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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 6  |  Page : 1239-1244

Clinical significance and expression of serum Golgi protein 73 in primary hepatocellular carcinoma


1 Department of Public Health, Qingdao University Medical College, Qingdao, China
2 Department of Oncology, Affiliated Hospital of Qingdao University Medical College, Qingdao, China

Date of Web Publication28-Nov-2018

Correspondence Address:
Lianhua Cui
Department of Public Health, Qingdao University Medical College, 38 Dengzhou Road, Qingdao 266021
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.199784

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 > Abstract 


Background: Golgi protein 73 (GP73) is a potential serum marker for the diagnosis of hepatocellular carcinoma (HCC). However, the diagnostic value of GP73 for HCC remains controversy, and little is known about the relationship between serum GP73 concentration and clinical characteristics of HCC. This study was designed to analyze the clinical values of GP73 in diagnosing HCC and the relationship between GP73 level and clinical characteristics in HCC patients.
Materials and Methods: In this study, a total of 443 serum samples including 180 patients with HCC, 61 patients with liver cirrhosis (LC), 99 chronic hepatitis patients, and 103 healthy individuals were enrolled from November 2011 to April 2013. Enzyme-linked immunosorbent assay and chemiluminescent immunoassay were used to detect the serum level of GP73 and other biomarkers.
Results: GP73 level in HCC group was significantly higher than LC group, chronic hepatitis B group, and healthy control group. In HCC group, GP73 level significantly increased in patients with lymphatic metastasis; moreover, GP73 level in Child–Pugh Class B and C groups was statistically significantly higher than that in Child–Pugh Class A group (P < 0.05). The area under the receiver operating characteristic (AUROC) curve of GP73 and alpha-fetoprotein (AFP) was 0.840 and 0.718, respectively, when diagnosing HCC. Moreover, the AUROC curve by use of the combination of GP73 and AFP was 0.903. The differences among these three aspects were statistically significant (P < 0.05).
Conclusion: GP73 was better than AFP for the diagnosis of HCC, and the expression of serum GP73 is related with the clinical characteristics of HCC patients.

Keywords: Early diagnosis, Golgi protein 73, hepatocellular carcinoma, liver diseases, tumor markers


How to cite this article:
Jiao C, Cui L, Piao J, Qi Y, Yu Z. Clinical significance and expression of serum Golgi protein 73 in primary hepatocellular carcinoma. J Can Res Ther 2018;14:1239-44

How to cite this URL:
Jiao C, Cui L, Piao J, Qi Y, Yu Z. Clinical significance and expression of serum Golgi protein 73 in primary hepatocellular carcinoma. J Can Res Ther [serial online] 2018 [cited 2022 Dec 3];14:1239-44. Available from: https://www.cancerjournal.net/text.asp?2018/14/6/1239/199784




 > Introduction Top


Primary hepatocellular carcinoma (HCC) is one of the most common malignant tumors, and it is the third most common cause of cancer-related mortality.[1] HCC are highly heterogeneous in nature; early diagnosis and early surgical extraction are imperative for improving the survival of HCC patients.[2] A combination of alpha-fetoprotein (AFP) testing and certain liver enzymes in serum, physical assessments, and imaging technologies (e.g., ultrasound or computed tomography) is widely used in the diagnosis of HCC.[3] However, AFP has relatively poor sensitivity and specificity as a surveillance test, particularly during the early disease stages.[4],[5] The ultrasonics is a much better surveillance tool than AFP. However, ultrasonics surveillance for HCC requires specific training to acquire the degree of expertise to enable efficient use of the diagnostic capabilities of the modern equipment, which restrict its wide application for screening and early diagnosis of HCC. Therefore, there is an urgent need to develop more sensitive and specific serum markers for the early detection of HCC in the at-risk population.

A number of candidate biomarkers have recently been suggested as new serum tumor markers for HCC screening.[6],[7] One of the useful biomarkers for HCC is Golgi protein 73 (GP73) which is a Type II Golgi membrane protein and contains a transmembrane domain, a short N-terminal cytoplasmic domain, and a larger luminal C-terminal domain which is the major functional domain of GP73.[8],[9] In 2000, Kladney et al.[8] first isolated GP73 in a genetic screen and showed that GP73 expression occurs in the liver tissue cell lines of hepatitis and cirrhosis patients, but not in normal liver cells by in vitro experiments. Subsequently, they also demonstrated that GP73 expression is strikingly increased in Hep3B cells following infection with adenovirus.[10] Then, several studies suggested that GP73 protein and messenger RNAs (mRNAs) were increased in serum and liver tissue of patients with various acute and chronic liver diseases.[11],[12] The correlation between serum GP73 levels and a diagnosis of HCC in people has been confirmed recently.[13],[14] And, it may be elevated even when small undetectable tumors are present.[15] Moreover, a recent meta-analysis also indicated that GP73 level was superior to AFP level for the early diagnosis and screening of HCC.[16] In recent years, many investigations showed that GP73 is related to hepatic impairment and chronic fibrosis and might be a useful single marker for diagnosing significant fibrosis and cirrhosis in patients with chronic hepatitis B virus (HBV) infections,[14],[17] which indicates that GP73 expression is correlated with liver injury.

However, the sensitivity and specificity of GP73 in the diagnosis of HCC diagnostic have large differences[18],[19] and lack information on the relationship between serum GP73 concentration and clinical characteristics of HCC. In this study, we collected relatively large objects and used a more mature enzyme-linked immunosorbent assay (ELISA) to detect GP73 expression levels in serum of four groups (HCC, cirrhosis, hepatitis, and control), and further explored the relationship between GP73 level and clinical characteristics in HCC patients.


 > Materials and Methods Top


Patients

All the patients including 180 patients with HCC, 61 patients with liver cirrhosis (LC), 99 chronic hepatitis patients, and 103 healthy individuals were enrolled in the study from November 2011 to April 2013. Written informed consent was obtained from each patient. Demographic and clinical information was obtained from clinical case reports or medical examination reports, and a blood sample was collected from each patient. The HCC diagnosis was based on histopathology, and if histopathology was not available, it was performed on two imaging modalities (magnetic resonance imaging, computed tomography, or contrast enhanced ultrasound). The diagnosis of cirrhosis and hepatitis was based on clinical, laboratory, and imaging evidence of hepatic decompensation or portal hypertension.[20] Patients must be newly diagnosed, and cases with another cancer or underwent treatments were excluded from the study. Tumor staging was determined by the United Network of Organ Sharing-modified tumor-node-metastasis (TNM) staging system for HCC. The baselines adopted for evaluating liver function were Child–Pugh Class A (5–6 scores), B (7–9 scores), and C (10–15 scores).

Measurement of serum markers

Tumor markers (AFP, carcino-embryonic antigen [CEA], carbohydrate antigen 19-9 [CA19-9]), and liver function parameters (total protein [TP], serum total bilirubin [STB], alanine aminotransferase [ALT], and aspartate aminotransferase [AST]) were tested using commercially available electrochemiluminescence immunoassay (Roche Diagnostics Ltd., Shanghai, China). Quantitative determination of GP73 in serum was performed using commercially available ELISA kits (Hotgen Biotech Inc., Beijing, China), according to the manufacturer's protocol.

Statistical analysis

All the data were statistically analyzed using the SPSS software version 17.0 (SPSS Inc, Chicago, IL, USA). All values were reported as mean ± standard deviation or median (upper quartile-lower quartile) as the data were not normally distributed. The measurement data of multiple groups were compared with Kruskal–Wallis H-test, and the comparison between two groups was performed by Mann–Whitney U-test as the distribution of serum GP73 and AFP was nonnormal distribution. Chi-square test was used to study the relations between GP73 and pathological biochemical index. To determine the optimal cut-off value for diagnosis of HCC, receiver operating characteristic (ROC) curves were constructed, and comparisons were tested using the U test.


 > Results Top


Characteristics and Golgi protein 73 expression level

The patients in the study included 180 cases of HCC, 61 LC, 99 chronic hepatitis, and 103 normal controls. There was no statistically significant difference on age and sex between the four groups (P > 0.05). The difference of AFP among the four groups has a statistical significance. The median serum level of GP73 was 172.84 ng/mL (upper quartile-lower quartile, 123.21–215.48) in the HCC group, significantly higher than 109.61 ng/mL (92.12–147.02) in the LC group, 105.92 ng/mL (93.86–118.90) in hepatitis group, and 46.95 ng/mL (40.71–52.06) in healthy control group (P < 0.001). Meanwhile, GP73 in the hepatitis group and LC group was significantly higher than that in healthy group (P < 0.001) [Table 1].
Table 1: Characteristics and comparison of the serum Golgi protein 73 level of the four groups

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Relationship between Golgi protein 73 and demographic, clinical, and laboratory data

The serum levels of GP73 were uncorrelated with tumor TNM stage, tumor size, AFP, CEA, CA19-9, and liver function-related biochemical indicators (TP, STB, ALT, and AST) (P > 0.05). However, the serum levels of GP73 were strongly increased in patients with lymphatic invasion (P < 0.001). The serum levels of GP73 in Child–Pugh Class B and C group were statistically significantly higher than that in Child–Pugh Class A group (P < 0.001) [Table 2].
Table 2: The relationship between clinical characteristics and serum Golgi protein 73 concentration in hepatocellular carcinoma group

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Diagnostic value of Golgi protein 73

ROC curves were plotted to define the optimal cutoff values and to identify the sensitivity and specificity for serum GP73 and AFP in differentiating patients with HCC versus those with hepatitis. The area under the ROC (AUROC) curve for GP73 was 0.840 (95% confidence interval [CI]: 0.749–0.886), with a sensitivity of 78.3%, specificity of 85.4%, and an optimal cutoff point of 117.53 ng/mL; while the AUROC for AFP was 0.718 (95% CI: 0.659–0.778), with a sensitivity of 51.1%, specificity of 99%, and a cutoff of 176.91 ng/mL [Figure 1]. GP73 had a better AUROC compared to AFP (P < 0.001). The AUROC curve for the combination of GP73 and AFP was 0.903 (95% CI: 0.868–0.907), in which the diagnostic value is better than the single diagnosis of GP73 (P = 0.018) and AFP (P < 0.001) [Table 3].
Figure 1: Receiver operating characteristic curve of Golgi protein 73, alpha-fetoprotein, and the combination of Golgi protein 73 and alpha-fetoprotein for the diagnosis of hepatocellular carcinoma

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Table 3: Comparison of serum Golgi protein 73 and alpha-fetoprotein of diagnostic value for hepatocellular carcinoma

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 > Discussion Top


In the present study, we analyzed the serum levels of GP73 in four groups (healthy controls, chronic hepatitis, LC, and HCC) and found that the serum GP73 levels significantly increased in patients with liver disease, especially in HCC patients. In HCC group, we further found that the serum GP73 had correlations with other markers including lymphatic invasion and Child–Pugh class. Meanwhile, our results have proved again that the serum GP73 is a better biomarker in the early diagnosis of HCC than the conventional AFP.

GP73 is a Type II Golgi membrane protein with 400 amino acids and the 73 kDa molecular weight and has an N-terminal transmembrane domain and a C-terminal coiled-coil domain located on the lumenal surface of the Golgi apparatus.[21] In normal human liver, GP73 is expressed in biliary epithelial cells, but is barely detectable in hepatocytes.[8] GP73 is upregulated at high levels in hepatocytes of patients with acute and chronic hepatitis and HCC.[8],[10],[12],[22],[23] With the recovery of acute hepatitis, GP73 expression reverses, whereas biliary epithelial cell expression remains unchanged.[10],[23] Upregulation of GP73 is also induced in human Hep3B hepatoma cells infected with human adenovirus.[10] However, the mechanism of elevated sGP73 expression in liver disease is unclear. Iftikhar et al.[23],[24] reported that there are two mechanisms to regulate GP73; the first of which is triggered during acute hepatocellular injury and the second during the progression of chronic liver disease. Then, Bachert et al.[24] proposed that upregulated intracellular GP73 expression enhances its intracellular trafficking, most likely through the endosomal pathway, which provides the opportunity for endoproteolytic cleavage of GP73, resulting in the secretion of the truncated GP73. In the present study, GP73 expression was analyzed in detailed classified liver disease and healthy controls by using more sensitive ELISA analyses. The results showed that GP73 was significantly increased in groups with liver diseases (including hepatitis, LC, and HCC) compared with healthy controls.

HBV, which is a major cause of chronic liver diseases including cirrhosis and HCC, affects over 350 million people worldwide.[25] Moreover, many investigators have reported that the viral status in HBV-infected individuals affects the recurrence and posttreatment outcomes of HCC patients.[26],[27] Kladney et al. found that HepG2 2.2.15, which was stably transfected with the entire HBV genome, had robust expression of GP73, whereas its parental line HepG2 failed to express GP73.[10],[28] In recent years, some results also demonstrated that serum GP73 levels were consistent with chronic HBV infections.[17],[29] However, another study has reported that GP73 expression was higher in non-HBV- and non-HCV-related cirrhosis than those with the virus infection.[13] In the present study, the results also demonstrated that GP73 levels were higher in HCC patients with the HBV infection than those without virus. However, no significant difference was found between HBV-positive and HBV-negative patients within HCC groups. Hence, HBV infection might be one of the factors that upregulates GP73 expression, but it is not the most important factor. Moreover, some studies reported that GP73 mRNA is regulated by estrogens and calcitriol, and female patients had a higher expression of GP73 than male patients.[30],[31] However, our results show that there is no correlation between gender and serum GP73 level within HCC groups. The extremely high expression of GP73 in HCC cancer cells might overshadow the significance of induction factors of estrogen.

Liver function injury, associated with almost of all liver diseases, is believed to be a critical factor leading to hepatic dysfunction in HCC patients. The accurate assessment of liver function is a vital need for successful treatment decision, individualized management, and prognosis judgment. To our knowledge, LC, a “final” common outcome of injury in the liver, is believed to be a critical factor leading to hepatic dysfunction. Some experimental research showed that hepatic stellate cells also expressed GP73, and GP73 protein and mRNA expression increase gradually in activated stellate cells.[23],[32] Moreover, Huang and Chang suggested that protein secretion from the Golgi complex is pH-dependent, and the increasing GP73 is a consequence of abnormal cytosolic pH.[33] Homeostatic imbalance may result in the genesis of hepatitis, fibrosis, cirrhosis, and carcinoma, along with the progression of the liver disease. Based on recent reports, it is observed that serum GP73 concentration is also related with the progression of chronic liver diseases, hepatic impairment, and chronic fibrosis.[14],[17],[34],[35] Within HCC patients, we also found that the GP73 concentration was highest in the Child–Pugh Class C group and lowest in the Child–Pugh Class A group, which indicates that liver injury contributes to the elevation of sGP73. However, no significant difference was found between serum GP73 level and laboratory parameters (TP, STB, ALT, and AST), which can reflect liver function in HCC. Maybe those markers are not specific to liver function and are easily interfered by various factors, as bilirubin is easily influenced by bile duct obstruction. In this case, those parameters have difficulty in reflecting the substantial status of liver functions. Therefore, the data in this study need to be confirmed by more sensitive liver function-related parameters, such as albumin, prothrombin time, and liver biopsy.

HCC biomarkers have also been reported to be predictive of specific clinicopathological variables representing the malignant potential of the tumor. Many studies revealed that high-expression of GP73 was associated with tumor size, differentiation, grade, and vein invasion.[22],[34] However, serum levels of GP73 in patients with HCC were not consistently affected by the tumor sizes.[36] In our study, we analyzed the association between serum GP73 levels and variables representing tumor growth and invasiveness such as tumor size, the presence of lymphatic invasion, and TNM staging. We found that the serum GP73 level is correlated with lymphatic invasion and independent of other clinicopathological variables.

AFP has served as a standard biological tumor marker of HCC since the 1970s. However, AFP is not a very good screening test since it can be produced in patients with other liver diseases, such as chronic liver disease and cirrhosis.[5] Many studies have reported that AFP has a lower sensitivity of 39%–64% and a positive predictive value of 9%–32%.[37],[38] In addition, the levels of AFP are correlated with the tumor size and it fail to increase in 80% of small HCC.[39] GP73 is a newly identified serum marker for the diagnosis of HCC.[32],[40],[41] GP73 is constitutively expressed by biliary epithelial cells in normal human liver, but it is barely detectable in hepatocytes.[23] However, GP73 is upregulated at high levels in hepatocytes of patients with viral and nonviral liver disease.[8],[23],[42] Moreover, serum GP73 concentrations are increased in patients with chronic liver disease.[11],[12] In particular, serum GP73 levels are higher in patients with early HCC than that in patients with other liver diseases including hepatitis and cirrhotic.[11],[40] These studies indicated that GP73 may be a potential marker for the early detection of HCC. In recent years, there is a growing body of evidence that GP73 is a valuable tumor biomarker for HCC and it is superior to AFP level for the early diagnosis and screening of HCC.[13],[16],[34],[43] However, it seems doubtful that whether GP73 will ultimately be a better serum biomarker than AFP.[14],[18],[19] The clinical usefulness of these biomarkers needs to be carefully evaluated and validated. Our results showed that GP73 levels were upregulated in HCC patients' serum when compared with healthy individuals, hepatitis patients, and LC patients. We evaluated the potential utility of circulating GP73 for differentiating HCC from hepatitis patients by ROC curve. The results showed that GP73 was superior to AFP in diagnosing HCC with a ROC curve area of 0.84 (95% CI: 0.75–0.89), a sensitivity of 78.3%, and a specificity of 85.4% (AFP: 0.72, 51.1%, 99.0%). As HCC is under a diverse class of diseases and it is unlikely for a single biomarker to detect HCC with high specificity and sensitivity, Wang's and Mao's reports suggested that combining GP73 with AFP would possibly improve the sensitivity and specificity in the diagnosis of HCC.[13],[44] Our results showed that the combined effect of GP73 and AFP testing increased the sensitivity and specificity for HCC detection markedly, which is consistent with the previous research.


 > Conclusion Top


We found that GP73 level was significantly increased in HCC group compared to other liver disease patients and healthy controls group. In addition, the GP73 concentration was significantly increased in the Child–Pugh Class C and B groups compared with the Child–Pugh Class A group; however, no correlation was found between the GP73 levels and liver function-related parameters. Further studies are warranted to assess the relationship between GP73 expression and liver function injury. Moreover, the serum GP73 level is correlated with lymphatic invasion which represented the malignant potential of the tumor. At the same time, our results also demonstrated that GP73 gives a more sensitive indication than AFP in detecting liver cancer. Combination of GP73 with AFP greatly increases the sensitivity and specificity for HCC diagnosis, and this can be used as a practical means in early clinical diagnosis for small HCC.

Financial support and sponsorship

This work was supported in part by the National Natural Science Foundation of China (Contract No. 30872169), the Shandong Province Natural Science Foundation of China (Contract No. ZR2011HM031), and the Municipal Science and Technology Bureau of Qingdao of China (Contract No. 13-1-4-192-jch).

Conflicts of interest

There are no conflicts of interest.



 
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