Metabolomics Study of Stepwise Hepatocarcinogenesis From the Model Rats to Patients: Potential Biomarkers Effective for Small Hepatocellular Carcinoma Diagnosis

Abstract

The aim of this study is to find the potential biomarkers from the rat hepatocellular carcinoma (HCC) disease model by using a non-target metabolomics method, and test their usefulness in early human HCC diagnosis. The serum metabolic profiling of the diethylnitrosamine-induced rat HCC model, which presents a stepwise histopathological progression that is similar to human HCC, was performed using liquid chromatography-mass spectrometry. Multivariate data analysis methods were utilized to identify the potential biomarkers. Three metabolites, taurocholic acid, lysophosphoethanolamine 16:0, and lysophosphatidylcholine 22:5, were defined as "marker metabolites," which can be used to distinguish the different stages of chemical hepatocarcinogenesis. These metabolites represented the abnormal metabolism during the progress of hepatocarcinogenesis, which could also be found in patients. To test their diagnosis potential 412 sera from 262 patients with HCC, 76 patients with cirrhosis and 74 patients with chronic hepatitis B were collected and studied, it was found that 3 marker metabolites were effective for the discrimination of small liver tumor (solitary nodules of less than 2 cm in diameter) patients, achieved a sensitivity of 80.5% and a specificity of 80.1%,which is better than those of ␣-fetoprotein (53 and 64%, respectively). Moreover, they were also effective for the discrimination of all HCCs and chronic liver disease patients, which could achieve a sensitivity of 87.5% and a specificity of 72.3%, better than those of ␣-fetoprotein (61.2 and 64%). These results indicate metabolomics method has

UPLC-based metabonomic applications for discovering biomarkers of diseases in clinical chemistry

“…Five metabolites quinaldic acid, β-sitosterol, arachidyl carnitine, oleamide and tetradecanal were observed for the first time. Nine metabolite lysophosphatidylethanolamines, glycerophosphocholine, LPCs, CDCA glycine conjugate and Lphenylalanine had been reported as serum metabolite biomarkers for HCC diagnosis in previous research [39][40][41].…”

Power of metabolomics in diagnosis and biomarker discovery of hepatocellular carcinoma

“…A nontarget metabolomics method was to find the potential biomarkers from the rat HCC disease model and test their usefulness in early human HCC diagnosis. 32 Three metabolites, taurocholic acid, lysophosphoethanolamine 16:0, and lysophosphatidylcholine 22:5 were defined as ''marker metabolites,'' which can be used to distinguish the different stages of hepatocarcinogenesis and represent the abnormal metabolism during the progress of HCC in patients. Moreover, they were also effective for the discrimination of all HCC and chronic LD patients, which could achieve high sensitivity and specificity, better than those of AFP.…”

Metabolomics for tumor marker discovery and identification based on chromatography–mass spectrometry

“…As liver-specific metabolites, bile acids are considered to be potential markers related to HCC in many metabolomic studies [59][60][61][62][63]. Recent studies also revealed that some rarely detected bile acids in healthy adults may be potential indicators of HCC, such as fetal bile acids and sulfated bile acids [61][62][63].…”

“…Bile acids are commonly considered to be indicators of liver injury and may vary during the development of hepatocarcinogenesis [59]. As liver-specific metabolites, bile acids are considered to be potential markers related to HCC in many metabolomic studies [59][60][61][62][63].…”

“…Even small tumors can change metabolic profiles, regardless of the appearance of cirrhosis lesions in the liver. On the basis of this work and to overcome the challenges in collecting samples from liver cancer patients, the authors used a two-step strategy to explore and differentiate metabolites in diethylnitrosamine-induced rat models with different liver diseases, which were then validated with 412 human serum samples [59]. Three metabolites, taurocholic acid, lysophosphoethanolamine 16:0 and lysophosphatidylcholine 22:5, were validated as 'marker metabolites', which were effective for distinguishing HCCs from chronic liver disease patients with a sensitivity of 87.5% and a specificity of 72.3%, which were better values than AFP ( sensitivity of 61.2% and specificity of 64%).…”