ABSTRACT
BACKGROUND: Hepatocellular carcinoma (HCC) is a primary malignancy of the liver with a high worldwide prevalence and poor prognosis. Previous data, by Affymetrix microarray analysis, has shown a decrease in genes involved in phospholipid catabolism, fatty acid catabolism, choline metabolism, and bile acid metabolism in HCC compared with control tissue. The aim of this study was to better understand metabolic processes in relation to the development of HCC. MATERIALS AND METHODS: Tumor, plasma, and bile samples were collected at the time of hepatic resection for HCC. All bile specimens were collected from the gallbladder at the beginning of the case. Normal bile and plasma were collected from patients undergoing cholecystectomy for non-neoplastic disease. Liver biopsy samples were taken from both tumor and adjacent normal tissue. Phospholipid levels were evaluated by enzyme-linked immunosorbent assay (ELISA) and high performance thin layer chromatography (HPTLC). RESULTS: Targeted phospholipid analysis by HPTLC and ELISA showed a modified choline metabolic profile within the liver, bile, and serum, culminating in an increased synthesis of lysophosphatidic acid (LPA). Choline was significantly increased in tumor tissue; lysophosphatidylcholine (LPC) was increased within bile while LPA was increased in all three biological samples of HCC patients compared with controls. Phosphatidylcholine was not significantly changed. CONCLUSIONS: HCC is congruent with a reprogramming of choline catabolism and phospholipid metabolism. Increased LPA may provide a potent mitogenic and proliferative microenvironment via autocrine/paracrine activation of high-affinity G-protein-coupled receptors. Additional research is required to better understand the role of these pathways in HCC development.
Subject(s)
Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Gene Expression Regulation, Neoplastic/physiology , Lipid Metabolism/genetics , Lipid Metabolism/physiology , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Bile/metabolism , Carcinoma, Hepatocellular/physiopathology , Case-Control Studies , Choline/metabolism , Gene Expression Profiling , Humans , Liver/metabolism , Liver Neoplasms/physiopathology , Lysophosphatidylcholines/metabolism , Lysophospholipids/metabolism , Phospholipids/metabolism , Receptors, G-Protein-Coupled/metabolismABSTRACT
Nuclear factor-kappaB (NF-kappaB) has been shown to play an important role in the development and progression of cancer. In this study, we systematically examined NF-kappaBp65 signaling pathway in both human hepatocellular carcinoma (HCC) tissue and HCC cell lines. NF-kappaBp65 signaling pathway is aberrantly expressed and activated in both human HCC tissue and HCC Hep3B cells. Inhibition of NF-kappaB activity significantly reduced proliferation and invasion of Hep3B cells as well as down-regulated the expression of invasion-related molecules including matrix metalloproteinase (MMP)-2, MMP-9, membrane type-1 MMP (MT1-MMP), urokinase plasminogen activator (uPA) and vascular endothelial growth factor (VEGF). Hep3B cells exhibited a dose-dependent increase in apoptosis after receiving sorafenib treatment. Inhibition of NF-kappaB activity strongly sensitized Hep3B cells to sorafenib-induced cell death. Mechanistically, combined treatment of sorafenib and NF-kappaB inhibition enhanced inhibition of MAPK signaling and down-regulation of anti-apoptotic protein Mcl-1 expression. These observations indicate that inhibition of NF-kappaB may be a potential antineoplastic therapy for HCC, especially the combination of NF-kappaB inhibition and sorafenib provides a novel therapeutic strategy for patients with advanced-stage HCC.
