties are the same as those found in the p53trp248 product of the p53 mutation associated with the Li-Fraumeni syndrome. Although less is known about the human p53ser249 product associated with hepatocellular carcinoma, the mutant murine p53ser246 protein shares the known properties of the human gene product.
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PMID:Characterization of a murine p53ser246 mutant equivalent to the human p53ser249 associated with hepatocellular carcinoma and aflatoxin exposure. 760 78

Nuclear DNA ploidy analysis, p53 immunohistochemical overexpression and PCNA Labeling Index (PCNA LI) were studied in 80 cases of resected "single nodular" human hepatocellular carcinoma (HCC) tissue sections. Aneuploid pattern was found in forty-six cases (57.7%) and p53 overexpression in fifteen cases (18.8%). The rate of aneuploid pattern was significantly higher in patients with carcinomas more than 2 cm in diameter, fc-inf positive growth and more than Stage II. p53 overexpression was not found in patients with well-differentiated HCCs and Stage I. Positive rate of p53 overexpression was significantly higher in patients with HCV-Ab positive and PCNA LI > or = 40%. It was high in patients with vp-positive, vv-positive and aneuploid pattern. PCNA LI of HCCs were significantly higher in patients with HBs-Ag positive, high serum AFP level, massive type and single nodular type with proliferation into surrounding area, fc-inf positive, im-positive, Stage III + IV, aneuploid pattern and p53 overexpression. The postoperative prognoses of patients with aneuploid pattern and PCNA LI > or = 40% were significantly poorer than those of the diploid one and PCNA LI < 40% in cumulative survival rates. Those prognoses were remarkably poorer in the early postoperative period. Patients with p53 overexpression had poorer prognosis than those with no p53 overexpression in the early postoperative period. These results suggest that nuclear DNA ploidy analysis, p53 immunohistochemical overexpression and PCNA LI were useful markers of biological malignant potentials in "single nodular" human HCCs.
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PMID:[DNA ploidy pattern, p53 immunohistochemical overexpression and PCNA labeling index in "single nodular" human hepatocellular carcinomas from the viewpoint of biological malignant potential]. 761 70

Human hepatocarcinoma cells (SK-HEP-1) were induced to die through apoptosis by treatment with delta 12-prostaglandin (PG)J2, as characterized by the appearance of a typical DNA ladder. The induction of apoptosis by delta 12-PGJ2 was specifically blocked by cycloheximide (CHX). Western analysis using anti-p53 or anti-WAF1 monoclonal antibodies demonstrated that these two protein levels were increased 3 h after delta 12-PGJ2 treatment, and accumulated for up to 12 h. The induction of p53 protein seemed to be dependent on the increase of p53 mRNA level, which was inhibited by CHX treatment. However, delayed addition of CHX after delta 12-PGJ2 treatment failed to affect both p53 mRNA levels and DNA fragmentation following delta 12-PGJ2 treatment, indicating that the inhibition of p53 synthesis may contribute to the protective effect of CHX against delta 12-PGJ2-mediated cytotoxicity. Therefore, our results suggest that the initial events caused by delta 12-PGJ2, leading ultimately to SK-HEP-1 cell death, involve a certain process required for p53 induction. However, the finding that delta 12-PGJ2 is also active against Hep 3B cells which are devoid of a functional p53 indicates that p53 may not be the critical requirement for inducing apoptosis by delta 12-PGJ2.
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PMID:Induction of p53 and apoptosis by delta 12-PGJ2 in human hepatocarcinoma SK-HEP-1 cells. 762 35

The present study describes mutations of the tumour suppressor gene p53 in a local collection of colorectal and hepatocellular carcinomas (HCCs). Tumour DNA was extracted from both fresh and paraffin-embedded tissues and exons 5-8 of the p53 gene were amplified by polymerase chain reaction (PCR). Mutations were detected by single-strand conformation polymorphism (SSCP) analysis followed by direct DNA sequencing. Of the 38 colorectal carcinomas and 42 HCCs examined, 15 (39%) and 13 (31%), respectively, showed p53 mutations. Two-thirds (10/15) of the mutations in colorectal carcinomas were base transitions with a predominance at CpG dinucleotide sites--a pattern characteristic to an endogenous process in cancer development. Three mutational hotspots at codons 175, 248 and 282 were also identified. Mutations did not correlate with histological grade, Dukes stage, or metastasis. However, tumours at the distal site of the colorectum showed a higher proportion of mutations than the proximal site. In the case of HCCs, majority (9/13) of the mutations were base transitions and no mutations were observed at codon 249. This is in contrast to results from other high-incidence areas such as Africa and China, where aflatoxin is believed to be a major aetiologic factor for liver cancers. The results therefore suggest that other risk factors, rather than dietary exposure to aflatoxin, may contribute to the high HCC incidence in Singapore.
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PMID:Mutations of the tumour suppressor gene p53 in colorectal and hepatocellular carcinomas. 765 61

A recombinant vaccinia virus was constructed using the wild-type human p53 gene as an insert. The p 53 protein produced by this recombinant virus was used to investigate p53 binding proteins in seventeen cell lines, including 10 derived from human hepatocellular carcinoma, four from other human cancers, and three from non-human primate tissues. In all 17 cell lines tested, two proteins of 40 kD and 50 kD were identified that bound to wild-type p53 and that may be cellular regulators of p53 function.
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PMID:Identification of two p53-binding proteins using a recombinant vaccinia virus containing the wild-type human p53 gene. 765 64

Recently, p53 gene aberrations have been recognized as a relevant factor in hepatocarcinogenesis, in tumors from both high-risk and low-risk areas. Because p53 gene mutations typically result in increased p53 levels in tumor cells, this cellular protein might become immunogenic during tumor development. To test this hypothesis, we have analyzed sera from 80 European patients with hepatocellular carcinoma for the presence of p53 antibodies. For this purpose we developed an immunoblot assay using recombinant p53 as antigen. Sixty-seven sera from patients with different acute and chronic liver diseases were used as controls. In addition, serum alpha-fetoprotein assays were performed. Circulating antibodies against p53 were found in 25% (20 of 80) of the sera from patients with hepatocellular carcinoma but not in various nonmalignant liver diseases. The association of p53 antibodies with malignancy was highly significant (p < 0.00003). In 73.8% (59 of 80) of the hepatocellular carcinoma sera the alpha-fetoprotein levels were elevated. Among the 21 alpha-fetoprotein-negative hepatocellular carcinoma sera, 5 were found to contain p53 antibodies (23.8%). In conclusion, an antibody response against p53 developed in a significant proportion of patients with hepatocellular carcinoma but not in those with nonmalignant liver diseases. Serological testing for p53 antibodies gives the opportunity to identify a subgroup of patients with hepatocellular carcinoma not detected by conventional tests for serum alpha-fetoprotein.
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PMID:The humoral immune response to p53 in patients with hepatocellular carcinoma is specific for malignancy and independent of the alpha-fetoprotein status. 768 31


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