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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 3  |  Page : 777-783

Evaluation of the relationship between glutathione peroxidase 1 polymorphism and hepatocellular carcinoma


1 Department of Clinical Pathology, Faculty of Medicine, National Liver Institute, Menoufia University, Shebin El-Kom, Menoufia Governorate, Egypt
2 Department of Hepatology, National Liver Institute, Menoufia University, Shebin El-Kom, Menoufia Governorate, Egypt
3 Department of Clinical Pathology, National Liver Institute, Menoufia University, Shebin El-Kom, Menoufia Governorate, Egypt

Date of Submission28-Dec-2017
Date of Acceptance09-Feb-2018
Date of Web Publication17-Oct-2019

Correspondence Address:
Sara M A Aboagiza
16 Mahmoud Allam Street, Shebin El-Kom 32511, Menoufia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_906_17

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  Abstract 

Objective
The objective of this study was to investigate association of genetic polymorphism of glutathione peroxidase 1 (rs1050450) with liver fibrosis and hepatocellular carcinoma (HCC).
Materials and methods
Electronic searches were conducted in PubMed, Embase and Cochrane Library from the start of the database to 2017. The initial search presented 215 articles of which 20 met the inclusion criteria. The articles studied the relation between glutathione peroxidase 1 (GPX1) and liver fibrosis and HCC. Extraction was performed, including the assessment of the quality and the validity of the papers that met with the prior criteria that describe the review. If the studies did not fulfil the inclusion criteria, they were excluded. Study quality assessment included when ethical approval was obtained, eligibility criteria defined, sufficient information, convenient controls and known assessment measures. Each study was reviewed independently; the data obtained were rebuilt in a new manner according to the need of the researcher and arranged into topics through the article. Then, comparisons were made with the results tabulated.
Results
In total, 20 potentially relevant publications were included. The studies indicate a significant association between GPX1 polymorphism and liver diseases.
Conclusion
We found that the GPX1 Pro198Leu (rs1050450) GPX1 polymorphism plays a major role in liver fibrosis progression and HCC development.

Keywords: fibrosis, gene, glutathione peroxidase 1, hepatocellular carcinoma, polymorphism


How to cite this article:
El-Saeid GK, Rady MA, Montaser BA, Mohammed Ghanem HS, Aboagiza SM. Evaluation of the relationship between glutathione peroxidase 1 polymorphism and hepatocellular carcinoma. Menoufia Med J 2019;32:777-83

How to cite this URL:
El-Saeid GK, Rady MA, Montaser BA, Mohammed Ghanem HS, Aboagiza SM. Evaluation of the relationship between glutathione peroxidase 1 polymorphism and hepatocellular carcinoma. Menoufia Med J [serial online] 2019 [cited 2019 Nov 19];32:777-83. Available from: http://www.mmj.eg.net/text.asp?2019/32/3/777/268865




  Introduction Top


Hepatocellular carcinoma (HCC) is rapidly becoming one of the most prevalent cancers worldwide, the sixth most common cancer worldwide and the third most common cause of cancer death [1]. In Egypt it is one of the health problems facing the health authorities [2]. Viral hepatitis: hepatitis B virus, hepatitis C virus (HCV) and excessive alcohol intake are the leading risk factors worldwide [3].

HCV, and its long-term resultant consequences, is a serious public health problem worldwide and a major endemic medical health problem in Egypt [4]. Although around 30% of patients may clear the virus spontaneously, the main health burden occurs from the majority of patients who develop chronic HCV [5]. Liver injury leads to increased production and release of extracellular free radicals, cytokines and signalling molecules [6]. In contrast, antioxidant enzymes, such as glutathione peroxidase (GPX) 1 play a crucial role eliminating reactive oxygen species (ROS) and maintaining the redox balance [7].

GPXs (EC 1.11.1.9 and EC 1.11.1.12) catalyse the reduction of hydrogen peroxide to water or corresponding alcohols using reduced glutathione [8]. GPX1, also known as GPX1, is an enzyme that in humans is encoded by the GPX1 gene on chromosome 3p21.3 and it is composed of two exons with a 1.42 kbp region [9]. Overall, 38 single nucleotide polymorphisms (SNPs) have been reported for GPX1. However, the most studied is the Pro198Leu polymorphism [dsSNP ID: rs1050450, minor allele frequency (Leu)=0.21], located at codon 198 (C>T) resulting in an amino acid variation from proline (CCC) to leucine (CTC). This amino acid substitution causes a change of the structural conformation of the active site region and modifies the enzyme activity [10]. Also, this substitution has been implicated in increased risk to many types of cancer such as breast, lung, colorectal, bladder and pathogenesis of diabetes and cardiovascular diseases [11].

Many studies were performed over last two decades, investigating the relation between GPX1 polymorphism and liver diseases. This study, was performed by integration of previous studies to evaluate the association between the gene polymorphism of antioxidant enzyme and HCC occurrence.


  Materials and Methods Top


Search strategy

Searches were conducted in PubMed (http://www.ncbi.nlm.nih.gov/pubmed), Embase database (http://www.embase.com) and Cochrane Library up to November 2017. Meanwhile, related case–control studies were found by the methods of literature back. The following search terms were used: antioxidant enzyme, glutathione peroxidase, genotype, mutation, polymorphism, variant, reactive oxygen species, hepatitis C virus, liver damage, liver fibrosis, cirrhosis and hepatocellular carcinoma. All identified studies were retrieved and their references as well as related articles were also checked. No publication date restriction was applied. We used the latest publication when a study had several publications on certain aspects.

Study selection

Studies fulfilling the following selection criteria were included in this study: (i) cohort or case–control study, in which the case group included patients with HCC and chronic hepatitis and the control group was healthy people; (ii) published English literature associated with the antioxidant enzyme gene (GPX) polymorphisms and HCC were included; (iii) the studies that report GPX1 Pro198Leu genotype distribution; (iv) studies that provide or calculate genotype and allele number of the case group and the control group were included; (v) reports, comments and letters were eliminated.

Data extraction

The following variables were extracted from each study if available: name of first author, publication year, countries, ethnicity of study participants, study design, numbers of cases and controls, case ascertainment, source of control, genotyping methods and the genotype distribution in the case group and the control group. Information was carefully checked by two of the investigators. The accuracy of the data was verified by comparing collection data from each investigator. Any discrepancy was resolved by discussion.

Literature quality was evaluated according to the Newcastle–Ottawa Scale, which was considered as an evaluation criterion of case–control study and recommended by Agency for Healthcare Research and Quality [12]. Any disagreement was resolved by consensus. The content of evaluation (a total of 9 points) included the object selection (a total of 4 points), the comparable evaluation (a total of 2 points) and the exposure assessment (a total of 3 points). Total score ranged from 0 (worst) to 10 (best) for case–control studies.

If the studies did not fulfil the above criteria, they were excluded such as, studies on other antioxidant enzymes, studies about liver fibrosis or HCC without assessment of GPX1 activity or polymorphism, report without peer-review, not within national research program, letters/comments/editorials/news and studies not focused on GPX1 in HCC. For overlapping studies, only the one with the largest sample size was included.

The assessed studies were evaluated according to evidence-based medicine (EBM) criteria using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM in addition to the Evidence Pyramid [Figure 1] [13].
Figure 1: Evidence-based medicine pyramid ‘lowest evidence is at the bottom, in-vitro research’. MA, meta-analysis; RCT, randomized controlled trial; SR, systematic review.

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US Preventive Services Task Force:

  1. Level I: Evidence obtained from at least one properly designed randomized controlled trial
  2. Level II-1: Evidence obtained from well-designed controlled trials without randomization
  3. Level II-2: Evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one centre or research group
  4. Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence
  5. Level III: Opinions of respected authorities, based on clinical experience, descriptive studies or reports of expert committees.


Quality assessment

The quality of all the studies was evaluated. Important factors included design of the study, possessing ethical approval, evidence of a power calculation, specified eligibility criteria, appropriate controls, sufficient information and specified assessment measures. It was expected that confounding factors would be reported and controlled for and appropriate data analysis done in addition to an explanation of any missing data.

Data synthesis

A structured systematic review was performed with the results tabulated.


  Results Top


Study selection and characteristics

In total 215 potentially relevant publications were identified, 195 articles were excluded as they did not meet our inclusion criteria [Figure 2]. A total of 20 studies were included in the review as they were deemed eligible by fulfilling the inclusion criteria. Of these 20 articles included in this review, 12 were human studies and eight were animal studies. All studies examined the effects of GPX1 level, activity and polymorphisms on different liver diseases including: liver fibrosis, cirrhosis, steatosis and finally ending to HCC. The studies were analysed with respect to the study design using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM.
Figure 2: Flowchart of study selection in this review. GPX1, glutathione peroxidase 1.

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Effect of GPX1 deficient/overexpression on its activity and its implication on liver health

The relation between GPX1 deficiency/overexpression was investigated in five studies, three animal studies [Table 1] [14],[15],[16] (which comes in the base of the Evidence Pyramid and provides the least strength of evidence) and two human studies [Table 2] [17],[18].
Table 1: Animal studies investigating the effects of deficiency and overexpression of GPX1 on its activity and its implication on liver

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Table 2: Relation between GPX1 enzyme activity and liver disease human studies

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Studies showed that GPX1 deficient mice were more liable to hepatic steatosis and liver damage. Full expression of GPX1 in liver of rats had a complete protection against ROS induced liver necrosis and apoptosis.

Human studies showed that there was an inverse relationship between GPX1 and different hepatic diseases.

Effect of selenium level on GPX1

The relation between selenium level and its effect on GPX1 activity and consequently liver diseases was shown in five in-vivo and in-vitro studies [Table 3] [19],[20],[21],[22],[23].
Table 3: Relation between selenium level and different liver diseases in-vivo and in-vitro studies

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Studies showed that GPX1 expression is diminished by selenium deficiency in cell culture systems as well as in in-vivo studies.

Effect of GPX1 polymorphism on liver diseases in animal studies

The effect of GPX1 rs1050450 was investigated in two animal studies [Table 4] [24],[25]. Studies showed that GPX1 Leu/Leu more susceptible to drug induced liver injury. Also, GPX1 activity decrease with mutant Leu allele than Pro allele, inducing liver damage.
Table 4: Animal studies investigating the effects of GPX1 (rs1050450) mutation on liver

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Effect of GPX1 polymorphism on liver diseases in human studies

The effect of GPX1 rs1050450 was investigated in eight human studies [Table 5] [26],[27],[28],[29],[30],[31],[32]. Regarding the human studies, there was six case–control study which comes in level II or (level B) EBM, two cohort studies with (level A) EBM. All studies reported that there was significant association between this polymorphism and HCV outcomes and HCC development, indicating that Leu allele had a higher risk.
Table 5: Human studies investigating the effects of GPX1 (rs1050450) mutation on liver

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  Discussion Top


Liver cancer is the sixth most common cancer worldwide and the third most common cancer related death [1]. Similar to many cancers, genes variants are involved in multistage carcinogenesis and may determine an individual's susceptibility to develop HCC. SNPs are the most common type of genomic sequence variation and are thought to be associated with population diversity, susceptibility to disease and individual response to drug treatment [33].

GPX1, an antioxidant enzyme playing a critical role in liver health, is encoded by the GPX1 gene on chromosome 3p21.3 in human and it is composed of two exons with a 1.42 kbp region [9].

Reviewing studies about GPX1 deficiency [14],[15], it was found that there was fatal response in GPX1−/− mice within the first 24 h. Superficially, GPX1-deficient mice appeared normal; however, these mice were highly sensitive to oxidant generators and were more susceptible to target tissue damage, such as liver parenchymal cell death.

Thus, lack of GPX1 enhances cell injury, apoptosis and cell death in many in-vitro models of disease and toxicity.

It is possible that in the context of GPX1 deficiency, excess accumulation of cellular ROS alters cellular NF-κB responses. Activation of NF-κB in the presence of excess hydrogen peroxide has been shown to enhance the duration and intensity of the NF-κB activation. These alterations in the composition or quantity of the NF-κB dimer have been found to alter downstream target gene expression, contributing, in some cells, to increased expression of proinflammatory genes and a proapoptotic environment.

Regarding human studies [17],[18], it was found that there was persistent low activity of GPX1 in alcoholic patients, indicating that alcoholic patients did not scavenge free radicals as readily as controls. These results indicate excessive oxidative stress in chronic alcoholic patients and linked that to multiple morbidities in these patients.

Reviewing studies about overexpression of GPX1 [16], it was found that overexpression was protective against many apoptotic stimuli via many mechanisms including: attenuated activation of caspase 8 and caspase 3, diminished release of cytochrome c into the cytosol, modification the ratio of Bax: Bcl-2 in favour of more antiapoptotic environment, regulation of apoptogen-mediated signalling, alteration the activation of NF-κB and modulation Akt pathways.

GPX1 overexpression, however, is protective against apoptosis only in circumstances where there is a disruption in normal redox balance favouring oxidation (i.e. under conditions of oxidative stress). Thus, in some tumour cells, doxorubicin-induced apoptosis apparently does not rely on oxidant generation, as GPX1 overexpression fails to protect against apoptosis. Alternatively, the level of ROS generated in these cells may not be overcome by only overexpressing a single antioxidant enzyme, or, perhaps, the basal level of hydrogen peroxide is low such that its removal may promote apoptosis.

Given the role of hydrogen peroxide in promoting both protective and apoptotic pathways, GPX1 modulation of intracellular hydrogen peroxide flux will ultimately regulate both apoptotic and survival pathways. The net result of manipulating GPX1 expression on apoptosis will depend on levels of other intracellular antioxidant enzymes; regulation of oxidant producing enzymes, such as nitric oxide and possibly, the subcellular compartment in which ROS are produced.

Considering studies about effect of selenium level and GPX1 activity [19],[20],[21],[22],[23], studies showed that GPX1 expression is diminished by selenium deficiency in cell culture systems as well as in in-vivo studies. Importantly, these effects are not due to alterations in transcription, but have been thought to be due, in part, to nonsense-mediated mRNA decay and/or suppression of translation.

Nonsense-mediated mRNA decay is a cotranslational mechanism that recognizes premature stop codons and targets such nonsense codon transcripts for degradation. One theory is that this process occurs specifically when a UGA is in the middle of an open reading frame and at least 50 nucleotides upstream from a splice junction. The TGA codon, encoding selenium, is found in the first exon of the human GPX1 gene at amino acid 48 (of about 203 total), and it is located 105 nucleotides from the splice junction, suggesting that the GPX1 gene transcript may be susceptible to nonsense-mediated decay [21].

In animals [21],[22],[23], an insufficient selenium supply via depletion of cellular selenium stores leads to the downregulation of functional selenoproteins. In rats and mice, the liver as the main organ of selenium metabolism is most affected by dietary selenium deficiency because the organ has not only to maintain its own cellular selenoproteins but it is also liable for the synthesis of some major plasma selenoproteins like plasma selenoproteins GPX1 [22].

Selenium deficiency leads to cellular damage. Dependent on species, the tissues are affected differently by dietary selenium deficiency. In rats and mice, the liver is the main target organ of dietary selenium deficiency. In rats, multiple organ necrosis was also observed. In rabbits, selenium causes liver necrosis and muscular dystrophy [23].

Concerning GPX1 gene polymorphism, there are about 38 SNPs reported for GPX1. However, the most studied is the Pro198Leu polymorphism [dsSNP ID: rs1050450, minor allele frequency (Leu)=0.21], located at codon 198 (C>T) resulting in an amino acid variation from proline (CCC) to leucine (CTC). This amino acid substitution causes a change of the structural conformation of the active site region and modifies the enzyme activity [10]. Also, this substitution has been implicated in increased risk to many types of cancer such as breast, lung, colorectal, bladder and pathogenesis of diabetes and cardiovascular diseases [11].

In the present analysis, all studies [24],[25],[26],[27],[28],[29],[30],[31],[32] reported that Leu allele was significantly associated with liver fibrosis progression and HCC development.


  Conclusion Top


This review demonstrated that GPX1 enzyme activity is low in different liver diseases including alcoholic hepatitis, viral hepatitis, autoimmune hepatitis and cryptogenic liver cirrhosis. Also, GPX1 enzyme activity is dependent to greater extent on selenium level due to post-transcriptional and cotranslational regulation. In addition, the GPX1 Pro198Leu (rs1050450) gene polymorphism plays a major role in liver fibrosis progression and HCC development. Also, there are many factors affecting the relation between GPX1 and liver diseases. Thus, we propose more information about living habits, living environment, diet, calorie intake, antioxidant intake to identify novel polymorphisms located in potential regulatory regions of the GPX1 gene, which may modify gene expression and their association with HCC risk.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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