ABSTRACT
BACKGROUND: Tenofovir (TDF) is one of the most widely used antiretroviral drug. Despite the high degree of tolerability a small percentage of patients experienced alteration in tubular function during TDF use. Intracellular TDF disposition is regulated by ATP-binding cassette (ABC) drug efflux transporters and, a reduced transport activity may be implicated in accumulation of TDF into the cells. The aim of our study was to assess the major determinants of TDF associated tubular dysfunction (KTD) in a real-life setting including the usefulness of single-nucleotide polymorphisms (SNPs) mapping into ABCC2, ABCC4 and ABCC10 genes. METHODS: We retrospectively analyzed all HIV positive patients who were followed at the Infectious Diseases Unit, DIBIC Luigi Sacco, University of Milan from April 2013 to June 2016. All patients treated with TDF who underwent a genotypization for the functional variants mapping in ABCC2 rs717620 (-24 C > T), ABCC4 rs1751034 (3463 A > G) and ABCC10 rs2125739 (T > C) were evaluated. KTD was defined as the presence of urine phosphate wasting and/or proteinuria at 24 h urine analysis. RESULTS: One hundred fifty-eight patients were genotyped, of which 42 (26.6%) experienced signs of KTD. No statistical significant differences were observed among patients with or without KTD regarding age, gender, ethnicity and comorbidities (hypertension and diabetes). The percentage of patients with KTD was higher among those with "GG" genotype at rs1751034 of ABCC4 compared to patients without KTD [6 (14.3%) vs 4 (3.5%), p = 0.01]. No statistical significant differences were observed regarding the distribution of ABCC2 and ABCC10 SNPs. Carriers of "G" allele in homozygous status at rs1751034 of ABCC4 showed a significant association with KTD (Odds Ratio 4.67, 95% CI 1.25-17.46, p = 0.02) in bivariate analysis, but this association was lost in multivariable analysis. A significant association between bone diseases and KTD was observed (Odds Ratio 3.178, 95%CI 1.529-6.603, p = 0.002). CONCLUSIONS: According to our results ABCC4 rs1751034 could be a genetic determinant of KTD; however validation studies are needed for therapy personalization. Noteworthy, a strong association between bone disease and KTD was also observed.
Subject(s)
Anti-HIV Agents/adverse effects , Kidney Diseases/chemically induced , Kidney Diseases/genetics , Polymorphism, Single Nucleotide , Tenofovir/adverse effects , Adult , Alleles , Cohort Studies , Female , HIV Infections/drug therapy , Humans , Kidney Diseases/physiopathology , Male , Middle Aged , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/genetics , Proteinuria/chemically inducedABSTRACT
Single-nucleotide polymorphisms (SNPs) related to hereditary thrombophilia were investigated as risk factors for thromboembolism in cancer patients. Their effect in metastatic colorectal cancer (mCRC) has never been explored so far. Our aim was to analyse the effect of coagulation factor V (FVL G1691A), prothrombin (PT G20210A), methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and plasminogen activator inhibitor type 1 (PAI-1 5G/4G) allelic variants in this setting. Fifty-two patients treated with first-line chemotherapy plus bevacizumab who developed a thromboembolic event in their lifetime were initially genotyped. A contemporary cohort of 127 patients who did not experience any thromboembolic event was also analysed. DNA was extracted from peripheral blood and genotypes were determined by real-time PCR, using LightSNiP (TIB MOLBIOL) on LightCcler 480 (Roche). The association between thromboembolism and SNPs was investigated by univariable and multivariable analyses. All SNPs were in Hardy-Weinberg equilibrium (χ2 test P>0.20). FVL G1691A and PT G20210A were present only in heterozygosis in 4 (2.2%) and 7 (3.9%) patients, respectively; MTHFR C677T in homozygosis in 29 (16.2%), MTHFR A1298C in homozygosis in 13 (7.3%); PAI-1 5G/4G in 98 (54.7%) and 4G/4G in 41 (23%) patients. At univariable analysis, treatment duration was significantly associated with thromboembolism (P<0.001), whereas gender, age, obesity, platelets count and chemotherapy backbone were not. Similarly, FVL G1691A and PT G20210A as well as MTHFR C677T and PAI-1 4G allele were significantly associated, whereas MTHFR A1298C was not. At multivariable model including PT G20210A, MTHFR C677T and PAI-1 4G (age, obesity, treatment duration and chemotherapy backbone were included as adjustment factors), the three SNPs were significantlty associated with higher risk of thromboembolism (P=0.025, <0.0001 and P=0.033, respectively). Further validation studies are warranted in order to design a prospective trial of thromboprophylaxis in mCRC patients with high-risk genotypes.
Subject(s)
Colorectal Neoplasms/genetics , Factor V/genetics , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Plasminogen Activator Inhibitor 1/genetics , Polymorphism, Single Nucleotide/genetics , Prothrombin/genetics , Thromboembolism/genetics , Adult , Aged , Alleles , Bevacizumab/therapeutic use , Colorectal Neoplasms/drug therapy , Female , Genetic Predisposition to Disease/genetics , Genotype , Humans , Male , Middle Aged , Prospective Studies , RiskABSTRACT
Toll-like receptors (TLRs) are a class of pattern recognition receptors that are deputed to recognise a range of molecular structures in pathogens. One of the most studied members of this family is the TLR4, which is essential for the signalling of lipopolysaccharide. The gene encoding for TLR4 is highly polymorphic and this genetic variability may explain in part the interindividual variability observed in several clinical setting, including the response to vaccination. Herein, we review and systematise the available scientific evidence about the effect of TLR4 polymorphisms on vaccine response, including approved prophylactic, new therapeutic cancer vaccines and recently approved vaccine adjuvants. Data reviewed in this analysis indicate that TLR4 polymorphisms significantly affect vaccine response. If these results are confirmed by further analyses, the use of these genetic biomarkers may become a useful tool to tailor vaccination in specific subsets of patients.
Subject(s)
Toll-Like Receptor 4/genetics , Vaccines/immunology , Adjuvants, Immunologic/physiology , Animals , Cancer Vaccines/immunology , Humans , Measles Vaccine/immunology , Meningococcal Vaccines/immunology , Pertussis Vaccine/immunology , Polymorphism, Single NucleotideSubject(s)
Benzoates/adverse effects , Glucuronosyltransferase/genetics , Iron Chelating Agents/adverse effects , Multidrug Resistance-Associated Proteins/genetics , Thalassemia/genetics , Triazoles/adverse effects , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/genetics , Benzoates/blood , Benzoates/therapeutic use , Child, Preschool , Deferasirox , Female , Humans , Iron Chelating Agents/therapeutic use , Multidrug Resistance-Associated Protein 2 , Neoplasm Proteins/genetics , Polymorphism, Single Nucleotide , Thalassemia/blood , Thalassemia/drug therapy , Triazoles/blood , Triazoles/therapeutic useABSTRACT
Until now, the occurrence of adverse reactions among individuals inoculated with identical vaccines has been ascribed to unpredictable stochastic processes. Recent advances in pharmacogenomics indicate that some features of host response to immunisation are influenced by genetic traits, henceforth predictable. The ability to predict the adverse reaction to vaccination would represent an important step towards the development of personalised vaccinology and could enhance public confidence in the safety of vaccines. Herein, we have reviewed all the available information on the association between genetic variants and the risk for healthy subjects to develop adverse reactions.
Subject(s)
Drug-Related Side Effects and Adverse Reactions/genetics , Genetic Variation/genetics , Vaccination/adverse effects , Vaccines/adverse effects , Humans , Pharmacogenetics/methods , RiskABSTRACT
BHLHB3 is a basic helix-loop-helix (bHLH) domain-containing protein that acts as a transcriptional repressor. We found that BHLHB3 transcript levels were low in three human lung cancer cell lines and downregulated in human lung adenocarcinomas as compared to normal lung tissue. BHLHB3 gene overexpression inhibited colony formation of A549, NCI-H520 and NCI-H596 lung cancer cells. The reduced colony growth was likely due to inhibition of cell proliferation as suggested by the downregulation of cyclin D1 (CCND1) expression in NCI-H520 cells transfected to overexpress the BHLHB3 gene; no evidence of apoptosis was observed. These results point to the potential role of the BHLHB3 protein as a tumor suppressor for lung cancer.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/physiology , Lung Neoplasms/prevention & control , Tumor Suppressor Proteins/physiology , Basic Helix-Loop-Helix Transcription Factors/genetics , Cell Line, Tumor , Cholesterol 7-alpha-Hydroxylase/genetics , Cholesterol 7-alpha-Hydroxylase/metabolism , Cyclin D1/genetics , Humans , Promoter Regions, Genetic , RNA, Messenger/analysisABSTRACT
Evidence in animal models has suggested an association between susceptibility to lung tumorigenesis and gene-expression profiles in normal lung. Here, we compared RNA pools from normal lung tissue of lung adenocarcinoma patients (cases) or non-lung cancer patients (controls) by hybridization of whole-human genome expression arrays. Principal component analysis identified a gene-expression signature of 85 genes that distinguishes cases from controls as well as smokers from nonsmokers. Elevated mRNA levels of one of these genes, AZGP1, were significantly associated with disease status. These results support the hypothesis that differences in the gene-expression levels of the normal tissue may be predictive of genetic predisposition to lung cancer in humans.
Subject(s)
Adenocarcinoma/genetics , Biomarkers, Tumor/metabolism , Carrier Proteins/genetics , Glycoproteins/genetics , Lung/metabolism , RNA, Messenger/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adipokines , Aged , Biomarkers, Tumor/genetics , Blotting, Western , Carcinoma, Mucoepidermoid/genetics , Carcinoma, Mucoepidermoid/metabolism , Carcinoma, Mucoepidermoid/pathology , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Carrier Proteins/metabolism , Case-Control Studies , Female , Gene Expression Profiling , Glycoproteins/metabolism , Humans , Lung/pathology , Male , Middle Aged , Oligonucleotide Array Sequence Analysis , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tissue Array AnalysisABSTRACT
The RASSF8 gene, which maps close to the KRAS2 gene, contains a RAS-associated domain and encodes a protein that is evolutionarily conserved from fish to humans. Analysis of the RASSF8 transcript revealed a complex expression pattern of 5'-UTR mRNA isoforms in normal lung and in lung adenocarcinomas (ADCAs), with no apparent differences. However, RASSF8 gene transcript levels were approximately seven-fold-lower in lung ADCAs as compared to normal lung tissue. Expression of RASSF8 protein by transfected lung cancer cells led to inhibition of anchorage-independent growth in soft agar in A549 cells and reduction of clonogenic activity in NCI-H520 cells. These results raise the possibility protein encoded by RASSF8 is a novel tumor suppressor for lung cancer.
Subject(s)
Adenocarcinoma/genetics , Genes, Tumor Suppressor , Lung Neoplasms/genetics , Tumor Suppressor Proteins/genetics , 5' Untranslated Regions , Adenocarcinoma/pathology , Base Sequence , Cell Adhesion/genetics , Cell Division/genetics , Cell Line, Tumor , Cloning, Molecular , DNA Primers , Down-Regulation , Humans , Lung Neoplasms/pathology , Molecular Sequence Data , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , TransfectionABSTRACT
Italian and Japanese non-small-cell lung-cancer patients were genotyped for an intragenic L-myc EcoRI restriction site polymorphism previously reported to be associated with lung-tumor prognosis in Asian populations but not in Caucasians. Screening of the L-myc sequence in Italian samples allowed identification of 2 additional 3'-UTR SNPs, located 2.3-3.0 kb from the EcoRI polymorphism, but no coding polymorphism was found. No significant association was found between any of the 3 SNPs and lung-tumor prognosis in Italian patients, consistent with the reported difference between Caucasian and Asian populations. Moreover, the newly discovered polymorphisms in the Italian group were not present in Japanese patients. Significant LD between EcoRI and the 2 other SNPs was detected in the Italian population, whereas no significant LD between the 2 3'-UTR markers was detected despite their close proximity (0.7 kb). Thus, the disparate conclusions about the role of L-myc polymorphism in tumor prognosis among different populations may rest in population-specific LD between the functional gene and the L-myc polymorphism.
Subject(s)
Adenocarcinoma/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Genes, myc/genetics , Linkage Disequilibrium , Lung Neoplasms/genetics , Adenocarcinoma/pathology , Alleles , Carcinoma, Non-Small-Cell Lung/pathology , Female , Genetic Markers/genetics , Humans , Italy , Japan , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Pilot Projects , Polymorphism, Single Nucleotide , Prognosis , Sequence Analysis, DNAABSTRACT
The parathyroid hormone-related protein (PTHrP) gene (Pthlh) maps in the distal region of mouse chromosome 6 that contains a quantitative trait locus associated with genetic predisposition to skin tumorigenesis. Here, we report a genetic polymorphism located in the osteostatin encoding region of the Pthlh gene and that produces Thr/ Pro PTHrP variants. PthlhThr and PthlhPro alleles were significantly linked with resistance and susceptibility to skin carcinogenesis in phenotypically selected Car-R and Car-S outbred mice. Transfection of human NCI-H520 squamous cell carcinoma cells with the PthlhPro allele resulted in cells growing in clusters, tending to pile up, and growing at a significantly faster rate in nude mice than non-transfected and PthlhThr-transfected cells. These results point to the role of the Pthlh gene as a cancer modifier gene in skin tumorigenesis.
Subject(s)
Neoplasms, Squamous Cell/genetics , Proteins/genetics , Skin Neoplasms/genetics , Animals , Base Sequence , Cell Division , Disease Susceptibility , Gene Expression , Genetic Predisposition to Disease/genetics , Humans , Immunity, Innate/genetics , Mice , Mice, Nude , Molecular Sequence Data , Parathyroid Hormone-Related Protein , Phenotype , Polymorphism, Genetic , Proteins/physiology , Transfection , Tumor Cells, CulturedABSTRACT
Fhit protein has a putative tumor suppressor function in several types of human and experimental cancers. To assess whether Fhit is involved in fetal development we have examined the distribution of Fhit protein in the 12- through 16-day postcoitum mouse fetus and in postnatal day 0 mouse pups by immunocytochemistry. High levels of Fhit protein were observed in the endodermal derivatives, namely, bronchi, trachea, esophagus, stomach, and intestine, in the 12- to 16-day postcoitum mouse fetus and in the postnatal day 0 pup. Other tissues showed a more restricted pattern of Fhit protein expression. These results suggest that Fhit may play a role in the development of specific tissues during mouse development.
Subject(s)
Acid Anhydride Hydrolases , Lung/chemistry , Lung/embryology , Neoplasm Proteins , Proteins/analysis , Proteins/genetics , Animals , Endoderm/chemistry , Gene Expression Regulation, Developmental , Kidney/chemistry , Kidney/embryology , Liver/chemistry , Liver/embryology , Mesoderm/chemistry , Mice , Mice, KnockoutABSTRACT
By using linkage disequilibrium (LD) analysis in 21 strains of known susceptibility to lung cancer and by assembling a YAC contig, we mapped to a approximately 1.5-Mb region on distal mouse chromosome 6 the Pas1 locus, the major determinant of lung cancer predisposition in mice. Our results, on the basis of haplotype and phenetic analysis, suggest that the Pas1(s) susceptibility allele is shared by several mouse-inbred strains of independent origin, which show either high or intermediate predisposition to lung tumorigenesis. Therefore, the Pas1(s) allele is probably derived from an ancestral mouse rather than from independent mutations of the same gene. We showed the feasibility of LD in common inbred strains for the fine mapping of disease loci, and provided the biological basis and the reagents for the cloning of the Pas1 gene.
Subject(s)
Adenoma/genetics , Genetic Predisposition to Disease/genetics , Lung Neoplasms/genetics , Animals , Chromosomes/genetics , Genetic Markers , Haplotypes , Linkage Disequilibrium , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Mice, Inbred CBA , Mice, Inbred DBA , Mice, Inbred Strains , Muridae , Phylogeny , Physical Chromosome MappingABSTRACT
The retinoic acid receptor alpha (Rara) gene, which maps in the same region as the pulmonary adenoma resistance (Par1) locus on mouse chromosome 11 (Manenti G et al., Nature Genet 12:455-457, 1996), was tested as a candidate gene for Par1. We report here the analysis of loss of heterozygosity, nucleotide sequence comparison, gene expression, and biochemical activity of the Rara gene from the Mus spretus(Par1/+) and A/J (Par1/-) mouse strains. The two Rara alleles were distinguished by two amino-acid variations but had similar biochemical activity and expression levels, leading to the exclusion of Rara as a candidate Par1 gene.
Subject(s)
Adenoma/genetics , Biomarkers, Tumor/genetics , Genes, Tumor Suppressor/genetics , Lung Neoplasms/genetics , Receptors, Retinoic Acid/genetics , Alleles , Animals , Gene Expression Regulation, Neoplastic , Loss of Heterozygosity , Mice , Molecular Sequence Data , Retinoic Acid Receptor alphaABSTRACT
Genetic linkage experiments using crosses between mouse inbred strains with an inherited predisposition and resistance to lung cancer make it possible to investigate the genetics of the complex inheritance of susceptibility and resistance to lung cancer. We have previously mapped a major locus (pulmonary adenoma susceptibility 1, Pas1) affecting inherited predisposition to lung cancer in mice onto chromosome 6, near Kras2. Appropriate crosses that include Pas1/+ mice provide a model system for identifying loci that can modify the lung cancer predisposition phenotype caused by Pas1. Using this approach, we mapped the pulmonary adenoma resistance 1 (Par1) locus on to mouse chromosome 11; this locus selectively inhibits lung tumor development in Pas1/+ animals and therefore behaves like a modulator gene of Pas1. More recently, we have mapped lung tumor modifier loci specifically affecting the initiation and progression of lung cancer. Thus experimental models provide an essential tool for the mapping of lung cancer susceptibility/resistance genes and for the subsequent cloning of candidate genes.
Subject(s)
Adenoma/genetics , Chromosome Mapping , Genetic Predisposition to Disease , Lung Neoplasms/genetics , Animals , Genetic Linkage , Humans , MiceABSTRACT
The mapping near Kras2 of pulmonary adenoma susceptibility 1 (Pas1), a major locus affecting inherited predisposition to lung cancer in mice prompted us to test the homologous human region (12p12) for association with lung adenocarcinoma, by a population-based study. We genotyped 213 lung adenocarcinoma patients and 219 healthy blood donor subjects for five polymorphic markers mapping in the putative region of interest. Three marker polymorphisms, located in a region spanning approximately 700 kb, were significantly associated with lung adenocarcinoma risk. Furthermore, polymorphisms in KRAS2 and PTHLH loci were also associated with tumor prognosis. These results suggest the existence of a human Pas1 homologous locus on chromosome 12p12.
Subject(s)
Adenocarcinoma/genetics , Chromosomes, Human, Pair 12/genetics , Lung Neoplasms/genetics , Polymorphism, Genetic/genetics , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Alleles , Chromosome Mapping , Genetic Markers , Humans , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Middle Aged , Prognosis , RiskABSTRACT
We analyzed the expression of the cytosolic aldehyde dehydrogenase 1 (Aldh1) gene in mouse lung tumors by northern blotting and immunocytochemical analysis. Aldh1 was abundantly expressed in normal lung tissue, with a predominant cellular localization on bronchiolar cells. However, expression of Aldh1 was strongly reduced (more than tenfold) in lung tumors. As aldehyde dehydrogenases metabolize some antitumor alkylating drugs to inactive compounds, the low expression of Aldh1 in lung tumors may account for the drug sensitivity of these tumors to chemotherapeutic agents.
Subject(s)
Aldehyde Dehydrogenase/metabolism , Lung Neoplasms/enzymology , Aldehyde Dehydrogenase/genetics , Animals , Bronchi/enzymology , Down-Regulation , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Mice , Mice, Inbred A , Mice, Inbred C3H , RNA, Messenger/geneticsABSTRACT
Lung cancer, a major cause of death in the Western world, has a poor prognosis. So far, therapeutic strategies have had only a limited effect. Lung cancer risk is strongly associated with cigarette smoking and lung cancer pedigrees are rare. However, a possible polygenic nature of inherited predisposition to this cancer has been envisaged. Mouse inbred strains with inherited predisposition and resistance to lung cancer provide an important tool for the dissection of the genetics of this complex disease. The A/J strain carries the pulmonary adenoma susceptibility 1 (Pas1) locus and develops many lung tumours. We have mapped the M. spretus-derived locus that strongly resists the lung tumorigenesis in Pas1/+ mice. This locus, pulmonary adenoma resistance 1 (Par1) maps to mouse chromosome 11, near the Rara locus, with a lod score of 5.3. In Pas1/+ mice Par1 accounts for 23% of the phenotypic variance and 10 fold reduction in total tumour volume. These results provide evidence for a major resistance locus affecting the expression of an inherited predisposition to lung cancer.
Subject(s)
Adenoma/genetics , Chromosome Mapping , Genes, Tumor Suppressor , Lung Neoplasms/genetics , Adenoma/pathology , Animals , Base Sequence , Crosses, Genetic , DNA Primers/genetics , Female , Genetic Linkage , Lung Neoplasms/pathology , Male , Mice , Mice, Inbred A , Mice, Inbred C57BL , Molecular Sequence Data , Muridae , Polymorphism, Single-Stranded ConformationalABSTRACT
The A/J mouse strain is genetically susceptible to pulmonary tumorigenesis. We have performed a genetic linkage analysis to map pulmonary adenoma susceptibility (Pas) loci in an urethane-treated (A/J x Mus spretus) x C57BL/6J (ASB) interspecific testcross. In this interspecific cross we have confirmed our previous results in AC3F2 mice on the mapping of the Pas1 locus to the distal region of chromosome 6, near Kras2 (Nature Genetics 3: 132-136, 1993). The A/J and M. spretus strains differed at the Pas1 locus, with the M. spretus providing the resistant allele. In the latter strain, we studied the nucleotide sequence of a portion of the second intron of Kras2 that contains polymorphisms associated with lung tumor susceptibility in several inbred strains. The lung tumor-resistant M. spretus strain had the same specific nucleotide sequence of susceptible strains. Mutations in codon 61 of Kras2 in urethane-induced lung tumors from ASF1 hybrids involved the A/J allele in all cases, while the M. spretus allele was never affected. Our results indicate that the M. spretus and A/J mice have an identical structure of the second intron of the Kras2 gene, but they differ in genetic susceptibility to pulmonary tumorigenesis and in mutability of their Kras2 allele.
Subject(s)
Chromosome Mapping , Introns , Lung Neoplasms/genetics , Neoplasm Proteins/genetics , Analysis of Variance , Animals , Base Sequence , Crosses, Genetic , DNA Primers , Deoxyribonucleases, Type II Site-Specific , Exons , Female , Genetic Predisposition to Disease , Male , Mice , Mice, Inbred A , Mice, Inbred C57BL , Molecular Sequence Data , Muridae , Polymerase Chain Reaction , Polymorphism, Genetic , Polymorphism, Restriction Fragment Length , Sequence Homology, Nucleic AcidABSTRACT
A rabbit antiserum developed against purified rat liver daunorubicin-binding protein of M(r) 54,000 (DNR-BP54) cross-reacted with a mouse protein of the same molecular weight. This protein was expressed in the liver and several other organs of mice. A series of tumors and cell lines tested for the presence of the protein were negative. By immunocytochemistry, we found that DNR-BP54 was abundantly expressed in the cytoplasm of normal hepatocytes but was expressed at much lower levels in urethane-induced mouse liver tumors. By immunoscreening of a mouse liver cDNA library, we cloned the cDNA coding for DNR-BP54 and we found that this protein is aldehyde dehydrogenase-2 (EC 1.2.1.3). This result was confirmed by the dehydrogenase activity found in pure preparations of DNR-BP54 from normal rat and mouse livers, assayed with acetaldehyde as substrate and NAD as cofactor. The enzyme activity was inhibited by daunorubicin. The inhibition was found to be competitive with respect to NAD.
Subject(s)
Aldehyde Dehydrogenase/biosynthesis , Carrier Proteins/biosynthesis , Liver Neoplasms, Experimental/metabolism , Aldehyde Dehydrogenase/antagonists & inhibitors , Aldehyde Dehydrogenase/genetics , Animals , Blotting, Northern , Blotting, Western , Carrier Proteins/antagonists & inhibitors , Carrier Proteins/genetics , Daunorubicin/pharmacology , Down-Regulation , Female , Gene Expression Regulation, Neoplastic , Immunohistochemistry , Male , Mice , Mice, Inbred A , Mice, Inbred C3H , Rats , Tumor Cells, CulturedABSTRACT
The C3H/He mouse represents a good experimental model of genetic predisposition to hepatocellular tumor development. We analyzed an interspecific test-cross population of 106 urethane-treated male (C3H/He x Mus spretus) x C57BL/6J mice, typed with 222 genetic markers to locate precisely the hepatocellular tumor susceptibility (Hcs) loci. Three regions, on chromosomes 2, 5, and 19, showed a significant linkage with hepatocellular tumor development, as indicated by different quantitative indexes estimating liver tumor size. Liver tumor frequency was not genetically controlled. These loci are different from three other Hcs loci that we have previously mapped in an F2 progeny of the C3H/He mouse crossed with the resistant laboratory strain A/J. The present result indicates a multigenic model of inheritance for hepatocellular tumor susceptibility.