The possible role of Dickkopf-1, Golgi protein- 73 and Midkine as predictors of hepatocarcinogenesis: a review and an Egyptian study

Abdel-Rahman N Zekri,Reham Mohamed Gabr,Reem Mostafa Hassan,Ola S Ahmed,Marwa Mohanad,Mohamed El Kassas,Mai M Lotfy,Abeer A Bahnassy,El Sayedtarekabd El Salam,Rania A Talaat Abdel-Zaher

doi:10.1038/s41598-020-62051-6

Abdel-Rahman N Zekri, Reham Mohamed Gabr + Show 8 more

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https://doi.org/10.1038/s41598-020-62051-6

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Abstract

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death worldwide. The use of alpha fetoprotein (AFP) alone was not an accurate biomarker for HCC despite its high specificity. Therefore, we assessed the possible role of serum biomarkers that have been mentioned briefly in previous studies on Egyptian patients ion top of HCV. However these studies included small number of patients and did not assess the different stages of hepatocarcinogenesis. In the current study we assessed 1) the expression levels of Golgi protein 37(GP73),Midkine (MDK) and Dickkopf-1(DKK-1) proteins separately and in combination at different stages of hepatocarcinogenesis. GP73, MDK and DKK-1 proteins were assessed in 238 individuals divided into 4 groups (HCC, chronic HCV, and chronic HCV with cirrhosis and healthy subjects as a control) Serum levels of GP73, MDK, and DKK-1 were assessed in all subjects by ELISA. Serum levels of the studied markers were significantly higher in HCC compared to other groups (p < 0.001). The ROC curve analysis for the studied markers showed 1) 88.5% sensitivity, 80.6% specificity, 69% PPV, 93.5% NPV and (AUC 0.91)for MDK; 2) 93.6%, 86.9%, 77.7%, 96.5% for DKK-1. 3) 91%, 85%, 74.7%, 95% (AUC 0.96) for GP73 and 4) 74.4%, 84.4%, 69.9%, 87.1% (AUC 0.81) for AFP. Serum levels of GP73, MDK, and DKK-1 are comparable to AFP as promising predictor biomarkers for HCC patients from Egypt. A two markers panel including Gp73 and DKK-1 showed the highest specificity and sensitivity among different markers combinations.

Highlights

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death worldwide
Recent studies have shown that other proteins could be used as sensitive and specific markers for hepatitis as well as for HCC including the Golgi protein 73 (GP73); which is named Golgi phosphoprotein 2 “GOLPH2, the Dickkopf-1(DKKpf-1 or DKK-1), and Midkine (MDK)
These findings suggest that the three www.nature.com/scientificreports markers panel (GP73, MDK and DKK-1) with or without AFP could improve the diagnostic efficacy for discriminating HCC patients from cirrhotic and non-cirrhotic hepatitis C virus carriers

Summary

Introduction

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death worldwide. Alpha-fetoprotein(AFP) is one of the thoroughly investigated biomarkers in different solid tumors, premalignant lesions or inflammatory conditions It is a glycoprotein which is synthesized in large amounts by the yolk sac and liver during embryonic development. Recent studies have shown that other proteins could be used as sensitive and specific markers for hepatitis as well as for HCC including the Golgi protein 73 (GP73); which is named Golgi phosphoprotein 2 “GOLPH2, the Dickkopf-1(DKKpf-1 or DKK-1), and Midkine (MDK). These biomarkers have been used as potential, accurate, simple and non-invasive biomarkers for early detection of HCC6–8. Some studies demonstrated that GP73 serum level in HCC patients are markedly overlapped by the presence of cirrhosis, which affects its diagnostic accuracy[10]

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