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Expression of Hbx and COX-2 in Chronic Hepatitis B, Cirrhosis and Hepatocellular Carcinoma: Implication of Hbx in Upregulation of COX-2

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Expression of Hbx and COX-2 in Chronic Hepatitis B, Cirrhosis and Hepatocellular Carcinoma: Implication of Hbx in Upregulation of COX-2 Modern Pathology (2004) 17, 1169–1179 & 2004 USCAP, Inc All rights reserved 0893-3952/04 $30.00 www.modernpathology.org Expression of HBx and COX-2 in chronic hepatitis B, cirrhosis and hepatocellular carcinoma: implication of HBx in upregulation of COX-2 Alfred S-L Cheng1, Henry L-Y Chan1, Wai K Leung1,KaFTo2, Minnie Y-Y Go1, John Y-H Chan3, Choong T Liew2 and Joseph J-Y Sung1 1Department of Medicine & Therapeutics; 2Department of Anatomical & Cellular Pathology and 3Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong Hepatitis B virus is a major etiological factor of hepatocellular carcinoma, but the underlying mechanisms remain unclear. We have previously demonstrated that upregulation of cyclooxygenase (COX)-2 in chronic hepatitis B persisted despite successful antiviral therapy. In this study, we investigated the relationship between the transactivator HBx and COX-2 in hepatitis B virus-associated chronic liver diseases. Expressions of HBx and COX-2 in tissue specimens were determined by single and double immunohistochemistry. The effects of HBx on COX-2 and prostaglandin E2 production were studied by transfection. HBx was expressed in 11/11 (100%) of chronic hepatitis B, 23/23 (100%) of cirrhosis, and 18/23 (78%) of hepatocellular carcinoma, whereas no immunoreactivity was found in four nonalcoholic steato-hepatitis controls. COX-2 expression was also detected in all specimens of liver lesions except in only 29% of poorly differentiated hepatocellular carcinoma. Significant correlation between HBx and COX-2 immunoreactivity scores was found in different types of chronic liver diseases (chronic hepatitis B, rs ¼ 0.68; cirrhosis, rs ¼ 0.57; hepatocellular carcinoma, rs ¼ 0.45). Double immunohistochemistry showed colocalization of HBx and COX-2 in hepatic parenchymal cells. Similar to COX-2, there was no significant change in HBx expression in patients with chronic hepatitis B after interferon and lamivudine therapy when hepatitis B virus DNA became undetectable and inflammation subsided. Transfection of Hep3B hepatocellular carcinoma cells with HBx increased COX-2 expression and prostaglandin E2 production. HBx was localized mainly in the cytoplasm and less in nucleus, as found in the liver lesions. In conclusion, our results strongly suggested that there was a close relationship between HBx and COX-2. COX-2 might represent an important cellular effector of HBx that contributes to hepatitis B virus- associated hepatocarcinogenesis. Modern Pathology (2004) 17, 1169–1179, advance online publication, 25 June 2004; doi:10.1038/modpathol.3800196 Keywords: chronic hepatitis B; cyclooxygenase-2; hepatocarcinogenesis; X protein of hepatitis B virus Hepatitis B virus is a major etiological agent of the underlying mechanisms of HBx-mediated onco- hepatocellular carcinoma; and it increases the risk genicity remain unclear. of developing hepatocellular carcinoma by over 200- Cyclooxygenase (COX) catalyzes the rate-limiting fold.1 The smallest hepatitis B virus open-reading step of prostaglandin biosynthesis. Two COX iso- frame encodes the X protein of hepatitis B virus forms have been identified: COX-1 is expressed (HBx) that appears to be important for hepatocel- constitutively, whereas COX-2 is induced by growth lular transformation in vitro2 and hepatocellular factors, tumor promoters, and cytokines.5 Over- carcinoma formation in transgenic mice.3,4 However, expression of COX-2 has been reported in tumors of colon, pancreas, esophagus, and stomach as well as in the corresponding premalignant lesions.6–9 Gene deletion studies have demonstrated that Correspondence: Dr JJ-Y Sung, MD, PhD, Department of Medicine COX-2 plays a critical role in the development of & Therapeutics, Prince of Wales Hospital, Shatin, New Territories, intestinal neoplasia.10 Using a genetic gain-of- Hong Kong. function approach, enhanced COX-2 expression is E-mail: [email protected] 11 Received 13 November 2003; revised and accepted 24 March shown to be sufficient to induce tumorigenesis. 2004; published online 25 June 2004 Recently, COX-2 upregulation is also found in HBx and COX-2 in chronic liver diseases AS-L Cheng et al 1170 cirrhosis and well-differentiated hepatocellular car- inflammation (Table 1). Pre- and post-treatment liver cinoma, but less so in poorly differentiated hepato- biopsies were processed for immunohistochemical cellular carcinoma, suggesting that COX-2 is staining. The histology activity index16 of the speci- involved in early steps of hepatocarcinogenesis.12,13 mens was scored by a single pathologist (KFT). Liver We have previously demonstrated upregulation of biopsy specimens from four nonalcoholic steato- COX-2 in hepatocytes of chronic hepatitis B, which hepatitis patients, in whom hepatitis B virus and persisted even after successful antiviral therapies.14 hepatitis C virus coinfection, autoimmune hepatitis Therefore, upregulation of COX-2 does not simply and metabolic diseases were excluded, were used as reflect inflammatory activity. Instead, it might be controls for the study. related to the presence of hepatitis B virus genome in the hepatocytes. As both HBx and COX-2 are related to hepatocarcinogenesis, we hypothesized that the integrated HBx gene in host hepatocytes is Immunohistochemistry the cause of COX-2 upregulation. In this study, we Liver tissues were fixed in 10% buffered forma- investigated (1) the relationship between HBx and lin and embedded in paraffin. Sections (5 mmin COX-2 in chronic liver diseases and (2) in vitro thickness) were cut and mounted on 3-amino- induction of COX-2 gene expression by HBx. propyltriethoxysilane-coated slides (Marienfeld, Badmergentheim, Germany). Sections were depar- affinized and rehydrated to Tris-buffered saline, Materials and methods followed by microwave treatment for 10 min. En- Patient Samples dogenous peroxidase activity was blocked with 3% H2O2 in methanol for 20 min. Nonspecific binding In all, 23 surgically resected hepatocellular carcino- was blocked with 2% swine serum (DAKO, Glostr- ma tissues with adjacent nontumorous cirrhotic up, Denmark), and then incubated with a rabbit livers and 11 chronic hepatitis B biopsies were used polyclonal antibody to HBx (a gift from Dr Mark A in this study. Each hepatocellular carcinoma was Feitelson, Thomas Jefferson University, Philadel- histologically graded into one of three categories: phia, PA, USA) in Tris-buffered saline containing well-differentiated, moderately differentiated, or 1% bovine serum albumin overnight. The specificity poorly differentiated, according to the criteria of this anti-HBx antibody has been rigorously proposed by the Liver Cancer Study Group of tested.17 Tissue section was incubated with the Japan.15 Six chronic hepatitis B patients received same buffer without the antibody as negative lamivudine 100 mg per day for 1 year and five control. This was followed by biotinylated swine patients received interferon-alfa 5–10 MU three anti-rabbit immunoglobulins (1:200; DAKO) and times per week for 16–24 weeks. Liver biopsy was streptavidin/horseradish peroxidase complex performed before treatment and follow-up biopsy (1:400; DAKO) incubation, both for 45 min. The was performed at second year for patients on color was developed in 3,30-diaminobenzidine (Sig- lamivudine, and at 1 year post-treatment for patients ma, St Louis, MO, USA). The sections were then on interferon. All patients responded to lamivudine counterstained with Mayer’s hematoxylin. As the or interferon therapy by a sustained hepatitis B e anti-HBx antibody crossreacts with CK 18,18 we used antigen sero-conversion to anti-hepatitis B e anti- a monoclonal anti-human antibody (1:10; DAKO) as bodies, disappearance of hepatitis B virus DNA in an internal control for the immunostaining experi- serum (bDNA assay, Chiron Diagnostic, Emeryville, ments. Cytokeratin 18 immunoreactivity was only CA, USA), normalization of alanine aminotransfer- observed in epithelial cells of the bile ducts and bile ase and resolution of histological hepatic necro- ductules but not in hepatocyte (data not shown). Table 1 Serological and histological data of chronic hepatitis B patients upon antiviral treatments Antiviral treatment (n ¼ 11) Pretreatment Posttreatment P HBeAg + À Anti-HBe À + Detectable HBV-DNA 10/11 0/11 HBV-DNA (Meq/ml)a 56.98 (o0.7–1494) o0.7 (o0.7–o0.7) Serum ALT (IU/L)a 184 (69–613) 30 (18–36) o0.001 Necro-inflammatory scorea,b 8.5 (5–11) 2 (1–4) o0.001 aData are expressed in median (range). bn ¼ 10 due to inadequate tissue for necro-inflammatory scoring in one specimen. HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; ALT, alanine aminotransferase; +, positive; À, negative. Modern Pathology (2004) 17, 1169–1179 HBx and COX-2 in chronic liver diseases AS-L Cheng et al 1171 COX-2 immunostaining was performed using a goat modified Eagle medium (Invitrogen) supplemented polyclonal antibody (1:100; Santa Cruz Biotechnol- with 10% heat-inactivated fetal bovine serum ogy, Santa Cruz, CA, USA) as previously de- (Invitrogen) and 100 U/ml penicillin and 100 mg/ml scribed.14 Anti-COX-2 antibody neutralized by streptomycin (Invitrogen). Hep3B cells (3 Â 105) preabsorption with the blocking peptide (five-fold were plated in 35-mm dishes and maintained in a excess by weight, Santa Cruz Biotechnology) served humidified atmosphere of 95% air and 5% CO2 at as specificity control. 371C. In some dishes, Hep3B cells were applied to All specimens stained for HBx and COX-2 were coverslips placed on the bottom prior to cell scored by
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