Oncogenic SULF2 Protein Expression Is Associated with Pathogenesis of Cirrhosis and Hepatobiliary Carcinoma
Jin-Ping Lai, Phyu P Aung, Zengfeng Wang, Avi Rosenberg, David Kleiner, Lewis R Roberts, Markku Miettinen. National Cancer Institute, National Institutes of Health, Bethesda, MD; Mayo Clinic, Rochester, MN
Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide and often diagnosed at an advanced stage at which there are limited treatment options. There is a strong interest in identifying novel molecular targets for therapy of advanced HCC. Sulfatase 2 (SULF2) is a recently identified human heparin-degrading endosulfatase. We have previously reported that upregulation of tumor SULF2 mRNA desulfates cell surface heparan sulfate proteoglycans (HSPGs) leading to increased HCC cell proliferation in vitro and tumor growth in vivo, and is correlated with a rapid recurrence after surgery and short survival in patients with HCC (Lai, et al, Hepatology, 2008 and 2010). Syndecan 1 (Syn1) is one of the components of HSPGs.
Design: To further investigate the role of SULF2 in pathogenesis of cirrhosis and hepatobiliary carcinoma as well as the interaction between SULF2 and Syn 1, we measured the SULF2 mRNA/18S in 35 benign liver specimens with or without cirrhosis by Real-time RT-PCR and evaluated SULF2 and Syn1 expression in 65 benign livers, 40 HCCs and 21 cholangiocarcinomas (CCs) by immunohistochemistry.
Results: We found that SULF2 mRNA was significantly up-regulated in benign liver with cirrhosis (n=19) as compared to that in benign liver without cirrhosis (n=14) (P=0.0003). This result was also confirmed in the selected 65 benign livers (35 with cirrhosis, score 6, Ishak modified staging) by immunohistochemistry using antibody against SULF2. For HCCs and CCs, each case was scored with 3+, 2+,1+ or – for both SULF2 and Syn1. High level of SULF2 (2+ and 3+) was found in 33 (82%) HCCs and 17 (80%) CCs, and low level (1+ and -) in 7 (18%) HCCs and 4 (20%) CCs. High level of Syn1 (2+ and 3+) was found in 25 (62%) HCCs and 7 (33%) CCs, and low level (1+ and -) in 15 (38%) HCCs and 14 (67%) CCs. There was a significant negative correlation between SULF2 and Syn1 in HCCs (n=40, P=0.011), but not in CCs (n=21, P=0.490).
Conclusions: This is the first report regarding the role of SULF2 in cirrhosis and the interaction between SULF2 and Syn1 in HCCs and CCs. Oncogenic SULF2 may desulfate Syn1 in both cell surface and extracellular matrix promoting pathogenesis of cirrhosis and hepatobiliary carcinoma.
Tuesday, March 20, 2012 9:30 AM
Poster Session III # 247, Tuesday Morning