J Pathol Transl Med.  2016 May;50(3):181-189. 10.4132/jptm.2016.03.18.

Nuclear Expression of Hepatitis B Virus X Protein Is Associated with Recurrence of Early-Stage Hepatocellular Carcinomas: Role of Viral Protein in Tumor Recurrence

• Jin J
• Jung HY
• Lee KH
• Yi NJ
• Suh KS
• Jang JJ
• Lee KB

• KMID: 2164594
• DOI: http://doi.org/10.4132/jptm.2016.03.18

Abstract

BACKGROUND
Hepatitis B virus (HBV) plays well-known roles in tumorigenesis of hepatocellular carcinoma (HCC) in infected patients. However, HBV-associated protein status in tumor tissues and the relevance to tumor behavior has not been reported. Our study aimed to examine the expression of HBV-associated proteins in HCC and adjacent nontumorous tissue and their clinicopathologic implication in HCC patients.
METHODS
HBV surface antigen (HBsAg), HBV core antigen (HBcAg), and HBV X protein (HBx) were assessed in 328 HBV-associated HCCs and in 155 matched nontumorous tissues by immunohistochemistry staining.
RESULTS
The positive rates of HBsAg and cytoplasmic HBx staining in tumor tissue were lower than those in nontumorous tissue (7.3% vs. 57.4%, p < .001; 43.4% vs. 81.3%, p < .001). Conversely, nuclear HBx was detected more frequently in tumors than in nontumorous tissue (52.1% vs. 30.3%, p < .001). HCCs expressing HBsAg, HBcAg, or cytoplasmic HBx had smaller size; lower Edmondson-Steiner (ES) nuclear grade, pT stage, and serum alpha-fetoprotein, and less angioinvasion than HCCs not expressing HBV-associated proteins. Exceptionally, nuclear HBx-positive HCCs showed higher ES nuclear grade and more frequent large-vessel invasion than did nuclear HBx-negative HCCs. In survival analysis, only nuclear HBx-positive HCCs had shorter disease-free survival than nuclear HBx-negative HCCs in pT1 and ES nuclear grade 1-2 HCC subgroup (median, 126 months vs. 35 months; p = .015).
CONCLUSIONS
Our data confirmed that expression of normal HBV-associated proteins generally decreases in tumor cells in comparison to nontumorous hepatocytes, with the exception of nuclear HBx, which suggests that nuclear HBx plays a role in recurrence of well-differentiated and early-stage HCCs.

Keyword

Hepatitis B X protein; Hepatitis B surface antigens; Hepatitis B core antigens; Carcinoma, hepatocellular

MeSH Terms

alpha-Fetoproteins
Antigens, Surface
Carcinogenesis
Carcinoma, Hepatocellular*
Cytoplasm
Disease-Free Survival
Hepatitis B Core Antigens
Hepatitis B Surface Antigens
Hepatitis B virus*
Hepatitis B*
Hepatitis*
Hepatocytes
Humans
Immunohistochemistry
Recurrence*
Antigens, Surface
Hepatitis B Core Antigens
Hepatitis B Surface Antigens
alpha-Fetoproteins

Figure

• 

  Fig. 1. Representative pictures of hepatitis B virus (HBV) surface antigen (HBsAg), HBV core antigen (HBcAg), and HBV X protein (HBx) proteins in hepatocellular carcinoma. Positive HBsAg (A), positive HBcAg (B), positive HBx in nuclei (C), and positive HBx (D) in the cytoplasm.

• 

  Fig. 2. Cumulative disease-free survival curves of 99 patients with pT1 and well-differentiated hepatocellular carcinoma in relation to the presence of hepatitis B virus (HBV) surface antigen (HBsAg) and HBV X protein (HBx) in a tumor, nontumorous tissue, and serum. HBsAg in tumors (A), HBsAg in nontumorous tissue (B), HBsAg in serum (C), nuclear HBx (HBx nu) in tumors (D), HBX nu in nontumorous tissues (E), and cytoplasmic HBx (HBx cyto) (F) in tumors. *p<.05.

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