Apurinic/apyrimidinic endonuclease-1 and hepatocellular carcinoma.

563 Background: The enzyme apurinic/apyrimidinic endonuclease-1 (APE1) is associated with protection against DNA damage and oxidative damage congruent with cancer. The purpose of this study is to investigate hepatic APE1 levels in association with hepatocellular carcinoma (HCC) in order to better stratify patients with underlying liver disease for the development of HCC and identify novel targets for therapy. Methods: Hepatic APE1 levels were determined by immunohistochemistry staining and ELISA within liver and tumor samples from patients with HepC±HCC. Hepatic APE1 staining was semi-quantitated using a scale of 0-100. Serum APE1 levels were determined by ELISA. In addition, APE1 staining was quantified in hepatic paraffin embedded sections from MDR2 −/− mice with HCC and within MDR2 −/+ mice controls that do not develop HCC. Results: Hepatocyte APE1 staining was lower in livers from patients with HepC and HCC when compared to patients with HepC without HCC. In a similar manner, hepatic APE1 levels were significantly lower in patients with HepC and HCC patients when compared to HepC controls. In contrast, serum APE1 level was greater in patients with HepC and HCC when compared to patients with HepC and no HCC. Moreover, APE1 levels were greater in HCC tumors when compared to non-malignant liver tissue. Hepatocyte APE1 staining in MDR −/− mice with HCC was lower when compared to MDR2 −/+ mice that do not develop HCC. In addition, cytosolic APE1 staining was increased in HCC tumor of MDR2 −/− mice when compared to controls. Conclusions: Increased APE1 is a potential biomarker of HCC risk in patients with underlying liver disease and is a novel target for therapy in patients with underlying liver disease whom have a higher risk of developing HCC. Consequently, targeted APE1 inhibition may increase chemotherapy response by reducing tolerance to DNA damage. Additional studies are required to better understand the role of APE1 inhibition in HCC in the face of reduced background hepatic APE1 levels.