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

By the cellular cytotoxic test in vitro it was demonstrated that lymphocytes of the spleen and lymphnodes from normal mice C3HA and mice given a carcinogen--o-AAT during 30 days show a cytotoxic effect on the hepatoma 22a culture. It was found that the cytotoxic activity of splenic and lymphnode lymphocytes in mice, given the carcinogen for 60 days, was reduced. In a number of experiments splenic lymphocytes of these mice were found to stimulate the hepatoma 22a cells growth in vitro.
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PMID:[Antitumor cytotoxins in the early stages of liver carcinogenesis]. 745 44

Hepatocarcinogenesis is deterministic in transgenic mice expressing in the liver gene construct Alb-DS4 that encodes autocrine growth factor IgEGF (D Stern et al. (1987), Science 235: 321-324), causing their death within 7.1 months. Hepatic expression of construct AAT-myc encoding murine c-myc causes liver cancer in 44% of the mice at 14.8 months. Cooperation of these genes was evident in CD2F1 transgenics bearing Alb-DS4 plus AAT-myc, in which accelerated hepatocellular carcinoma (HCC) formation caused death of all mice within 4.4 months. Alb-DS4 also cooperates with the Hcs locus, which in C3H/HeJ mice mediates high susceptibility to spontaneous hepatocarcinogenesis, causing accelerated formation of HCC to which mice succumbed at 5.1 months. Thus, genes that predispose to HCC formation cooperate in transgenic mice and their interaction is a key to understand mechanisms that cause liver cancer.
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PMID:Autocrine mitogen IgEGF cooperates with c-myc or with the Hcs locus during hepatocarcinogenesis in transgenic mice. 786 54

Large cell liver cell dysplasia (LCD), a suggested preneoplastic change progressing to hepatocellular carcinoma, has been reported associated with alpha-1-antitrypsin deficiency which in some countries has an increased frequency of hepatocellular carcinoma. We examined the nonneoplastic liver from 13 alpha-1-antitrypsin deficiency patients for LCD and, using a labeled streptavidin-biotin technique, for immunohistochemical markers: AAT (1/200), hepatitis B surface (HBsAg, prediluted) and core (HBcAg, 1/400) antigens, and monoclonal (1/20) and polyclonal (1/40) mutant p53, a tumor suppressor gene. There were eight males and five females ranging from 2 mo to 76 yr (mean 40 yr). Nine livers showed cirrhosis, one chronic persistent hepatitis, one portal fibrosis, and two cholestatic hepatitis (in the two infants). The nine cases with LCD included five males and four females of mean age 46 yr (range, 17-71), eight with cirrhosis and one with portal fibrosis. Only one liver with LCD and cirrhosis had HBcAg in cirrhotic and dysplastic cells. No patient had developed hepatocellular carcinoma. All 13 livers were immunonegative for HBsAg and mutant p53, and immunopositive for AAT present in normal, cirrhotic, and dysplastic liver cells. Thus, LCD was identified in 82% of adult alpha-1-antitrypsin deficiency livers (69% including infantile patients), 89% with cirrhosis, and none with malignancy. HB expression was rarely present; serology for HB and/or hepatitis C was positive in 46% adults. Immunoreactive AAT was present in dysplastic cells. p53 gene mutations do not appear to have a role in the pathogenesis of LCD in alpha-1-antitrypsin deficiency.
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PMID:Liver cell dysplasia in alpha-1-antitrypsin deficiency. 815 50

The cDNA for the rat cytosolic branched chain aminotransferase (BCATc) has been cloned. The BCATc cDNA encodes a polypeptide of 410 amino acids with a calculated molecular mass of 46.0 kDa. By Northern blot analysis, BCATc message of approximately 2.7 kilobases was readily detected in rat brain, but was absent from liver, a rat hepatoma cell line, kidney, and skeletal muscle. When expressed in COS-1 cells, the enzyme is immunologically indistinguishable from the native enzyme found in rat brain cytosol. Comparison of the rat BCATc sequence with available data bases identified the Escherichia coli (and Salmonella typhimurium) branched chain aminotransferase (BCAT) and revealed a Haemophilus influenzae BCAT, a yeast BCAT, which is hypothesized to be a mitochondrial form of the enzyme, and the murine BCATc (protein ECA39). Calculated molecular masses for the complete proteins are 33.9 kDa, 37.9 kDa, 42.9 kDa, and 43.6 kDa, respectively. The rat BCATc sequence was 84% identical with murine BCATc, 45% identical with yeast, 33% identical with H. influenzae, 27% identical with the E. coli and S. typhimurium BCAT, and 22% identical with the evolutionary related D-amino acid aminotransferase (D-AAT) (Tanizawa, K., Asano, S., Masu, Y., Kuramitsu, S., Kagamiyama, H., Tanaka, H., and Soda, K. (1989) J. Biol. Chem. 264, 2450-2454). Amino acid sequence alignment of BCATc with D-AAT suggests that the folding pattern of the overlapping mammalian BCATc sequence is similar to that of D-AAT and indicates that orientation of the pyridoxal phosphate cofactor in the active site of the eukaryotic BCAT is the same as in D-AAT. Thus, BCAT are the only eukaryotic aminotransferases to abstract and replace the proton on the re face of the pyridoxal phosphate cofactor. Finally, requirements for recognition of substrate L-amino acid and alpha-carboxylate binding are discussed.
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PMID:Cloning and expression of the mammalian cytosolic branched chain aminotransferase isoenzyme. 853 Apr 59

Aberrations of the p53 and Rb tumour suppressor genes were examined in 12 human hepatocellular carcinoma (HCC)-derived cell lines from different geographic areas and 9 local HCCs by restriction fragment length polymorphisms (RFLP), polymerase chain reaction-single-strand conformation polymorphisms (PCR-SSCP) and DNA sequencing. The relationships between genetic changes and hepatitis B virus (HBV) DNA integration in samples were compared. None of the cell lines and tumours showed structural changes in the Rb gene, while 6 cell lines and 2 tumours had mutation or deletion in exons 5 to 8 of p53. Mutations include an AGG --> AGT (Arg --> Ser) transversion at codon 249 in PLC/PRF/5 and Mahlavu, an AAT --> AAA (Asn --> Cys) transversion at codon 200 in TONG/HCC, an AAG --> GAG (Lys --> Glu) transition at codon 139 in HCC-T, a CAT --> CGT (His --> Arg) transition at codon 214 in SC4, and a CCC --> CTC (Pro --> Leu) transition at codon 250 in SC8. In Huh4, an 18-bp deletion from codon 264 to 270 resulted in loss of Leu-Gly-Arg-Asn-Ser-Phe from the amino acid sequences 265 to 270, whereas Hep3B had a 7-kb deletion after exon 7 of p53. Our data indicate that whereas Rb may not have pleiotropic effects on HCC, p53 aberrations are frequently involved in hepatocarcinogenesis. Further, HBV infection appears to be unrelated to the micro-genetic changes of p53. The G to T codon-249-mutation is consistent with HCCs arising from areas at high risk for both aflatoxin B1 (AFB1) exposure and HBV infection.
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PMID:Tumour suppressor p53 and Rb genes in human hepatocellular carcinoma. 877 41

A new case of hepatoid adenocarcinoma was diagnosed in fragments obtained at transurethral resection (TUR) from a 71-year-old man who had complained of haematuria. The tumour was composed of trabeculae and small solid nests of polygonal atypical cells simulating hepatocarcinoma, together with glandular areas of an otherwise typical adenocarcinoma. Immunohistochemistry showed cytoplasmic reactivity to AFP, AAT, albumin and CAM 5.2. Membrane reactivity was seen in EMA immunostaining, and there was also positivity to polyclonal CEA following a canalicular pattern. Immunoperoxidase studies of hepatocyte growth factor (HGF) and its receptor, c-met, were positive. Their expression may be related to the aggressive behaviour of this tumour.
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PMID:Hepatoid adenocarcinoma of the urinary bladder. An unusual neoplasm. 1043 50

Biobanks containing formalin-fixed paraffin-embedded tissue, as well as frozen serum or plasma, are important resources for molecular epidemiologic studies. However, few studies have compared the reliability of formalin-fixed tissue samples and archival plasma samples for genotyping. We determined the genotype of four proposed genetic risk factors for hepatocellular carcinoma [hereditary hemochromatosis (HFE 63 and 282), alpha(1)-antitrypsin deficiency (AAT 342) and cystic fibrosis (CFTR 508)] on formalin-fixed tissue samples, stored for up to 25 years, from 318 patients diagnosed with hepatocellular carcinoma and on plasma or serum samples from 31 of these patients. The genotypes were analyzed by RFLP or allele-specific amplification as well as by TaqMan assays. In addition, genotyping was attempted after whole genome amplification by multiple displacement amplification (MDA). Genotyping was successful in 94% of the tissue samples and successful and identical to the tissue samples from the same subjects in 98% of the plasma/serum samples. DNA from plasma samples could be amplified >5,000-fold by MDA and genotyping after MDA gave identical results to the genotyping of the same subjects before whole genome amplification. MDA amplification of the tissue samples was not successful. In summary, archival plasma was found to be an adequate source of efficiently amplifiable DNA. MDA on plasma samples allows analysis of multiple genotypes in epidemiologic studies.
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PMID:Comparison of archival plasma and formalin-fixed paraffin-embedded tissue for genotyping in hepatocellular carcinoma. 1566 2

OBJECTIVE. Severe (PiZZ) alpha(1)-antitrypsin (AAT) deficiency is a risk factor for liver disease, i.e. juvenile cirrhosis in infancy, and cirrhosis and hepatoma in adulthood. Little is known about the risk of liver disease in individuals with moderate (PiSZ) AAT deficiency. To investigate the natural course of AAT deficiency, a cohort of PiZZ and PiSZ individuals identified by the Swedish National neonatal screening programme in 1972-74 is followed regularly. The aim of this study was to compare liver function in this cohort with healthy control subjects aged 30 years. MATERIAL AND METHODS. Blood samples were obtained from 89 PiZZ, 40 PiSZ, and 84 control subjects (PiMM), and plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl (GT) transpeptidase were analysed. RESULTS. The mean values of all liver enzymes were within the normal range in all Pi subgroups. However, the mean AST was higher in the PiZZ and PiSZ subgroups than in the PiMM subgroup (p < 0.001), and the mean ALT was higher in the PiZZ individuals than in the controls (p < 0.05), while GT did not differ significantly among the Pi subgroups. The PiZZ women taking oral contraceptives had higher mean AST and ALT (p < 0.01) and GT (p < 0.05) than the control women taking oral contraceptives. CONCLUSIONS. At the age of 30 years, PiZZ and PiSZ individuals have normal plasma levels of the transaminases AST and ALT, although they are significantly higher than those in healthy control subjects. Use of oral contraceptives seems to influence liver enzymes in PiZZ women.
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PMID:The liver in 30-year-old individuals with alpha(1)-antitrypsin deficiency. 1989 86

Advanced hepatocellular carcinoma (HCC) is an important cause of cancer mortality. Epithelial-mesenchymal transition (EMT) has been shown to be an important biological process in cancer progression and metastasis. We have focused on elucidating factors that induce EMT to promote carcinogenesis and subsequent metastasis in HCC using the BNL CL.2 (BNL) and BNL 1ME A. 7R.1 (1MEA) cell lines. BNL cells are normal hepatocytes whereas the 1MEA cells are HCC cells derived from chemical transformation of the BNL cells. Their morphological characteristics were examined. Expression levels of hepatocyte growth factor (HGF), markers of EMT and mediators of HGF signaling were determined and functional characteristics were compared. BNL cells were treated with HGF and effects on EMT-marker and mediators of HGF signaling were analyzed. BNL cells display characteristic epithelial morphology whereas 1MEA cells display mesenchymal characteristics. 1MEA cells express and secrete more HGF than BNL cells. There was significantly decreased expression of E-cadherin, albumin, AAT and increased expression of fibronectin, collagen-1, vimentin, snail and slug in 1MEA cells. There was also increased expression of cyclooxygenase-2 (COX-2), Akt and phosphorylated Akt (pAkt) in 1MEA cells. Moreover, 1MEA cells had increased migratory capacity inhibited by inhibition of COX-2 and Akt but not extracellular signal regulated kinase (ERK). Molecular mesenchymal characteristics of 1MEA cells were reversed by inhibition of COX-2, Akt and ERK. Treatment of BNL cells with HGF led to decreased expression of E-cadherin and increased expression of fibronectin, vimentin, snail, slug, COX-2, Akt, pAkt and increased migration, invasiveness and clonogenicity. We conclude that development of HCC is associated with upregulation of HGF which promotes EMT and carcinogenesis via upregulation of COX-2 and Akt. Consequently, HGF signaling may be targeted for therapy in advanced and metastatic HCC.
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PMID:Hepatocyte growth factor upregulation promotes carcinogenesis and epithelial-mesenchymal transition in hepatocellular carcinoma via Akt and COX-2 pathways. 2174 57

Selective replication in tumor cells is a highly desirable feature for oncolytic viruses. Recent studies have shown that microRNAs (miRNAs) play important roles in controlling gene expression, and that certain tissue-specific miRNAs are frequently downregulated in malignant cells. miR-122 is a liver-specific microRNA. It is abundantly expressed in normal hepatocytes but is absent in many hepatocellular carcinoma (HCC) cells. We hypothesized that expression of an essential viral gene by a liver-specific promoter would initially restrict virus replication to cells of hepatic origin and that adding miR-122 complementary sequences to the viral gene would make the transcripts degradable by miR-122 in normal hepatocytes, thus further confining its replication to HCC. We have constructed such an oncolytic herpes simplex virus by linking the essential viral glycoprotein H gene with the liver-specific apolipoprotein E (apoE)-AAT promoter and by adding the miR-122a complimentary sequence to the 3' untranslated region (3'UTR). To further increase the safety of this virus, complementary sequences from miR-124a and let-7 were also engineered into the same 3'UTR. Designated liver-cancer specific oncolytic virus (LCSOV), it was highly selective in killing HCC cells and in shrinking HCC xenografts. We conclude that LCSOV is a highly specific oncolytic virus that can precisely target HCC.
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PMID:Construction of an oncolytic herpes simplex virus that precisely targets hepatocellular carcinoma cells. 2214 41


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