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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 30  |  Issue : 3  |  Page : 693-699

Serum peroxiredoxin-3 as a useful biomarker for detection of hepatocellular carcinoma


1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Hepatology, National liver Institute, Menoufia University, Menoufia, Egypt
3 Department of Biochemistry, Faculty of Medicine, Menoufia University, Menoufia, Egypt
4 Cairo Fatemic Hospital, Cairo, Egypt

Date of Submission09-Aug-2016
Date of Acceptance23-Oct-2016
Date of Web Publication15-Nov-2017

Correspondence Address:
Mohamed H. S. Al-Karafy
Cairo, 11511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.218277

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  Abstract 

Objective
The aim of this study is to evaluate serum peroxiredoxin-3 (PRDX3) as a noninvasive serum marker for the diagnosis of hepatocellular carcinoma (HCC).
Background
Early diagnosis of HCC is the most important step in successful treatment. However, it is usually rare because of the lack of a highly sensitive and specific biomarker so that the HCC is usually fatal within a few months after diagnosis. PRDX3 is a c-Myc target gene that is required for mitochondrial homeostasis and neoplastic transformation. In our study, we attempted to evaluate the value of PRDX3 as a useful serum biomarker for the detection of HCC.
Patients and methods
PRDX3, α-fetoprotein (AFP), and other biochemical parameters were measured in serum samples from 50 patients. They were subdivided into three groups: 20 patients with cirrhosis and HCC (group I), 20 patients with liver cirrhosis (LC) without HCC (group II), and 10 healthy controls (group III). Correlations between serum PRDX3 expression and clinicopathological variables were analyzed.
Results
Serum PRDX3 was significantly higher in HCC patients than in the LC and healthy control groups. The sensitivity and specificity of serum PRDX3 for the diagnosis of HCC were 84.2 and 79.8%, respectively, at a cutoff of 162 ng/ml and the area under the curve was 0.877 compared with that of AFP (0.721) with a sensitivity of 70.1% and a specificity of 60%. Moreover, serum PRDX3 expression was strongly associated with AFP levels and focal lesion size.
Conclusion
Serum PRDX3 level, at a cutoff value of 162 ng/ml, could be a valuable marker for the detection of HCC in patients with LC.

Keywords: α-fetoprotein, biomarker, hepatocellular carcinoma, peroxiredoxin-3


How to cite this article:
Al-Atty EA, Al-Azab GI, Al-Hamid AE, Alghobashy YA, Al-Karafy MH. Serum peroxiredoxin-3 as a useful biomarker for detection of hepatocellular carcinoma. Menoufia Med J 2017;30:693-9

How to cite this URL:
Al-Atty EA, Al-Azab GI, Al-Hamid AE, Alghobashy YA, Al-Karafy MH. Serum peroxiredoxin-3 as a useful biomarker for detection of hepatocellular carcinoma. Menoufia Med J [serial online] 2017 [cited 2020 Jun 6];30:693-9. Available from: http://www.mmj.eg.net/text.asp?2017/30/3/693/218277


  Introduction Top


Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer; the mortality rates of patients with HCC remain very high (up to 94%), making HCC the third leading cause of cancer-related death worldwide [1],[2]. Late detection in addition to lack of effective therapies for advanced stages of the disease may be responsible for this high mortality rate [3].

Currently, abdominal ultrasound and serum α-fetoprotein (AFP) are the most widely used methods for HCC detection. However, this does not reliably detect disease in the early stage [4]. This could be because of the fact that ultrasonography is highly dependent on the experience of the operator [5]. Elevated AFP is the result of an altered hepatocyte–hepatocyte interface associated with loss of normal architectural arrangement rather than necrosis or active regeneration [6].

Diagnostic imaging modalities such as triphasic computed tomography (CT) and MRI are considered the gold standard for the definitive diagnosis of HCC [7]. The efficacy of CT is markedly decreased in small tumors (<2 cm) because of the hypovascularization of these small-sized tumors [8].

Therefore, it is critical to identify and characterize sensitive and specific diagnostic biomarkers for early detection and treatment of HCC in high-risk populations [9],[10].

The majority of studies have shown that the progression of HCC is closely correlated to oxidative stress [11]. Cancer cells usually show changes in key mitochondrial regulators of cell death or mitochondrial structure and function, which are different from those of normal cells. This enables them to use antioxidant systems to maintain the redox balance under high levels of oxidative stress [12].

Classical antioxidant genes related to cancer include superoxide dismutase, catalase, glutathione peroxidase, peroxiredoxins, and thioredoxin [13],[14].

Peroxiredoxin-3 (PRDX3) was identified as a member of the peroxiredoxin protein family, which acts as a cellular defense system against oxidative stress and plays an important roles in peroxide detoxification, and belongs to a family of thiol-specific antioxidant enzymes whose catalytic activity and protein sequences are different from those of other antioxidants [15].

Overexpression of PRDX3 has been reported in mesothelioma, HCC, breast cancer, and ovarian cancer, suggesting that it may be involved in tumorigenesis and cancer progression [16]. Abundant evidence has also confirmed that tissue-specific expression of PRDX3 plays an important role in hepatocarcinoma progression [17].


  Patients and Methods Top


Study design

This is a case–control cross sectional study carried out to verify the reliability of serum PRDX3 as a useful biomarker for the detection of HCC. This study was carried out at the Internal Medicine Department, Menoufia University, and the Hepatology Department of the National Liver Institute, Menoufia University, Egypt. The work was carried out between August 2014 and August 2015.

Patient population

This study was carried on 50 patients. The patients were classified into two groups: group I (HCC) included 20 patients with cirrhosis and HCC and group II [liver cirrhosis (LC)] included 20 patients with LC without HCC. The control group (group 3) included 10 healthy controls (HCs).

Inclusion criteria:patients with LC ± HCC were included. Patients were selected according to the symptoms and signs of LC on the basis of a clinical examination and ultrasonographic criteria suggestive of LC.

Exclusion criteria:patients with hepatic tumors other than HCC were excluded.

After the approval of the local ethical committee of Menoufia University was obtained, a written informed consent was obtained from all patients before participation in the study.

All patients were subjected to the following:

  • Full assessment of medical history including age and sex, history of viral hepatitis, or exposure to high-risk factors (parenteral antibilhazrial therapy, blood transfusion, previous operations), history of schistosomiasis or exposure to canal water, history of upper gastrointestinal bleeding, history suggestive of liver cell failure, history of other medical disorders (hypertension, diabetes mellitus), history of special habits (smoking, alcohol), history of newly discovered right hypochondrial pain, and/or significant weight loss
  • Thorough clinical examination and abdominal examination, with a special focus on signs of liver cell failure
  • Laboratory investigations that included liver function tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total and direct bilirubin, serum albumin, prothrombin time and international randomization ratio (INR)]. Hepatitis C virus antibody, and HBsAg by enzyme-linked immunosorbent assay. Positive cases were confirmed by quantitative PCR. Determination of serum AFP levels, complete blood picture, renal function tests (blood urea, serum creatinine), and determination of serum PRDX3 levels were also performed
  • Imaging Techniques including abdominal ultrasonography, with a special focus on criteria suggestive of chronic liver disease, any focal lesion (site, size and number). and the presence of ascites. Triphasic spiral CT was performed for all patients with ultrasonographically detected hepatic focal lesion(s)
  • Serum PRDX3 was measured using a commercially available enzyme-linked immunosorbent assay kit (BioVender research and Diagnostic Products, USA, Canada, and Mexico, BioVendor - Laboratory Medicine Inc., Karasek, Brno, Czech Republic).


Peripheral venous blood samples were obtained from all patients and controls under complete aseptic conditions; the samples were collected into sterile tubes without an additive and centrifuged at 1000g for 15 min at room temperature to obtain serum. Supernatants were transferred into eppendorf tubes and aliquoted, frozen, and stored at (−80°C) until a biochemical examination was performed.

Statistical analysis

Data were analyzed using the statistical program for social science, version 20.0 (SPSS, Chicago, USA). Quantitative data were expressed as mean ± SD. Qualitative data were expressed as frequency and percentage.

The following tests were performed: independent-samples t-test of significance was used when comparing between two means and a one-way analysis of variance when comparing between more than two means. The post-hoc test was used for multiple comparisons between different variables. The χ2-test of significance was used to compare proportions between two qualitative parameters. Pearson's correlation coefficient (r) test was used for correlating data. Receiver operating characteristic curve analysis was used to determine the overall predictivity of parameters and to determine the best cutoff value with detection of sensitivity and specificity at this cutoff value. P value less than or equal to 0.05 was considered significant, P value less than or equal to 0.001 was considered highly significant, and P value more than 0.05 was considered insignificant. Receiver operating characteristic curve analysis was carried out to validate the diagnostic value of serum PRDX3 compared with serum AFP to identify the optimal cutoff values, sensitivity, specificity, and positive and negative predictive values (PPV and NPVs) of PRDX3 and AFP.


  Results Top


There was no statistically significant difference between the patient groups (I and II) and the control group (III) in age. In terms of sex distribution, there were more men in group I (HCC), but without a statistically significant difference [Table 1].
Table 1: Comparison between study groups in age (years) and sex

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In terms of the etiology of LC including HCV and HBV, there was no statistically significant difference between the study groups, but there was HCV predominance; however, this was not statistically significant [Table 2].
Table 2: Comparison between groups in etiology

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There was no statistically significant difference between groups in comorbidity factors including diabetes mellitus, hypertension, bilharziasis, and smoking.

In terms of complain among groups (I and II), there was a significant difference between groups I and II in right hypochondrial pain and weight loss was more frequent among patients of group I (HCC), whereas easy fatigability and right hypochondrial tenderness were more frequent among patients of group II (LC).

AFP was significantly higher in group I (HCC) than in group II (LC) and the control group (III), with no significant difference between (LC) group II and the control group (III) [Table 3].
Table 3: Comparison between groups of AFP serum levels

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PRDX3 serum level was highly significant in group I (HCC) than in group II (LC) and control group (III), and significantly high in group II (LC) than the control group III (HCs) [Table 4] and [Figure 1].
Table 4: Comparison between groups of serum levels of PRDX3

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Figure 1: Comparison between groups of PRDX3 serum levels. HC, healthy control; HCC, hepatocellular carcinoma; PRDX3, peroxiredoxin-3; LC, liver cirrhosis.

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Total bilirubin, AST, ALT, and INR were significantly higher in group I (HCC) and group II (LC) than in the control group (III), whereas serum albumin was significantly lower in group I (HCC) and group II (LC) than in the control group (III) [Table 5].
Table 5: Comparison between groups of liver function

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Also, the hemoglobin level was lower in group I (HCC) than the control group III (HCs). The platelet count was significantly low in group I (HCC) and group II (LC) than the control group (III), with no difference between study groups in the white blood cell count and serum creatinine level.

In terms of ultrasonographic findings, there were no significant differences between groups I and II in the size of the liver and spleen, or portal vein diameter. However, portal vein thrombosis was present more frequently among the patients in group I (HCC) than group II (LC).

According to the finding of the CT, most of the focal lesions in group I (HCC) were single, with a mean size of 5.67 cm, and were more frequent in the right lobe.

There was a positive significant correlation between PRDX3 and AFP, and the size of focal lesion in group I (HCC) [Table 6] and [Figure 2], and also a positive significant correlation between PRDX3 and AFP in group II (LC).
Table 6: Correlation between PRDX3 and other parameters in group I (HCC)

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Figure 2: Correlation between PRDX3 and α-fetoprotein in group I (HCC). FL, focal lesion; HCC, hepatocellular carcinoma.

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Serum PRDX3 at a cutoff value of 162 ng/ml had a higher area under the curve (AUC) (0.877) compared with that of AFP (0.721) with a sensitivity and a specificity of 84.2 and 79.8%, respectively. The PPV and NPV for PRDX3 were 82 and 83.8%, respectively, compared with that of AFP 65 and 70%, respectively [Table 7] and [Figure 3].
Table 7: Diagnostic performance of PRDX3 and AFP in the diagnosis of the HCC group from the non-HCC group

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Figure 3: Receiver operating characteristic curve for the diagnostic sensitivities and specificities of PRDX3 and AFP for differentiating the HCC group from the non-HCC group. AFP, α-fetoprotein; HCC, hepatocellular carcinoma; PRDX3, peroxiredoxin-3.

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The combined sensitivity and specificity of PRDX3 and AFP were 90 and 84%, respectively, with a diagnostic accuracy of 91.2%.


  Discussion Top


HCC is the fifth most prevalent cancer, and the third leading cause of cancer-related death worldwide [1],[2]. HCC develops against a background of chronic liver disease, such as chronic inflammation or cirrhosis [18]. The incidence and mortality rates for HCC are almost identical, indicating the overall poor survival of patients with this tumor. Therefore, the most effective treatment relies on the early diagnosis of HCC [19]. The early detection of HCC is usually rare, making it fatal within a few months after diagnosis. Most imaging techniques help to discover HCC after a considerable time of onset. In most instances, oncologists depend on AFP as the most common and feasible marker for assessing HCC in addition to imaging. AFP is not a completely reliable marker in early HCC diagnosis, prevention, or therapy because of its low specificity and sensitivity [20]. Therefore, the use of AFP as a primary screening test for HCC has been questioned; hence, more sensitive and specific serum biomarkers for HCC are required [21].

Liver biopsy is an invasive procedure; thus, biochemical findings are still greatly appreciated [22].

Egypt is considered nowadays to be one of the hot spots in the international map of HCC. Obviously, there are several local factors contributing toward presenting HCC that differ from the internationally known factors for the same disease. Hepatitis C virus infection is a major risk factor in the development of HCC [23].

Both pathologically and clinically, HCC is a heterogeneous cancer with a poor prognosis and very high mortality. Hepatic tumor biomarkers should ideally have both high specificity and sensitivity, especially in the context of distinguishing HCC from LC. Moreover, an ideal biomarker should be easily accessible and quantifiable, and procedures for measuring a biomarker should be minimally invasive, inexpensive, accurate, and acceptable to both the patient and the physician. Although a variety of proteins and other characteristics associated with a type of cancer including DNA methylation, circulating tumor cells, and histone modifications have attracted the attention of researchers for early diagnosis and prognosis of HCC, the availability of clinically applicable biomarkers remains limited [24],[25],[26].

PRDX3 is a c-Myc target gene that is required for mitochondrial homeostasis and neoplastic transformation and predominantly localizes in the mitochondria [27]. Moreover, PRDX3 might serve as a first line of host defense against reactive oxygen species and in protecting cells from H2O2-induced apoptosis [13].

In our study, we attempted to evaluate the value of peroxiredoxins PRDX3 as a useful serum biomarker for the detection of HCC.

This study was carried out on 40 cirrhotic patients divided into two groups: group I, which included 20 patients with HCC, and group II, which included 20 cirrhotic patients without HCC; In addition, 10 HCs (group III) were also recruited.

In the present study, the age of the HCC patients ranged from 45 to 63 years. This finding is in agreement with the median age of HCC patients reported in high-incidence areas in which HCC is reported to develop in the fifth decade of life by El-Serag and Kanwal [28]. Also, Velazquez et al. [29] found that cirrhotic patients older than 54 years have a four-fold higher risk of developing HCC, whereas patients older than 60 years were at an 11-fold higher risk of developing HCC. This finding can be explained by the longer durations of LC in older age groups.

The current study showed male predominance for LC (55%). The same finding was obtained by El-Serag and Rudolph [30], who reported that LC was more common in men than women, and this finding can be explained by the fact that men are more likely to be infected with HCV and HBV.

In the present study, males constituted the higher percentage of cases of HCC (75%). This finding is in agreement with Yang and Roberts [31], who reported that the risk of HCC is three times higher in men than in women; the same finding was also reported by El-Zayadi et al. [32]. Although this ratio varies across the world, the explanation for this sex difference might be three-fold: first, men could have higher rates of environmental exposure to liver carcinogens (such as smoking or alcohol) and hepatitis virus infections; second, the effects of estrogen might suppress interleukin-6-mediated inflammation in women, reducing both liver injury and compensatory proliferation; and third, the effects of testosterone could increase androgen receptor signaling in men, promoting liver cell proliferation [33].

The present study found a significant increase in bilirubin, AST, ALT, and INR levels in patients with HCC. This was in consistent with Gebo et al. [34], who reported higher serum levels of ALT, AST, and bilirubin among patients with HCC. Also, the values of serum albumin were decreased. These findings are in agreement with the result of Gebo et al. [34], who found that all the synthetic and excretory functions of the liver were reduced in patients with LC.

We found AFP to be significantly increased in the HCC group in relation to the other two groups (P < 0.05). This is in agreement with Nagaoka et al. [35], who found that the mean plasma concentration of AFP was significantly higher in patients with HCC compared with patients with chronic liver disease.

We found PRDX3 to be significantly elevated in the HCC groups in relation to the other groups. Moreover, at a cutoff value of 162 ng/ml, serum PRDX3 showed a higher AUC of 0.877 with a sensitivity of 84.2%, a specificity of 79.8%, a PPV of 82%, and an NPV of 83.8% compared with AUC of AFP (0.721) with a sensitivity of 70.1%, a specificity of 60%, a PPV of 65%, and an NPV of 70%.

The combined use of PRDX3 and AFP increased the sensitivity to 90% and the specificity to 84%, with a diagnostic accuracy of 91.2%.

Our findings were in agreement with those of Shi et al. [36], who found serum PRDX3 to be significantly higher in HCC patients than in the patients with LC and HCs. They concluded that the sensitivity and specificity of serum PRDX3 for the diagnosis of HCC were 85.9 and 75.3%, respectively. Serum PRDX3 can be used as a noninvasive biomarker for the diagnosis and/or prognosis of HCC.

Analyses showed that the levels of serum PRDX3 were significantly associated with AFP levels and focal lesion size; this is in agreement with Shi et al. [36], who found that the levels of serum PRDX3 were significantly associated with AFP levels, tumor diameter, TNM stage, and portal vein invasion. HCC patients with tumor diameters of 3 cm or greater, TNM stages III or IV, high AFP serum levels, and evidence of portal vein invasion had higher PRDX3 expression levels than other patients. Moreover, Ismail et al. [37] reported a significantly positive correlation between PRDX3 and the size of HCC mass, but not between AFP and PRDX3.

An increase in PRDX3 in the LC group than in the control group was noted; the same finding was obtained by Shi et al. [36], who reported that as LC is a major risk factor for HCC, it may be that elevated serum PRDX3 is a feature of liver injury.


  Conclusion Top


Serum PRDX3 level is elevated in HCC. At a cutoff value of 162 ng/ml, it could be a valuable marker for the detection of HCC in patients with LC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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