Lysophospholipid variants in hepatocellular carcinoma

Background: The U. S. incidence of hepatocellular carcinoma (HCC) is increasing and is linked to hepatitis C (HepC) infection, alcohol toxicity, and obesity. This manuscript examines lysophosphatidic acid (LPA) variant biosynthesis as a biomarker and potential therapeutic target for HCC. Methods: Serum LPA variant levels were determined in patients with HepC +/- HCC, alcoholic cirrhosis +/- HCC, or nonalcoholic steatohepatitis +/- HCC by mass spectroscopy. To clarify the relationship between cancer and LPA variant profiles, LPA variants were evaluated in HepC+ HCC patients before and after liver transplantation. Moreover, LPA variant modification of gene expression was also determined in vitro by real-time polymerase chain reaction. Results: In patients diagnosed with HCC, 18: 2 LPA biosynthesis was decreased, whereas 20: 4 LPA biosynthesis and 20: 4 LPA: 18: 2 LPA ratio were increased. Three days after liver transplantation, serum LPA levels and 18: 2 LPA: 20: 4 LPA ratio were significantly reduced in patients with cancer. The 20: 4 LPA selectively stimulated LPA receptor and tumor necrosis factor a expression in Hep3B cells, whereas 18: 2 LPA did not. Conclusions: Serum LPA variant profiles are unique in patients with HCC allowing for the stratification of patients. Moreover, LPA variants impart individual mitogenic properties associated with tumorigenesis that may provide a potential therapeutic target. We envision that LPA profiling may accelerate diagnosis, help stratify patients at high risk of developing cancer, and provide potential targets for chemoprevention. (C) 2013 Elsevier Inc. All rights reserved.