Abstract
The liver is an active organ in energy metabolism, and hepatocellular carcinomas (HCC) therefore unavoidably induce a series of metabolic alterations in the serum metabolome. In this study, 587 sera from HCC patients, hepatitis B virus (HBV) infected subjects and healthy control subjects were employed to characterize metabolic alterations using a liquid chromatography tandem mass spectrometry-based metabolomics approach. d-Galactose significantly increased whereas undecanoyl-l-carnitine and PE (P-18:0/0:0) decreased in HCC patients when compared with non-HCC controls (HBVs and NCs). These metabolites were finally identified as independent diagnostic factors for HCC discrimination. The combination of discriminative metabolites and alpha-fetoprotein could also significantly improve the diagnostic performance for HCC in terms of the sensitivity, specificity and area under the curve of the receiver operating characteristic curve; these three parameters displayed values of 0.96, 0.92 and 0.98, respectively. Furthermore, network and pathway analyses were conducted to explore the latent relationship among differential metabolites. In the network analysis, metabolites of diverse categories (including amino acids, dipeptides, phospholipids, fatty acids, steroids and acylcarnitines) reflected the correlation between metabolite categories on material and energy conversion in HCC. Meanwhile, metabolites mapped in the pathways for primary bile acid biosynthesis and alanine, aspartate and glutamate metabolism revealed a centrality and significant variances. These results indicated that substantial biochemical perturbations occurred in these pathways in HCC patients. In summary, our study revealed the systematic landscape for metabolic alterations in the serum of HCC patients and provides useful information to clinicians and biologists.
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Abbreviations
- UPLC:
-
Ultra-performance liquid chromatography
- MS:
-
Mass spectrometry
- TOF:
-
Time-of-flight
- NMR:
-
Nuclear magnetic resonance spectroscopy
- HCC:
-
Hepatocellular carcinoma
- HBV:
-
Hepatitis B virus
- AFP:
-
α-Fetoprotein
- ROC:
-
Receiver operating characteristic
- AUC:
-
Area under the curve
- PCA:
-
Principle component analysis
- HCA:
-
Hierarchical cluster analysis
- PLS-DA:
-
Partial least square discriminant analysis
- OPLS-DA:
-
Orthogonal projection to latent structures discriminant analysis
- RF:
-
Random forest
- VIM:
-
Variable importance
- QC:
-
Quality control
- RT:
-
Retention time
- m/z :
-
Mass-to-charge ratio
- ALT:
-
Alanine aminotransferase
- AST:
-
Asparate aminotransferase
- BPC:
-
Basic peak chromatogram
- TNM:
-
Tumor node metastasis
- GLS:
-
Glutaminase
- ROS:
-
Reactive oxygen species
- PC:
-
Phosphatidylcholine
- PE:
-
Phosphatidylethanolamine
- LPC:
-
Lysophosphatidylcholine
- LPE:
-
Lysophosphatidylethanolamine
- FA:
-
Fatty acid
- DP:
-
Dipeptide
- ST:
-
Sterol lipid
- AA:
-
Amino acid
- Se:
-
Sensitivity
- Sp:
-
Specificity
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Acknowledgments
We express our appreciation to all the participants for donating their blood and clinical characteristic information to this study. We thank the stuff from the Department of Epidemiology and Biostatistics, Harbin Medical University, who helped in the data statistics and multivariate modeling. This work was supported by grant from Open Project of State Key Laboratory of Urban Water Resource and Environment of Harbin Institute of Technology (No. ES201115).
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The authors declare that they have no conflict of interest.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional committees and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Informed consent was obtained from all individual participants included in the study.
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Lu, X., Nie, H., Li, Y. et al. Comprehensive characterization and evaluation of hepatocellular carcinoma by LC–MS based serum metabolomics. Metabolomics 11, 1381–1393 (2015). https://doi.org/10.1007/s11306-015-0797-4
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DOI: https://doi.org/10.1007/s11306-015-0797-4