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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 35  |  Issue : 2  |  Page : 559-566

The Value of serum Golgi protein 73 as a biomarker for hepatocellular carcinoma


1 Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Menoufia University, Shebin Elkom, Egypt
2 Department of Hepatology, National Liver Institute, Menoufia University, Shebin Elkom, Egypt

Date of Submission29-Oct-2021
Date of Decision09-Dec-2021
Date of Acceptance12-Dec-2021
Date of Web Publication27-Jul-2022

Correspondence Address:
Hasnaa M Shibl
Department of Medical Biochemistry and Molecular Biology, Menoufia University, Shebin Elkom, 32511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_225_21

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  Abstract 


Background
Hepatocellular carcinoma (HCC) is the most common liver cancer arising from the hepatocytes. The most prevalent noninvasive biological marker for diagnosis of HCC is alpha-fetoprotein (AFP). Golgi protein 73 (GP73) was considered as an impending biological marker for the early diagnosis of HCC.
Objectives
To assess the value of GP73 in serum as a biological marker for HCC comparing its sensitivity and specificity with serum AFP.
Methods
This study included 90 participants (30 patients with hepatitis-C virus (HCV)-related HCC, 30 patients having liver cirrhosis on top of chronic HCV, and 30 healthy controls). The levels of AFP and GP73 in serum were measured by chemiluminescent immune-metric assay and enzyme-linked immunosorbent assay techniques, respectively.
Results
HCC and cirrhotic patients had considerably higher AFP (P < 0.001, <0.004) and GP73 (P < 0.001, 0.047) levels than controls, whereas HCC patients had significant higher values of AFP and GP73 than cirrhotic patients (P = 0.029, <0.001, respectively). Combined AFP + GP73 had the highest sensitivity and specificity (P < 0.001) for differentiating HCC patients from controls. In discrimination of HCC patients from cirrhotic patients, serum GP73 had the highest sensitivity and specificity (P < 0.001) than AFP (P = 0.009) and combined AFP + GP73 (P < 0.001). Moreover, in discrimination of metastatic patients from nonmetastatic ones, combined AFP + GP73 had the highest sensitivity (P < 0.001) than GP73 alone (P = 0.013), whereas AFP alone had the highest specificity (P = 0.058) than combined AFP + GP73.
Conclusion
GP73 is a reliable biological marker for early diagnosis and detection of distant metastasis of cancerous liver diseases in patients having liver cirrhosis on top of chronic HCV infection and it would yield better results when used combined with AFP.

Keywords: alpha-fetoprotein, Golgi protein 73, hepatitis-C virus, hepatocellular carcinoma, liver cirrhosis


How to cite this article:
Dawood AA, Ghanayem NM, Khamis AK, Shibl HM, Habieb MS. The Value of serum Golgi protein 73 as a biomarker for hepatocellular carcinoma. Menoufia Med J 2022;35:559-66

How to cite this URL:
Dawood AA, Ghanayem NM, Khamis AK, Shibl HM, Habieb MS. The Value of serum Golgi protein 73 as a biomarker for hepatocellular carcinoma. Menoufia Med J [serial online] 2022 [cited 2024 Mar 29];35:559-66. Available from: http://www.mmj.eg.net/text.asp?2022/35/2/559/352158




  Introduction Top


Hepatocellular carcinoma (HCC) is considered to be the sixth and fourth prevalent malignancy worldwide and in Egypt, respectively[1]. It is considered one of the most prevalent malignancies, with more than 800 000 deaths worldwide[2].

Cirrhosis is the most prevalent predisposing factor for HCC, which is produced by hepatitis-C and -B infection. Indeed, evidence shows that hepatitis-C virus (HCV) infection was found to be the cause of 25% of all HCC cases worldwide[3].

HCC has low prognosis and management choices. Diagnosis at early stages of HCC is very essential since surgical resection and/or ablation therapy are more effective when the tumor is small[4].

Alpha-fetoprotein (AFP) is considered to be one of the common extensively used HCC diagnostic indicators[5]. The fetal liver produces AFP, which is a glycoprotein specific to the fetus. Because of the low sensitivity of AFP, its use in clinical practice is limited[6], suggesting the need for new biological markers for diagnosis of HCC[7].

Golgi protein 73 (GP73) is considered a type-II transmembrane glycoprotein (400 amino acids) present in the Golgi membrane[8]. Only the epithelial cells of bile duct express GP73, whereas hepatocytes in a normal liver have low or nondetectable levels of expression. However, whatever the cause, GP73 expression by hepatocyte is significantly enhanced when livers became diseased, whereas its expression by biliary epithelial cell does not alter much[6].

GP73 levels are associated with many liver diseases such as hepatic fibrosis, liver cirrhosis, and HCC- and HBV-mediated acute on top of chronic liver failure[4] and tumor-metastasis prediction[9].

GP73 is considered to be a serum biomarker for detection of HCC[10]. However, this has been studied recently. Most of the studies revealed that serum GP73 is raised in HCC patients who have cirrhosis, but in those who do not have cirrhosis, it remained constant[11].

The purpose of this work was to assess the value of GP73 in the serum as a biological marker for HCC comparing its sensitivity and specificity with serum AFP.


  Methods Top


A written consent was taken from every participant participated in this research and this work was accepted by Ethical Committee of Medical Research, Faculty of Medicine, Menoufia University (no: BIO-10-2019).

The study was done on 90 participants, classified into three groups: group I involved 30 patients having HCV-related HCC and group II involved 30 patients having liver cirrhosis on top of chronic HCV. The patients were attendants of the outpatient clinic, hepatology inpatient department, National Liver Institute, Menoufia University, during the period from November 2019 to December 2020. Group III involved 30 of age- and sex-matched apparently healthy individuals. Eligibility criteria were patients older than 18 years and confirmed HCV infection by anti-HCV detection. Patients with positive hepatitis-B surface antigen (HBsAg), secondary liver disease, cirrhosis due to other causes other than HCV infection (e.g., nonalcoholic steatohepatitis-induced cirrhosis and cryptogenic cirrhosis), previous HCC chemotherapy or radiotherapy, Eastern Cooperative Oncology Group (ECOG) 3 and 4 and life expectancy less than 6 months, other malignant neoplasms, severe infectious diseases, or significant comorbidities (renal failure, liver failure, or heart failure) were exempted from this study.

The following was done to all members: full history taking, general clinical examination with assessment of performance status according to ECOG Performance Status. Body mass index (BMI) was measured by dividing body weight (kg) by height squared (meters). The diagnosis of cirrhosis was built on history, clinical examination, laboratory results, and imaging criteria (ultrasonography and computed tomography). HCC cases were diagnosed by triphasic spiral computed tomography and/or magnetic resonance imaging with characteristic HCC features together with elevated AFP and liver biopsy if available. HCC staging was achieved according to Barcelona Clinic Liver Cancer staging system (BCLC). Child–Pugh score was used to assess the severity of the liver disease.

Sample collection: 10 ml of venous blood was taken by venipuncture under fully aseptic circumstances and was distributed into three different tubes. About 2 ml were collected into tubes that contained EDTA for CBC measurement, 2 ml were placed in citrated tube for measurement of prothrombin-time percent, and the remaining 6 ml were put in a plain test tube, left to stand at room temperature for 15 min to clot. Serum was then separated after centrifugation of blood at 4000 r.p.m for 10 min. The serum obtained was kept at −20°C until used for measurement of liver-function tests (albumin, total bilirubin, direct bilirubin, alanine aminotransaminase [ALT], and aspartate aminotransaminase [AST]), viral markers, AFP, and GP73. CBC was measured with Pentra–80 automated blood counters (ABX – France – Rue du Caducee-Paris Euromedecine-BP-7290.34184 Montpellier-Cedex 4). Prothrombin time was measured by ATLAS MEDICAL Prothrombin Time (PT), Germany (Liquid Reagent)[12]. Liver-function tests (ALT, AST, serum albumin, and serum bilirubin) were carried out using the Beckman Coulter (Synchron CX 9 ALX) Clinical Autoanalyzer, USA (Diamond Diagnostics Kit, Holliston, Massachusetts 01746, US).

Serum HBsAg and serum HCV antibody were determined by electrochemiluminescence immunoassay 'ECLA', using Cobas immunoassay analyzer (Roche Diagnostic, Germany)[13],[14].

Measurement of AFP was achieved by IMMULITE 1000 system by a kit supplied by Siemens (Siemens Medical Solutions Diagnostics, Germany)[15].

Measurement of serum level of GP73 was attained by a quantitative sandwich enzyme immunoassay technique (enzyme-linked immunosorbent assay) using a commercially available kit (SunLong Biotech Co. Ltd, China; Catalogue Number: SL0795Hu)[16].

Statistical analysis

The collected data were put in tables and analyzed by SPSS (Statistical Package for Social Science) version 20 on IBM-compatible computer (IBM Corp., Armonk, NY). Numerical data were stated as mean ± SD (X¯±SD) if normally distributed, or median (interquartile range) if not normally distributed and analyzed by applying Analysis of variance ANOVA test when more than two groups of equally distributed variables were compared. Kruskal–Wallis test was applied to compare between more than two groups that were not equally distributed variables. Mann–Whitney test was applied for abnormally distributed numerical variables, to compare between two studied groups. Qualitative data were stated as number and percentage (No and %) and assessed by applying χ2 test, and if more than 20% of the cells have expected count less than 5, Monte Carlo correction was applied. Sensitivity and specificity at various cutoffs were calculated using receiver-operator characteristic curve analysis. The optimal cutoff was determined at the value where the sensitivity and the specificity were maximal. The statistical significant difference was established at P value of less than 0.05.


  Results Top


A significant statistical difference existed between the HCC group and cirrhosis group regarding sex (P = 0.020), whereas sex does not differ significantly between each of the HCC group and cirrhosis group when compared with the controls (P = 0.254, 0.371, respectively). In terms of age and BMI, there was not a significant statistical difference among the three tested groups (P = 0.082, P = 0.849, respectively). There were highly significant statistical variances between HCC patients and cirrhotic patients as compared with the controls regarding ALT (P < 0.001, =0.002), AST (P < 0.001, <0.001), platelet count (P < 0.001, <0.001), serum albumin (P < 0.001, =0.010), total bilirubin (P < 0.001, <0.001), PT (P < 0.001, <0.001), and direct bilirubin (P = 0.011, =0.011), whereas there was nonsignificant statistical variance between HCC patients and cirrhotic patients regarding the same parameters (P = 0.376, 0.649, 0.731, 0.428, 0.703, 0.913, and 0.998, respectively). HCC patients and patients having cirrhosis had significantly lower values of serum albumin and platelet count and higher total bilirubin, direct bilirubin, serum AST, serum ALT, and PT than the controls. There was nonsignificant statistical difference among the three tested groups concerning hemoglobin and white blood cells (P = 0.206, P = 0.187, respectively). There was a significant statistical increase of AFP (P < 0.001, <0.004) and GP73 (P < 0.001, 0.047) values in HCC patients and cirrhotic patients as compared with the controls and HCC patients compared with cirrhotic patients (P = 0.029, <0.001, respectively) [Table 1].
Table 1: Statistical comparison among the three tested groups according to demographic data and laboratory findings

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There was a significant statistical association between increased serum levels of AFP in HCC patients and vascular invasion (P = 0.009), tumor number (P = 0.025), and tumor size (P = 0.029), whereas there was a nonsignificant statistical difference regarding lymph node (LN) metastasis (P = 0.432), distant metastasis (P = 0.057), tumor site (P = 0.247), tumor-node metastasis (TNM) staging (P = 0.219), BCLC staging (P = 0.057), and Child–Pugh class (P = 0.057) [Table 2].
Table 2: Relation between AFP and clinical data in the HCC group (n=30)

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A significant statistical association existed between increased serum level of GP73 in HCC patients and each of vascular invasion (P = 0.011), distant metastasis (P = 0.011), TNM staging (P = 0.018), BCLC (P = 0.011), and Child–Pugh class (P = 0.034), whereas a nonsignificant statistical difference existed regarding LN metastasis (P = 0.104), tumor number (P = 0.413), tumor size (P = 0.207), and tumor site (P = 0.322) [Table 3].
Table 3: Relation between GP73 and clinical data in HCC group (n=30)

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Combined AFP + GP73 had the highest sensitivity (96.67%) and specificity (93.33%) for differentiating HCC patients from controls [Figure 1]a. To discriminate HCC patients from cirrhotic patients, serum GP73 had the highest sensitivity (90.0%) and specificity (63.33%) than AFP (80.0% and 56.67%, respectively) and combined AFP + GP73 (90.0% and 50.0%, respectively) [Figure 1]b. To discriminate metastatic from nonmetastatic patients, combined AFP + GP73 had the highest sensitivity (81.82%) than GP73 alone (72.73%), whereas AFP alone had the highest specificity (94.74%) than combined AFP + GP73 (84.21%) [Figure 1]c and [Table 4].
Figure 1: 1 Agreement (sensitivity and specificity) of alpha-fetoprotein (AFP) and Golgi protein 73 (GP73) in the diagnosis of hepatocellular carcinoma (HCC) patients. (a) Receiver-operator characteristic (ROC) curve for AFP (ng/ml), GP73 (ng/ml), and AFP plus GP73 to diagnose HCC patients (n=30) from controls (n=30). (b) ROC curve for AFP (ng/ml), GP73 (ng/ml), and AFP plus GP73 to differentiate HCC patients (n=30) from cirrhosis patients (n=30). (c) ROC curve for AFP (ng/ml), GP73 (ng/ml), and AFP plus GP73 to predict metastatic (n=11) vs. nonmetastatic patients (n=19).

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Table 4: Validity (AUC, sensitivity, and specificity) of AFP and GP73 to discriminate patients from controls

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  Discussion Top


HCC is often detected by ultrasonography and AFP. Despite that AFP has high specificity, its sensitivity is low[15]. Thus, there is a necessary need for developing novel biological markers for HCC with better diagnostic performance[17]. One of them is GP73[18]. It is an oncoprotein that promotes the cancerous change of primary cell lines, tumor development, migration, and metastasis[19].

This study found that cirrhotic and HCC patients exhibited considerably greater serum levels of AFP than the controls. Furthermore, HCC patients had considerably higher AFP levels than cirrhosis patients. These results were in accordance with Ali et al.[10] and Ebrahim et al.[20].

Abou Ammo et al.[21] explained the rise of AFP in HCC patients by an increase in selective transcriptional activation in AFP gene in the malignant hepatocytes.

Currently, this study displayed that HCC patients had a statistically significant rise in serum level of GP73 levels when compared with the cirrhotic patients and the controls. This agreed with Ali et al.[10].

The increased serum levels of GP73 expression found in HCC can be due to abnormal fucosylation of GP73 core by α1,6-fucosyltransferase enzyme, which is elevated in HCC[22].

In contrast, some previous studies showed contradictory results. Liu et al.[23] verified that GP73 was raised in cirrhotic HCC patients, but not in patients who did not have cirrhosis, suggesting that the underlying cirrhosis, not HCC per se, was the cause of GP73 upregulation.

Concerning the correlation between AFP and the clinical characteristics of HCC patients, this study revealed significant higher values of serum AFP in the attendance of vascular invasion, multiple tumors, and tumor size > 5 cm. However, AFP did not significantly differ as regards the occurrence of lymph-node metastasis, distant metastasis, tumor site, TNM staging, BCLC staging, and Child–Pugh score. This matched with the results reported by Liu et al.[24].

Concerning the relationship of GP73 with the clinical characteristics of HCC patients, the existing study demonstrated significantly high values of serum GP73 in HCC patients having vascular invasion, distant metastasis, advanced TNM stages (stage IV), advanced BCLC (C) class, and Child–Pugh score (C).

Consistently, Dong et al.[25] verified that the raised levels of serum GP73 were associated with vascular invasion and distant metastasis.

Sai et al.[24] found higher detection rates of GP73 in HCC patients having advanced TNM stages (stage III/IV vs. stage I/II).

Currently, the significant statistical increase of GP73 level in stage C as paralleled to stage B of BCLC staging of HCC patients was consistent with what has been found by Khalil et al.[11].

Jiao et al.[26] found a significant association between GP73 level and Child–Pugh score in HCC patients.

The existing study confirmed that the accuracy of AFP in the diagnosis of HCC was relatively low. This matched with Ali et al.[10].

Notably, the existing study proved that the GP73 had a better accuracy in HCC diagnosis than AFP. This was in agreement with Hasan et al.[3].

Because HCC is under a various class of diseases and it is unlikely for one biological marker to diagnose HCC with high specificity and sensitivity, Mao et al.[27] suggested that GP73 plus AFP would possibly improve the sensitivity and specificity in the discovery of HCC.

In the existing study, we showed that AFP plus GP73 yielded the best sensitivity and a specificity for the discernment between HCC and each of controls and cirrhotic patients. This agreed with the studies of Ali et al.[10], Jiao et al.[26], and Mao et al.[27].

In contrast, Gatselis et al.[28] showed that GP73 plus AFP did not enhance the accuracy of the diagnosis for detecting HCC in the total population.

On an attempt to study the potential utility of serum GP73 in differentiating metastatic patients from nonmetastatic ones, the existing study revealed that GP73 was greater than AFP in spotting distant metastasis in HCC, whereas the utility of AFP plus GP73 yielded the best results.

It was documented that GP73 drives HCC metastasis through activation of epidermal growth-factor receptor/receptor tyrosine-kinase signaling[29], so potentially it may be used as a metastatic biomarker.


  Conclusion Top


GP73 may be considered as a noninvasive biological marker in the diagnosis of HCC and has better sensitivity than AFP in HCC detection. It may be used as a relevant biological marker for the diagnosis at early stages and for finding of cancerous liver lesions in cirrhosis patients owing to chronic HCV infection. Moreover, AFP plus GP73 in the diagnosis of HCC has improved the diagnostic performance better than using each biomarker alone. GP73 may be used as a reliable marker in detection of distant metastasis in HCC.

The Value of serum Golgi protein 73 as a biomarker for hepatocellular carcinoma.

Authors' contribution: All authors should have made substantial contributions to all of the following: Ahmed K. Khamis, paper review; Ashraf A. Dawood, conception and design and paper review; Hasnaa M. Shibl, data acquisition and paper preparation; Mona S. Habieb, Paper editing and statistical analysis; Naglaa M. Ghanayem, data analysis and interpretation.

All authors have approved the final article.

I confirm that all the named authors have agreed to the submission of the paper and have participated in the study to a sufficient extent to be named as authors.

List of abbreviations: AFP, alpha-fetoprotein; ALT, alanine aminotransaminase; AST, aspartate aminotransaminase; BCLC, Barcelona Clinic Liver Cancer; BMI, body mass index; CBC, complete blood count; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth-factor receptor; ELISA, enzyme-linked immunosorbent assay; GP73, Golgi protein 73; Hb, hemoglobin; HBsAg, hepatitis-B surface antigen; HBV, hepatitis-B virus; HCC, hepatocellular carcinoma; HCV, hepatitis-C virus; LN, lymph node; NASH, nonalcoholic steatohepatitis; PT, prothrombin time; RTK, receptor tyrosine kinase; TNM, tumor-node metastasis; WBCs, white-blood cells.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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