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 α 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.