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Aberrant iNOS signaling is under genetic control in rodent liver cancer and potentially prognostic for the human disease.

https://arctichealth.org/en/permalink/ahliterature92898
Source
Carcinogenesis. 2008 Aug;29(8):1639-47
Publication Type
Article
Date
Aug-2008
Author
Calvisi Diego F
Pinna Federico
Ladu Sara
Pellegrino Rossella
Muroni Maria R
Simile Maria M
Frau Maddalena
Tomasi Maria L
De Miglio Maria R
Seddaiu Maria A
Daino Lucia
Sanna Valeria
Feo Francesco
Pascale Rosa M
Author Affiliation
Department of Biomedical Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy.
Source
Carcinogenesis. 2008 Aug;29(8):1639-47
Date
Aug-2008
Language
English
Publication Type
Article
Keywords
Animals
Carcinoma, Hepatocellular - enzymology - epidemiology - genetics - pathology
Cell Line, Tumor
Genetic Predisposition to Disease
Humans
Incidence
Liver Neoplasms - enzymology - epidemiology - genetics - pathology
Male
Mice
Mice, Transgenic
Nitric Oxide Synthase Type II - genetics
Prognosis
Rats
Rats, Inbred BN
Rats, Inbred F344
Signal Transduction - physiology
Abstract
Mounting evidence underlines the role of inducible nitric oxide synthase (iNOS) in hepatocellular carcinoma (HCC) development, but its functional interactions with pathways involved in HCC progression remain uninvestigated. Here, we analyzed in preneoplastic and neoplastic livers from Fisher 344 and Brown Norway rats, possessing different genetic predisposition to HCC, in transforming growth factor-alpha (TGF-alpha) and c-Myc-TGF-alpha transgenic mice, characterized by different susceptibility to HCC, and in human HCC: (i) iNOS function and interactions with nuclear factor-kB (NF-kB) and Ha-RAS/extracellular signal-regulated kinase (ERK) during hepatocarcinogenesis; (ii) influence of genetic predisposition to liver cancer on these pathways and role of these cascades in determining a susceptible or resistant phenotype and (iii) iNOS prognostic value in human HCC. We found progressive iNos induction in rat and mouse liver lesions, always at higher levels in the most aggressive models represented by HCC of rats genetically susceptible to hepatocarcinogenesis and c-Myc-TGF-alpha transgenic mice. iNOS, inhibitor of kB kinase/NF-kB and RAS/ERK upregulation was significantly higher in HCC with poorer prognosis (as defined by patients' survival length) and positively correlated with tumor proliferation, genomic instability and microvascularization and negatively with apoptosis. Suppression of iNOS signaling by aminoguanidine led to decreased HCC growth and NF-kB and RAS/ERK expression and increased apoptosis both in vivo and in vitro. Conversely, block of NF-kB signaling by sulfasalazine or short interfering RNA (siRNA) or ERK signaling by UO126 caused iNOS downregulation in HCC cell lines. These findings indicate that iNOS cross talk with NF-kB and Ha-RAS/ERK cascades influences HCC growth and prognosis, suggesting that key component of iNOS signaling could represent important therapeutic targets for human HCC.
PubMed ID
18579559 View in PubMed
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[Activity of cytoplasmic proteinases from rat liver in Heren's carcinoma during tumor growth and treatment with medicinal herbs]

https://arctichealth.org/en/permalink/ahliterature20009
Source
Ukr Biokhim Zh. 2000 May-Jun;72(3):91-4
Publication Type
Article
Author
M M Marchenko
H P Kopyl'chuk
O V Hrygor'ieva
Author Affiliation
Yu. Fedkovich Chernivtsi State University, Ukraine.
Source
Ukr Biokhim Zh. 2000 May-Jun;72(3):91-4
Language
Ukrainian
Publication Type
Article
Keywords
Animals
Cytoplasm - enzymology
English Abstract
Hydrolysis
Liver - enzymology - pathology
Liver Neoplasms - enzymology
Organ Size - drug effects
Plant Extracts - pharmacology
Plants, Medicinal - chemistry
Rats
Abstract
The dynamics of the acid and neutral proteinases general enzymes activity change in the hepatocytes postnuclear fraction in the rats suffering from the Heren's carcinoma was investigated. It was determined that in the tumor development of the enzyme activity level of both the acid and neutral proteinases increased 2,6-fold. The natural preparation of the herbs (Calendula officinalis L., Echinacea purpurea L., Scorzonera humilis L., Aconitum moldavicum Hacq.) normalizes both the activity of the investigated enzymes and coefficients of the liver weights of the sick animals. The chemical medicinal preparation 5,6-benzcumarine-5-uracil normalizes the activity of the neutral cytoplasmatic proteinases and reduces the level of the proteolytic activity of the acid enzymes in comparison with the control group of the animals as well as increases of the liver weight coefficients.
PubMed ID
11200483 View in PubMed
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Cheese can reduce indexes that estimate fatty acid desaturation. Results from the Oslo Health Study and from experiments with human hepatoma cells.

https://arctichealth.org/en/permalink/ahliterature129035
Source
Appl Physiol Nutr Metab. 2012 Feb;37(1):31-9
Publication Type
Article
Date
Feb-2012
Author
Arne T Høstmark
Marianne S H Lunde
Author Affiliation
University of Oslo, Oslo, Norway. a.t.hostmark@medisin.uio.no
Source
Appl Physiol Nutr Metab. 2012 Feb;37(1):31-9
Date
Feb-2012
Language
English
Publication Type
Article
Keywords
Adult
Analysis of Variance
Carcinoma, Hepatocellular - enzymology
Cheese
Chromatography, Gas
Cross-Sectional Studies
Fatty Acid Desaturases - metabolism
Fatty Acids - blood - metabolism
Female
Health Surveys
Hep G2 Cells
Humans
Linear Models
Liver Neoplasms - enzymology
Male
Middle Aged
Norway
Abstract
Previously, cheese intake was shown to be inversely related to serum triglycerides, raising the possibility that cheese might inhibit triglyceride synthesis, which is governed by fatty acid desaturases. Therefore, analyses were done to study whether cheese intake was associated with indexes that reflect fatty acid desaturation in 121 healthy ethnic Norwegians aged 40-45 years, a subsample from the Oslo Health Study (N = 18 777). Experiments with human hepatoma cells (HepG2) were done to clarify whether cheese might have a causal effect on desaturases. Fatty acid distribution in lipids of human sera and HepG2 cells was determined by gas chromatography. ?9-Desaturase was estimated by the (16:1,n-7)/(16:0) and (18:1,n-9)/(18:0) ratios, abbreviated ds9_1 and ds9_2, and ?5-desaturase (ds5) by the (20:4,n-6)/(18:2,n-6) ratio. Correlation, ANOVA, and multiple linear regression models were used to study associations. Oslo Health Study: Subjects with cheese intake >4-6 times per week had 33% lower ds9_1 and 16% lower ds5 than subjects with intake = 4-6 times per week. The cheese intake vs. ds5 association prevailed when adjusting for sex, time since last meal, fatty fish, vegetables, fruit-berries, fruit juice, cod liver oil, coffee, alcohol, body mass index, physical activity, length of education, and smoking. HepG2 cells: An ethanol extract of Jarlsberg cheese lowered the desaturase indexes. Inhibition of ds9_1 increased with increasing amount cheese extract added. Thus, cheese may contain inhibitors of desaturases, thereby providing an explanation for the previously reported negative association between cheese intake and triglycerides.
PubMed ID
22148892 View in PubMed
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Cytochrome P4502A6 (CYP2A6) expression in human hepatocellular carcinoma.

https://arctichealth.org/en/permalink/ahliterature21813
Source
Hepatology. 1998 Feb;27(2):427-32
Publication Type
Article
Date
Feb-1998
Author
H. Raunio
R. Juvonen
M. Pasanen
O. Pelkonen
P. Pääkkö
Y. Soini
Author Affiliation
Department of Pharmacology and Toxicology, University of Oulu, Finland.
Source
Hepatology. 1998 Feb;27(2):427-32
Date
Feb-1998
Language
English
Publication Type
Article
Keywords
Animals
Antibodies, Blocking
Aryl Hydrocarbon Hydroxylases
Blotting, Western
Carcinoma, Hepatocellular - enzymology - mortality
Cytochrome P-450 Enzyme System - immunology - metabolism
Dose-Response Relationship, Immunologic
Humans
Immunohistochemistry
Liver Neoplasms - enzymology - mortality
Male
Mice
Mice, Inbred DBA
Microsomes, Liver - enzymology
Mixed Function Oxygenases - immunology - metabolism
Research Support, Non-U.S. Gov't
Survival Rate
Testosterone - metabolism
Abstract
The hepatic cytochrome P4502A6 (CYP2A6) enzyme mediates the oxidative metabolism of several procarcinogens that have liver as their primary target. Mouse models indicate that liver tumors invariably overexpress CYP2A forms, and that inflammation and cirrhosis may regulate the CYP2A expression pattern. In this study, the distribution of the CYP2A6 protein was investigated in a series of 24 human hepatocellular carcinoma (HCC) samples by immunohistochemical analysis. A polyclonal antibody was raised in chicken against CYP2A5, the mouse orthologue of CYP2A6. The antibody was characterized and found to be specific for CYP2A members. In DBA/2 mouse liver, a strong increase of CYP2A5 protein amount, localized in the perivenous region, occurred in response to treatment with pyrazole. In human HCC samples, overexpression of CYP2A6 protein was associated with the presence of chronic inflammation and cirrhosis. CYP2A6 protein was observed in 9 of 16 (56%) of samples with non-neoplastic hepatocytes and in 10 of 24 (42%) HCC samples. The staining for CYP2A6 protein was very heterogeneous in tumor cells, suggesting that increased expression of CYP2A6 occurred in a distinct subpopulation of neoplastic cells. In Kaplan-Meyer survival analysis, there was a tendency toward a more favorable prognosis in patients with CYP2A6-positive tumors in comparison with patients with CYP2A6-negative tumors. These data suggest that, in human HCC, in contrast to mouse liver tumors, CYP2A6 overexpression is not an invariable phenotype.
PubMed ID
9462641 View in PubMed
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Differential expression of matrix metalloproteinase (MMP)-2, MMP-9, and membrane type 1-MMP in hepatocellular and pancreatic adenocarcinoma: implications for tumor progression and clinical prognosis.

https://arctichealth.org/en/permalink/ahliterature20327
Source
Clin Cancer Res. 2000 Jul;6(7):2726-34
Publication Type
Article
Date
Jul-2000
Author
M. Määttä
Y. Soini
A. Liakka
H. Autio-Harmainen
Author Affiliation
Department of Pathology, University of Oulu, Finland.
Source
Clin Cancer Res. 2000 Jul;6(7):2726-34
Date
Jul-2000
Language
English
Publication Type
Article
Keywords
Adenocarcinoma - enzymology - genetics - mortality - pathology
Adolescent
Aged
Aged, 80 and over
Carcinoma, Hepatocellular - enzymology - genetics - mortality - pathology
Child
Comparative Study
Disease Progression
Female
Follow-Up Studies
Gelatinase A - analysis - genetics
Gelatinase B - analysis - genetics
Humans
Immunohistochemistry
Liver Neoplasms - enzymology - genetics - mortality - pathology
Male
Metalloendopeptidases - analysis - genetics
Middle Aged
Pancreatic Neoplasms - enzymology - genetics - mortality - pathology
Prognosis
RNA, Messenger - genetics
Research Support, Non-U.S. Gov't
Stromal Cells - enzymology - pathology
Survival Rate
Transcription, Genetic
Abstract
In the present study, we used in situ hybridization to study 36 primary hepatocellular carcinomas (HCCs) and 35 pancreatic adenocarcinomas to analyze the expressions of membrane-type 1 matrix metalloproteinase (MT1-MMP), MMP-2, and MMP-9 mRNAs. In HCCs, MT1-MMP mRNA was mainly expressed by cancer cells and to a lesser extent by stromal cells. MMP-2 mRNA was expressed predominantly by cells of tumor stroma, whereas MMP-9 mRNA was seen mainly in neoplastic epithelial cells. In pancreatic adenocarcinomas, MT1-MMP and MMP-9 mRNA were seen at moderate levels both in cancer and in stromal cells, whereas MMP-2 mRNA was predominantly expressed by the tumor stroma. Antigens of MMP-2, MMP-9, and MT1-MMP immunolocalized to the neoplastic epithelium and to the stromal cells in both tumor types. In gelatin zymography, increased amounts of latent and active MMP-2 were found in tumor samples of HCC as compared with adjacent nontumorous liver tissue. On the other hand, the latent form of MMP-9 was found in almost equal amounts both in tumor and normal liver samples, but its active form was present only in HCC. Expression of MT1-MMP mRNA had a tendency to be associated with a lower degree of differentiation in HCC, but such association was not noticed in pancreatic tumors. Correlation to the clinical data showed that MT1-MMP expression had a strong statistical association with a poor outcome of patients (P
PubMed ID
10914717 View in PubMed
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Erythrocyte porphobilinogen deaminase activity and primary liver cancer.

https://arctichealth.org/en/permalink/ahliterature23289
Source
J Intern Med. 1995 Mar;237(3):309-13
Publication Type
Article
Date
Mar-1995
Author
J. Kaczynski
G. Hansson
S. Thunell
L. Wetterberg
S. Wallerstedt
Author Affiliation
Department of Medicine, University of Göteborg, Ostra Sjukhuset, Sweden.
Source
J Intern Med. 1995 Mar;237(3):309-13
Date
Mar-1995
Language
English
Publication Type
Article
Keywords
Adult
Aged
Erythrocytes - enzymology
Female
Heterozygote
Humans
Hydroxymethylbilane Synthase - metabolism
Liver Neoplasms - enzymology - genetics
Male
Middle Aged
Porphyria, Acute Intermittent - enzymology - genetics
Prospective Studies
Tumor Markers, Biological - blood
Abstract
OBJECTIVES. To study whether primary liver cancer (PLC) could be associated with acute intermittent porphyria (AIP) carriership and whether the activity of erythrocyte porphobilinogen deaminase (PBGD) could be used as a tumour marker for PLC. DESIGN. Prospective study. SETTING. Medical and surgical wards in two general hospitals in G?teborg, Sweden. SUBJECTS. All patients with a strong suspicion of PLC (n = 109) who came to the authors' attention. MAIN OUTCOME MEASURES. Measurement of PBGD activity in erythrocytes. Comparison of the PBGD activity in groups with various final diagnoses-hepatocellular carcinoma (n = 58), cholangiocellular carcinoma (n = 2), malignancy other than PLC (n = 18), benign liver disorders (n = 11)--and according to presence of cirrhosis. RESULTS. None of the patients had a clinical or family history of AIP. Four cases with low PBGD activity, suggesting AIP gene carriership, were found, which is more than expected. However, the cases were evenly distributed amongst the groups. The mean activity of PBGD was higher in cirrhotic patients, irrespective of the presence of PLC, than in others. CONCLUSIONS. (i) Acute intermittent porphyria gene carriership might be associated with an increased risk not only for PLC but also for secondary malignancies and benign tumours in the liver. (ii) High activity of PBGD is not unusual in liver cirrhosis and the reason for this needs to be elucidated, but it seems to be of no clinical value as a tumour marker for PLC.
PubMed ID
7891052 View in PubMed
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Immunohistochemical study of colorectal tumors for expression of a novel transmembrane carbonic anhydrase, MN/CA IX, with potential value as a marker of cell proliferation.

https://arctichealth.org/en/permalink/ahliterature21569
Source
Am J Pathol. 1998 Jul;153(1):279-85
Publication Type
Article
Date
Jul-1998
Author
J. Saarnio
S. Parkkila
A K Parkkila
K. Haukipuro
S. Pastoreková
J. Pastorek
M I Kairaluoma
T J Karttunen
Author Affiliation
Department of Surgery, University of Oulu, Finland. juha.saarnio@oulu.fi
Source
Am J Pathol. 1998 Jul;153(1):279-85
Date
Jul-1998
Language
English
Publication Type
Article
Keywords
Adenocarcinoma - enzymology - metabolism
Adenoma - enzymology - metabolism
Antigens, Neoplasm
Carbonic Anhydrases
Cell Division
Colonic Polyps - enzymology - metabolism
Colorectal Neoplasms - enzymology
Comparative Study
Humans
Immunoenzyme Techniques
Intestinal Mucosa - enzymology - metabolism
Ki-67 Antigen - metabolism
Liver Neoplasms - enzymology - metabolism - secondary
Lymphatic Metastasis
Neoplasm Proteins - metabolism
Research Support, Non-U.S. Gov't
Tumor Markers, Biological - metabolism
Abstract
Carbonic anhydrase isoenzyme IX, MN/CA IX, is a recently discovered member of the carbonic anhydrase (CA) gene family with a suggested function in acid-base balance, intercellular communication, and cell proliferation. Increased expression of MN/CA IX has been observed with certain epithelial tumors. We investigated the expression of MN/CA IX in 69 colorectal neoplasms, consisting of 1 juvenile polyp, 8 hyperplastic polyps, 39 adenomatous lesions, 21 carcinomas, and 7 metastases. Tissue sections were immunostained with a monoclonal antibody specific to MN/CA IX. The proliferative activity of the tumor cells was evaluated by Ki-67 antigen immunoreactivity. The hyperplastic polyps showed a weak or moderate reaction for MN/CA IX only in the cryptal epithelium, as did the normal intestinal mucosa. The adenomas showed immunoreactivity mainly in the superficial part of the mucosa, whereas the distribution in the carcinomas and metastases was more diffuse. Comparative immunostaining of serial sections for Ki-67, a well established marker of cell proliferation, confirmed that MN/CA IX is expressed in areas with high proliferative capacity. Our results show abnormal MN/CA IX expression in colorectal neoplasms, suggesting its involvement in their pathogenesis. The co-occurrence of MN/CA IX and Ki-67 in the same tumor cells indicates its potential for use as a marker of increased proliferation in the colorectal mucosa.
Notes
Comment In: Am J Pathol. 1998 Jul;153(1):1-49665457
PubMed ID
9665489 View in PubMed
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Prolyl 4-hydroxylase isoenzymes I and II have different expression patterns in several human tissues.

https://arctichealth.org/en/permalink/ahliterature19603
Source
J Histochem Cytochem. 2001 Sep;49(9):1143-53
Publication Type
Article
Date
Sep-2001
Author
R. Nissi
H. Autio-Harmainen
P. Marttila
R. Sormunen
K I Kivirikko
Author Affiliation
Collagen Research Unit, Biocenter and Department of Medical Biochemistry, University of Oulu, Oulu, Finland.
Source
J Histochem Cytochem. 2001 Sep;49(9):1143-53
Date
Sep-2001
Language
English
Publication Type
Article
Keywords
Animals
Blotting, Western
Bone and Bones - enzymology
Capillaries - enzymology
Cell Differentiation
Cells, Cultured
Endothelium, Vascular - enzymology
Fetus
Fluorescent Antibody Technique
Humans
Isoenzymes - metabolism
Kidney - enzymology
Liver - cytology - enzymology
Liver Neoplasms - enzymology
Male
Mesoderm - enzymology
Mice
Microscopy, Immunoelectron
Muscle, Skeletal - cytology - enzymology
Organ Specificity
Placenta - enzymology
Procollagen-Proline Dioxygenase - metabolism
Research Support, Non-U.S. Gov't
Umbilical Veins - enzymology
Abstract
Prolyl 4-hydroxylase plays a central role in the synthesis of all collagens. We have previously reported that the recently identified Type II isoenzyme is its main form in chondrocytes and possibly in capillary endothelial cells, while Type I is the main form in many other cell types. We report here that the Type II isoenzyme is clearly the main form in capillary endothelial cells and also in cultured umbilical vein endothelial cells, whereas no Type I isoenzyme could be detected in these cells by immunostaining or Western blotting. The Type II isoenzyme was also the main form in cells of the developing glomeruli in the fetal kidney and tubular structures of collecting duct caliber in both fetal and adult kidney, in occasional sinusoidal structures and epithelia of the bile ducts in the liver, and in some cells of the decidual membrane that probably represented invasive cytotrophoblasts in the placenta. Osteoblasts in a fetal calvaria, i.e., a bone developing by intramembranous ossification, stained strongly for both types of isoenzyme. The Type I isoenzyme was the main form in undifferentiated interstitial mesenchymal cells of the developing kidney, for example, and in fibroblasts and fibroblastic cells in many tissues. Skeletal myocytes and smooth muscle cells appeared to have the Type I isoenzyme as their only prolyl 4-hydroxylase form. Hepatocytes expressed small amounts of the Type I enzyme and very little if any Type II, the Type I expression being increased in malignant hepatocytes and cultured hepatoblastoma cells. The data suggest that the Type I isoenzyme is expressed especially by cells of mesenchymal origin and in developing and malignant tissues, whereas the Type II isoenzyme is expressed, in addition to chondrocytes and osteoblasts, by more differentiated cells, such as endothelial cells and cells of epithelial structures. (J Histochem Cytochem 49:1143-1153, 2001)
PubMed ID
11511683 View in PubMed
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Regulation of Cyp2a5 transcription in mouse primary hepatocytes: roles of hepatocyte nuclear factor 4 and nuclear factor I.

https://arctichealth.org/en/permalink/ahliterature17735
Source
Biochem J. 2004 Aug 1;381(Pt 3):887-94
Publication Type
Article
Date
Aug-1-2004
Author
Johanna Ulvila
Satu Arpiainen
Olavi Pelkonen
Kaoru Aida
Tatsuya Sueyoshi
Masahiko Negishi
Jukka Hakkola
Author Affiliation
Department of Pharmacology and Toxicology, University of Oulu, P.O. Box 5000, 90014 Oulu, Finland.
Source
Biochem J. 2004 Aug 1;381(Pt 3):887-94
Date
Aug-1-2004
Language
English
Publication Type
Article
Keywords
5' Flanking Region - genetics
Animals
Aryl Hydrocarbon Hydroxylases - genetics
Base Sequence - genetics
Binding Sites
COS Cells - enzymology
Carcinoma, Hepatocellular - enzymology - genetics - pathology
Cell Line
Cell Line, Tumor
Cercopithecus aethiops
Chromosome Mapping - methods
Cloning, Molecular - methods
DNA Footprinting - methods
DNA, Neoplasm - metabolism
DNA-Binding Proteins - metabolism - physiology
Deoxyribonuclease I - metabolism
Gene Expression Regulation, Enzymologic - physiology
Hepatocyte Nuclear Factor 1
Hepatocyte Nuclear Factor 1-alpha
Hepatocyte Nuclear Factor 4
Hepatocytes - enzymology
Humans
Liver Neoplasms - enzymology - genetics - pathology
Male
Mice
Mice, Inbred DBA
Mixed Function Oxygenases - genetics
Molecular Sequence Data
Nuclear Proteins - metabolism - physiology
Phosphoproteins - metabolism - physiology
Promoter Regions (Genetics) - genetics
Protein Binding
Research Support, Non-U.S. Gov't
Transcription Factors - metabolism - physiology
Transcription, Genetic - physiology
Abstract
The cytochrome P4502a5 (Cyp2a5) gene is expressed principally in liver and olfactory mucosa. In the present study, the transcriptional mechanisms of hepatocyte-specific expression of Cyp2a5 were studied in mouse primary hepatocytes. The Cyp2a5 5'-flanking region -3033 to +10 was cloned in front of a luciferase reporter gene and transfected into hepatocytes. Deletion analysis revealed two major activating promoter regions localized at proximal 271 bp and at a more distal area from -3033 to -2014 bp. The proximal activation region was characterized further by DNase I footprinting, and a single clear footprint was detected in the studied area centred over a sequence similar to the NF-I (nuclear factor I)-binding site. The binding of NF-I was confirmed using an EMSA (electrophoretic mobility-shift assay). A putative HNF-4 (hepatocyte nuclear factor 4)-binding site was localized at the proximal promoter by computer analysis of the sequence, and HNF-4alpha was shown to interact with the site using an EMSA. The functional significance of HNF-4 and NF-I binding to the Cyp2a5 promoter was evaluated by site-directed mutagenesis of the binding motifs in reporter constructs. Both mutations strongly decreased transcriptional activation by the Cyp2a5 promoter in primary hepatocytes, and double mutation almost completely abolished transcriptional activity. Also, the functionality of the distal activation region was found to be dependent on the intact HNF-4 and NF-I sites at the proximal promoter. In conclusion, these results indicate that HNF-4 and NF-I play major roles in the constitutive regulation of hepatic expression of Cyp2a5.
PubMed ID
15115437 View in PubMed
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11 records – page 1 of 2.