12-hydroxy-5-8-10-14-eicosatetraenoic-acid and Liver-Neoplasms

Ischemia reperfusion injury (IRI) has been shown to increase the risk of tumor recurrence after liver surgery. Also, nonalcoholic fatty liver disease (NAFLD) is associated with increased HCC recurrence. ALOX12-12-HETE pathway is activated both in liver IRI and NASH. Also, ALOX12-12-HETE has been shown to mediate tumorigenesis and progression. Therefore, our study aims to investigate whether the ALOX12-12-HETE-GPR31 pathway involved in IRI induced HCC recurrence in NAFLD.. HCC mouse model was used to mimic the HCC recurrence in NAFLD. Western Blot, qPCR, Elisa and Immunofluorescence analysis were conducted to evaluate the changes of multiple signaling pathways during HCC recurrence, including ALOX12-12-HETE axis, EMT, MMPs and PI3K/AKT/NF-κB signaling pathway. We also measured the expression and functional changes of GPR31 by siRNA.. ALOX12-12-HETE pathway was activated in liver IRI and its activation was further enhanced in NAFLD, which induced more severe HCC recurrence in fatty livers than normal livers. Inhibition of ALOX12-12-HETE by ML355 reduced the HCC recurrence in fatty livers. In vitro studies showed that 12-HETE increased the expression of GPR31 and induced epithelial-mesenchymal transition (EMT) and matrix metalloprotein (MMPs) by activating PI3K/AKT/NF-κB pathway. Furthermore, knockdown of GPR31 in cancer cells inhibited the HCC recurrence in NAFLD.. ALOX12-12-HETE-GPR31 played an important role in HCC recurrence and might be a potential therapeutic target to reduce HCC recurrence after surgery in fatty livers.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Arachidonate 12-Lipoxygenase; Carcinoma, Hepatocellular; Cell Line, Tumor; Disease Progression; Epithelial-Mesenchymal Transition; Humans; Liver Neoplasms; Male; Mice; Neoplasm Recurrence, Local; Non-alcoholic Fatty Liver Disease; Receptors, G-Protein-Coupled; Reperfusion Injury; Signal Transduction; Sulfonamides

Chronic hepatitis B virus (HBV) infection is the main etiologic risk factor for hepatocellular carcinoma (HCC). Early studies indicated that the increase of omega-6-derived oxylipins may be involved in the pathogenesis of HBV-related HCC, yet their changes during the distinct clinical phases of chronic HBV infection remain unclear. To fill this gap, in this study we investigated the omega-6-derived oxylipin profiles in patients with three major clinical stages of chronic HBV infection (chronic hepatitis B, liver cirrhosis, and HCC).. Eighteen omega-6-derived oxylipins were quantified in serum samples of 34 patients with chronic hepatitis B, 46 patients with HBV-related liver cirrhosis, 38 patients with HBV-related HCC, and 50 healthy controls using liquid chromatography tandem mass spectrometry.. Seven oxylipins were found to be altered in patients with HBV-related liver diseases, including 9,10-dihydroxyoctadecenoic acid (9,10-DiHOME), 12,13-DiHOME, 14,15-dihydroxyeicosatrienoic acid (14,15-DiHETrE), 13-hydroxyoctadecadienoic acid (13-HODE), 12-hydroxyeicosatetraenoic acid (12-HETE), 11-HETE, and thromboxane B. This study for the first time shows the correlations between CYP450-derived oxylipins and the progression of chronic HBV infection, and sheds a new light on the surveillance of HBV-related live diseases using oxylipins.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adult; Aged; Biomarkers, Tumor; Carcinoma, Hepatocellular; Female; Hepatitis B, Chronic; Humans; Linoleic Acids; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Oleic Acids; Oxylipins; Thromboxane B2

The metabolic pathway disturbances associated with hepatocellular carcinoma (HCC) remain unsatisfactorily characterized. Determination of the metabolic alterations associated with the presence of HCC can improve our understanding of the pathophysiology of this cancer and may provide opportunities for improved disease monitoring of patients at risk for HCC development. To characterize the global metabolic alterations associated with HCC arising from hepatitis C (HCV)-associated cirrhosis using an integrated non-targeted metabolomics methodology employing both gas chromatography/mass spectrometry (GC/MS) and ultrahigh-performance liquid chromatography/electrospray ionization tandem mass spectrometry (UPLC/MS-MS).. The global serum metabolomes of 30 HCC patients, 27 hepatitis C cirrhosis disease controls and 30 healthy volunteers were characterized using a metabolomics approach that combined two metabolomics platforms, GC/MS and UPLC/MS-MS. Random forest, multivariate statistics and receiver operator characteristic analysis were performed to identify the most significantly altered metabolites in HCC patients vs. HCV-cirrhosis controls and which therefore exhibited a close association with the presence of HCC.. Elevated 12-hydroxyeicosatetraenoic acid (12-HETE), 15-HETE, sphingosine, γ-glutamyl oxidative stress-associated metabolites, xanthine, amino acids serine, glycine and aspartate, and acylcarnitines were strongly associated with the presence of HCC. Elevations in bile acids and dicarboxylic acids were highly correlated with cirrhosis.. Integrated metabolomic profiling through GC/MS and UPLC/MS-MS identified global metabolic disturbances in HCC and HCV-cirrhosis. Aberrant amino acid biosynthesis, cell turnover regulation, reactive oxygen species neutralization and eicosanoid pathways may be hallmarks of HCC. Aberrant dicarboxylic acid metabolism, enhanced bile acid metabolism and elevations in fibrinogen cleavage peptides may be signatures of cirrhosis.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Amino Acids; Bile Acids and Salts; Carcinoma, Hepatocellular; Chromatography, High Pressure Liquid; Dicarboxylic Acids; Gas Chromatography-Mass Spectrometry; Hepatitis C; Humans; Hydroxyeicosatetraenoic Acids; Liver Cirrhosis; Liver Neoplasms; Metabolome; Metabolomics; Multivariate Analysis; ROC Curve; Sphingosine; Tandem Mass Spectrometry; Xanthine