Reduced levels of N’-methyl-2-pyridone-5-carboxamide and lysophosphatidylcholine 16:0 in the serum of patients with intrahepatic cholangiocarcinoma, and the correlation with recurrence-free survival

Abstract

We searched for metabolic biomarkers that may predict the prognosis of patients with intrahepatic cholangiocarcinoma (IHCC). To this end, a total of 237 serum samples were obtained from IHCC patients (n = 87) and healthy controls (n = 150), and serum metabolites were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Two stratified algorithms were used to select the metabolites, the levels of which predicted the prognosis of IHCC patients. We performed MS/MS and multiple-reaction-monitoring MS analyses to identify and quantify the selected metabolites. Continuous biomarker levels were dichotomized based on cutoffs that maximized between-group differences in recurrence-free survival (RFS) in terms of the log-rank test statistic. These RFS differences were analyzed using the log-rank test, and survival curves were drawn with the aid of the Kaplan–Meier method. Six metabolites (l-glutamine, lysophosphatidylcholine [LPC] 16:0, LPC 18:0, N’-methyl-2-pyridone-5-carboxamide [2PY], fibrinopeptide A [FPA] and uric acid) were identified as candidate metabolic biomarkers for predicting the prognosis of IHCC patients. Of these metabolites, levels of l-glutamine, uric acid, LPC 16:0, and LPC 18:0 were significantly lower in the serum from IHCC patients, whereas levels of 2PY and FPA were significantly higher (p < 0.01). 2PY and LPC 16:0 showed significantly better RFS at low level than high level (2PY, median RFS: 15.16 months vs. 5.90 months, p = 0.037; LPC 16:0, median RFS: 15.62 months vs. 9.83 months, p = 0.035). The findings of this study suggest that 2PY and LPC 16:0 identified by metabolome-based approaches may be useful biomarkers for IHCC patients.

Individualized metabolic profiling stratifies pancreatic and biliary tract cancer: a useful tool for innovative screening programs and predictive strategies in healthcare

“…Furthermore, LysoPC can inhibit cholangiocyte apoptosis by inducing COX-2 expression via a Raf-1-dependent mechanism, and such anti-apoptotic effects might be important in biliary tract carcinogenesis in patients with compromised pancreaticobiliary ductal junctions [ 46 ]. Similar to other types of cancer, we found a reduced level of LysoPC in the serum of BTC patients [ 47 ], as well as significantly decreased levels of LysoPC in the bile of these patients compared with those with benign biliary tract disease [ 10 ]. These findings strongly imply that LysoPC may be useful for BTC diagnosis and prognosis [ 47 , 48 ].…”

“…Similar to other types of cancer, we found a reduced level of LysoPC in the serum of BTC patients [ 47 ], as well as significantly decreased levels of LysoPC in the bile of these patients compared with those with benign biliary tract disease [ 10 ]. These findings strongly imply that LysoPC may be useful for BTC diagnosis and prognosis [ 47 , 48 ].…”

An Updated Review of Pro- and Anti-Inflammatory Properties of Plasma Lysophosphatidylcholines in the Vascular System

“…In the context of cancer research decreased levels of certain LPCs were identified as potential biomarkers in colorectal cancer [ 144 , 145 , 146 ], hepatocellular carcinoma [ 147 ], ovarian cancer [ 148 , 149 ], cholangiocarcinoma [ 150 ], pancreatic and biliary tract cancer [ 151 ] as well as cervical cancer [ 152 ]. Of particular interest, LPC levels proved to correctly predict the recurrence of prostate cancer after surgery [ 153 ].…”

The Biochemical Pathways of Nicotinamide-Derived Pyridones

“…Pyridones and methyl-nicotinamide are measured in clinical settings to identify vitamin B3 deficiencies [ 48 , 49 ] and in metabolomics as they associate with increased NAD consumption [ 50 , 51 ] and cellular dysfunctions in tissues [ 51 , 52 , 53 , 54 , 55 ]. Unfortunately, over the years the nomenclature used to describe the pyridone’s nature thus characterized has been somewhat unsystematic and exquisitely confusing (e.g., [ 5 , 11 , 56 ]).…”