scholarly journals Peroxisomal Enzymes and 8-Hydroxydeoxyguanosine in Rat Liver Treated with Perfluorooctanoic Acid

2003 ◽  
Vol 19 (1) ◽  
pp. 19-25 ◽  
Author(s):  
Awad Abdellatif ◽  
Ahmad H. Al-tonsy ◽  
Mahmoud E. Awad ◽  
M. Roberfroid ◽  
M. Nezam Ullah Khan
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dna Damage ◽  
Carbon Tetrachloride ◽  
Liver Cancer ◽  
Selection Procedure ◽  
Basal Diet ◽  
Perfluorooctanoic Acid ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferators ◽  
Acyl Coa Oxidase

Although peroxisome proliferators are considered non-genotoxic agents, most of them, nevertheless, were found to promote and/or induce, hepatocellular carcinoma (HCC) in rodents. The aim of the present study is, first, to investigate whether the peroxisome proliferator perfluorooctanoic acid (PFOA) possesses inherent liver cancer promoting activity, and second, to study the possible mechanisms involved. To acheive these aims two protocols have been applied, a biphasic protocol (initiation by diethyl-nitrozamine (DEN) 200 mg/kg i.p. followed by treatment with 0.005% or 0.02% perflourooctanoic acid (PFOA) for 14 and 25 weeks) and a triphasic initiation, selection-promotion (IS) protocol (initiation by giving 200 mg/kg DEN i.p. followed by a selection procedure for 2 weeks consisting of giving 0.03% 2-acetylaminofluorene (2-AAF) in diet). In the middle of this treatment a single oral dose of carbon tetrachloride (2.0 ml/kg) was given, followed by giving diet containg 0.015% of PFOA for 25 weeks. After applying both protocols, our results showed slight increase in the catalase activity while acyl CoA oxidase activity was markedly increased. Both experiments indicated that PFOA has a liver cancer promoting activity. Other groups of rats were given either basal diet or diet containing 0.02% PFOA. Five or nine weeks later they were sacrificed and the levels of 8-hydroxydeoxyguanosine in the isolated DNA were estimated. The data showed a slight nonetheless insignificant increase in 8-hydroxydeoxyguanosine. From the present data, it is concluded that PFOA is a true liver cancer promoter that may not require extensive initial DNA damage for its promoting activity.

scholarly journals Localization and differential induction of cytochrome P450IVA and acyl-CoA oxidase in rat liver

1991 ◽  
Vol 275 (1) ◽  
pp. 247-252 ◽  
Author(s):  
D R Bell ◽  
R G Bars ◽  
G G Gibson ◽  
C R Elcombe
Keyword(s):  
Peroxisome Proliferator ◽  
Peroxisome Proliferators ◽  
Dependent Manner ◽  
Early Markers ◽  
Acyl Coa Oxidase ◽  
Significant Change ◽  
Kinetics Of ◽  
Dose Dependent ◽  
Induced Proteins ◽  
Hepatic Cytochrome

The peroxisome proliferators are structurally diverse chemicals which induce hyperplasia, hypertrophy and the proliferation of peroxisomes in the rodent liver. Cytochrome P450IVA1 and peroxisomal enzymes, such as acyl-CoA oxidase, are induced and are early markers of treatment with peroxisome proliferators. In this study, rats were dosed intraperitoneally with the potent peroxisome proliferator methylclofenapate and the hepatic induction response was studied. There was no significant change in the enzyme activities of laurate hydroxylase (cytochrome P450IVA1) or acyl-CoA oxidase in the first 8 h after treatment, but the activities had doubled at 24 h, suggesting that these enzymes are not involved in the mediation of early events in peroxisome proliferation. Hepatic cytochrome P450IVA1 mRNA was significantly increased at 6 and 8 h after treatment, rising to 15-fold above control values at 30 h. In contrast, acyl-CoA oxidase mRNA showed no significant change in the first 8 h, but increased to 13-fold above control values at 24 and 30 h, thereby demonstrating different kinetics of induction of the two mRNAs. In order to determine whether cytochrome P450IVA1 and peroxisomal enzymes were included in the same cells, rats were treated daily with sub-maximal (2 or 5 mg/kg) and maximal (25 mg/kg) inducing doses of methylclofenapate for 4 days. The lobular distribution of induced proteins was determined immunocytochemically with antibodies raised against P450IVA1 and acyl-CoA oxidase. Livers from control animals showed minimal staining for both proteins. However, in the livers of animals treated with 2 or 5 mg of methylclofenapate/kg, both acyl-CoA and P450IVA immunostaining was increased, mainly in the centrilobular area. Immunostaining of serial sections revealed that these proteins were induced in the same region of the lobule. A maximal inducing dose of methylclofenapate (25 mg/kg) caused panlobular induction of both proteins. The results demonstrate that these proteins are induced in a dose-dependent manner in the same, spatially distinct, sensitive region of the liver lobule.

The peroxisome proliferator-activated receptor:retinoid X receptor heterodimer is activated by fatty acids and fibrate hypolipidaemic drugs

1993 ◽  
Vol 11 (1) ◽  
pp. 37-47 ◽  
Author(s):  
I Issemann ◽  
R A Prince ◽  
J D Tugwood ◽  
S Green
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Physiological Role ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferators ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peroxisomal Enzyme ◽  
Oxidase Gene ◽  
Acyl Coa Oxidase ◽  
Peroxisome Proliferator Response Element

ABSTRACT The peroxisome proliferator-activated receptor (PPAR) is a member of the steroid hormone receptor superfamily and is activated by a variety of fibrate hypolipidaemic drugs and non-genotoxic rodent hepatocarcinogens that are collectively termed peroxisome proliferators. A key marker of peroxisome proliferator action is the peroxisomal enzyme acyl CoA oxidase, which is elevated about tenfold in the livers of treated rodents. We have previously shown that a peroxisome proliferator response element (PPRE) is located 570 bp upstream of the rat peroxisomal acyl CoA oxidase gene and that PPAR binds to it. We show here that the retinoid X receptor (RXR) is required for PPAR to bind to the PPRE, and that the RXR ligand, 9-cis retinoic acid, enhances PPAR action. Retinoids may therefore modulate the action of peroxisome proliferators and PPAR may interfere with retinoid action, perhaps providing one mechanism to explain the toxicity of peroxisome proliferators. We have also shown that a variety of hypolipidaemic drugs and fatty acids can activate PPAR. This supports the suggestion that the physiological role of PPAR is to regulate fatty acid homeostasis, and provides further evidence that PPAR is the target of the fibrate class of hypolipidaemic drugs. Finally, we have demonstrated that a metabolically stabilized fatty acid is a potent PPAR activator, suggesting that fatty acids, or their acyl CoA derivatives, may be the natural ligands of PPAR.

Assessment of miR-212 and Other Biomarkers in the Diagnosis and Treatment of HBV-infection-related Liver Diseases

2019 ◽  
Vol 20 (10) ◽  
pp. 785-798 ◽  
Author(s):  
Yigan Zhang ◽  
Huaze Xi ◽  
Xin Nie ◽  
Peng Zhang ◽  
Ning Lan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Chronic Hepatitis ◽  
Liver Cancer ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Liver Diseases ◽  
Meld Score ◽  
Hbv Infection ◽  
Expression Level ◽  
Control Group

Objective: Our study aims to detect the sensitivity of the new biomarker miR-212 existing in serum exosomes along with other hepatocellular carcinoma biomarkers such as AFP (alpha-fetoprotein), CA125 (carbohydrate antigen-ca125), and Hbx protein in the diagnosis of HBV-related liver diseases. We also aim to study the roles of these biomarkers in the progression of chronic hepatitis B and provide scientific data to show the clinical value of these biomarkers. Methods: We selected 200 patients with HBV-infection (58 cases of chronic hepatitis B, 47 cases of hepatocellular carcinoma, 30 cases of compensatory phase cirrhosis, and 65 cases of decompensatory phase cirrhosis), 31 patients with primary liver cancer without HBV infection, and 70 healthy individuals as the control group. The expression level of serum AFP and CA125 was detected with electrochemiluminescence immunoassay. The expression level of the Hbx protein was detected with ELISA. Meanwhile, the expression level of miR-212 in serum was analyzed with RT-qPCR. We collected patients’ clinical information following the Child-Pugh classification and MELD score criterion, and statistical analysis was made between the expression level of miR-212 and the collected clinical indexes. Lastly, we predicted the target genes of the miR-212 and its functions using bioinformatics methods such as cluster analysis and survival prediction. Results: Compared to the control group, the expression level of miR-212 in HBV infected patients was remarkably increased (P<0.05), especially between the HBV-infection Hepatocellular carcinoma group and the non-HBVinfection liver cancer group (P<0.05). The expression of miR-212 was increased in patients’ Child-Pugh classification, MELD score, and TNM staging. Moreover, the sensitivity and specificity of miR-212 were superior to AFP, CA125, and HBx protein. Conclusion: There is a linear relationship between disease progression and expression level of miR-212 in the serum of HBV infected patients. This demonstrates that miR-212 plays a significant role in liver diseases. miR-212 is expected to be a new biomarker used for the diagnosis and assessment of patients with HBV-infection-related liver diseases.

scholarly journals Possible Role of IRS-4 in the Origin of Multifocal Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2560
Author(s):  
Luis G. Guijarro ◽  
Patricia Sanmartin-Salinas ◽  
Eva Pérez-Cuevas ◽  
M. Val Toledo-Lobo ◽  
Jorge Monserrat ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Hepg2 Cells ◽  
Cellular Polarity ◽  
Ki 67 ◽  
Tissue Samples ◽  
Vitro Analysis ◽  
Tumoral Cells

New evidence suggests that insulin receptor substrate 4 (IRS-4) may play an important role in the promotion of tumoral growth. In this investigation, we have evaluated the role of IRS-4 in a pilot study performed on patients with liver cancer. We used immunohistochemistry to examine IRS-4 expression in biopsies of tumoral tissue from a cohort of 31 patient suffering of hepatocellular carcinoma (HCC). We simultaneously analyzed the expression of the cancer biomarkers PCNA, Ki-67, and pH3 in the same tissue samples. The in vitro analysis was conducted by studying the behavior of HepG2 cells following IRS-4 overexpression/silencing. IRS-4 was expressed mainly in the nuclei of tumoral cells from HCC patients. In contrast, in healthy cells involved in portal triads, canaliculi, and parenchymal tissue, IRS-4 was observed in the cytosol and the membrane. Nuclear IRS-4 in the tumoral region was found in 69.9 ± 3.2%, whereas in the surrounding healthy hepatocytes, nuclear IRS-4 was rarely observed. The percentage of tumoral cells that exhibited nuclear PCNA and Ki-67 were 52.1 ± 7%, 6.1 ± 1.1% and 1.3 ± 0.2%, respectively. Furthermore, we observed a significant positive linear correlation between nuclear IRS-4 and PCNA (r = 0.989; p < 0.001). However, when we correlated the nuclear expression of IRS-4 and Ki-67, we observed a significant positive curvilinear correlation (r = 0.758; p < 0.010). This allowed us to define two populations, (IRS-4 + Ki-67 ≤ 69%) and (IRS-4 + Ki-67 > 70%). The population with lower levels of IRS-4 and Ki-67 had a higher risk of suffering from multifocal liver cancer (OR = 16.66; CI = 1.68–164.8 (95%); p < 0.05). Immunoblot analyses showed that IRS-4 in normal human liver biopsies was lower than in HepG2, Huh7, and Chang cells. Treatment of HepG2 with IGF-1 and EGF induced IRS-4 translocation to the nucleus. Regulation of IRS-4 levels via HepG2 transfection experiments revealed the protein’s role in proliferation, cell migration, and cell-collagen adhesion. Nuclear IRS-4 is increased in the tumoral region of HCC. IRS-4 and Ki-67 levels are significantly correlated with the presence of multifocal HCC. Moreover, upregulation of IRS-4 in HepG2 cells induced proliferation by a β-catenin/Rb/cyclin D mechanism, whereas downregulation of IRS-4 caused a loss in cellular polarity and in its adherence to collagen as well as a gain in migratory and invasive capacities, probably via an integrin α2 and focal adhesion cascade (FAK) mechanism.

scholarly journals Profiling of tumour-associated microbiota in human hepatocellular carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Seiga Komiyama ◽  
Takahiro Yamada ◽  
Nobuyuki Takemura ◽  
Norihiro Kokudo ◽  
Koji Hase ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Fatty Liver Disease ◽  
Primary Liver Cancer ◽  
Epithelial Barrier ◽  
Sequence Variants ◽  
Alcoholic Fatty Liver ◽  
Uncultured Bacterium ◽  
Hepatitis C Viruses ◽  
Alcoholic Fatty Liver Disease

AbstractLiver cancer is the fourth leading cause of cancer-related death. Hepatocellular carcinoma (HCC) is a primary liver cancer that results from chronic hepatitis caused by multiple predisposing factors such as viral infection, alcohol consumption, and non-alcoholic fatty liver disease. Accumulating studies have indicated that dysfunction of the gut epithelial barrier and hepatic translocation of gut microbes may be implicated in the pathogenesis of HCC. However, the translocated bacteria in HCC patients remains unclear. Here, we characterised tumour-associated microbiota in patients with liver cancer and focused on HCC. We observed that the number of amplicon sequence variants in tumour-associated microbiota was significantly higher compared with that in non-tumour regions of the liver. The tumour-associated microbiota consisted of Bacteroidetes, Firmicutes, and Proteobacteria as the dominant phyla. We identified an unclassified genus that belonged to the Bacteroides, Romboutsia, uncultured bacterium of Lachnospiraceae as a signature taxon for primary liver cancer. Additionally, we identified Ruminococcus gnavus as a signature taxon for HCC patients infected with hepatitis B and/or hepatitis C viruses. This study suggests that tumour microbiota may contribute to the pathology of HCC.

scholarly journals Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1715
Author(s):  
Macus Hao-Ran Bao ◽  
Carmen Chak-Lui Wong
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Liver Cancer ◽  
Effective Treatment ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Metabolic Reprogramming ◽  
Combination Therapies ◽  
Low Oxygen ◽  
Treatment Regimens

Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.

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