Hepatocellular carcinoma (HCC) is a highly malignant tumor with poor prognosis and high mortality. There is a dearth of effective early diagnostic tools, so liver resection surgery and liver transplantation are the only effective medical treatments. The most commonly used marker for HCC detection is serum alpha fetoprotein (AFP), which has low sensitivity and specificity. Because aberrant DNA methylation of genes and miRNAs occurs early in most cancers, we explored whether circulating methylation markers could be promising clinical tools for HCC diagnosis. Using a whole-genome approach, we identified many hyper-methylated miRNAs in HCC. Furthermore, three abnormally methylated genes and one miRNA were combined to establish a methylation predictive model and tested for its diagnostic and prognostic potential in HCC. Using plasma samples, the predictive model exhibited high sensitivity and specificity (> 80%) for HBV-related HCC. Most importantly, nearly 75% of patients who could not be diagnosed with AFP at 20 ng/mL were detected by this model. Further, the predictive model exhibited an exceedingly high ability to predict 5-year overall survival in HCC patients. These data demonstrate the high diagnostic and prognostic potential of methylation markers in the plasma of HCC patients.
Objectives
The omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to have shared and independent effects on inflammation and on lipid and glucose metabolism. However, the differential effects of EPA and DHA on serum metabolome remain elusive in humans.
Methods
Twenty-one subjects (9 men and 12 women, 50–75 y) with chronic inflammation (C reactive protein > 2 μg/mL) were enrolled in a randomized, controlled crossover trial consisting of a 4-week lead-in phase (high oleic sunflower oil, 3 g/d; baseline) followed by randomization to two sequential 10-week supplementation phases with pure EPA and DHA (3 g/d each) separated by a 10-week washout. Primary metabolites (n = 129) were measured in fasting serum samples by gas chromatography-mass spectrometry. Linear-mixed model was created to compare changes in metabolites by EPA and DHA relative to baseline. Pathway analysis (MetaboAnalyst 4.0, https://www.metaboanalyst.ca) was performed to identify the biological pathways associated with affected metabolites.
Results
DHA altered a greater number of metabolites than EPA (19 vs 11). Both EPA and DHA significantly lowered constitutive metabolites of the TCA cycle and the alanine, aspartate and glutamate metabolism pathway, with DHA showing a greater reduction than EPA. EPA significantly increased UDP-glucuronic acid and glucuronic acid, and DHA increased only glucuronic acid, thus affecting pathways where these metabolites play key roles (ascorbate and aldarate metabolism; pentose and glucuronate interconversions).
Conclusions
DHA affected more metabolites than EPA. The greater impact of DHA on the TCA cycle and the larger effect of EPA on the glucose-derived glucuronic acid-related pathways suggest their differential ability to modulate metabolic pathways.
Funding Sources
Grant number: 2015–67,017-23,142 from the National Institute of Food and Agriculture, U.S. Department Of Agriculture.
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