Abstract

Objective Hepatitis B virus (HBV) causes inflammation of the liver and is the leading cause of both liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Serine protease inhibitor Kazal type 1 (SPINK1) is an acute-phase response protein that is overexpressed in liver cancer tissue. This study investigated the clinical value of SPINK1 with regard to the diagnosis of HBV-related diseases and its regulatory mechanism. Methods Serum levels of SPINK1 in HBV-infected patients and healthy participants were detected by enzyme-linked immunosorbent assay (ELISA). Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) and western blotting were used to detect differential expression of SPINK1 mRNA and protein in HepG2 and HepG2.2.15 cells. The HBV infectious clone pHBV1.3 and its individual genes were cotransfected into HepG2 cells with the SPINK1 promoter coupled to a luciferase reporter; luciferase activity was measured, and the expression levels of SPINK1 were examined. Results Serum SPINK1 levels of HBV-infected patients were significantly higher than those of healthy participants, and the serum levels of SPINK1 in patients who tested positive for HBeAg were significantly higher than those in patients who tested negative for HBeAg. The serum SPINK1 levels of patients with LC or HCC were markedly higher than those of patients with chronic hepatitis. The HBV X protein (HBx) activated the SPINK1 promoter to upregulate expression of SPINK1 at both mRNA and protein levels. Conclusions HBV enhances expression of SPINK1 through X. SPINK1 levels are increased during progression of HBV-related diseases and might be utilized as a biomarker for the diagnosis of HBV-related diseases.

Highlights

  • Hepatitis B virus (HBV) infection is a serious public health problem worldwide

  • This study investigated the effect of HBV infection on serine protease inhibitor Kazal type 1 (SPINK1) expression, analyzed the relationship between serum SPINK1 levels and the progression of HBVrelated diseases, and explored the molecular mechanism underlying the regulation of SPINK1 expression by HBV X protein (HBx)

  • The 248 patients infected with HBV were divided into three groups: 104 patients with chronic hepatitis B (CHB), 82 patients with liver cirrhosis (LC), and 62 patients with hepatocellular carcinoma (HCC); 167 HBV-infected patients were tested positive for HBeAg and 81 negative for HBeAg

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Summary

Introduction

250 million people have chronic HBV infection; of these cases, approximately 20% to 30% develop into liver cirrhosis (LC). Approximately 2% to 5% of cirrhosis cases progress to liver cancer [1, 2]. The gene serine protease inhibitor Kazal type 1 (SPINK1), known as tumor-associated trypsin inhibitor (TATI) or pancreatic secretory trypsin inhibitor (PSTI), is located on chromosome 5q32, approximately 7.5 kb long, and contains four exons [3]. HBV and hepatitis C virus (HCV) upregulate expression of serine protease inhibitor Kazal (SPIK), and SPINK1 is overexpressed in HCV-positive hepatocellular carcinoma (HCC) and is a promising prognostic marker for this cancer [8,9,10]

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