title: Dynamic metabolic change is indicative of inflammation-induced transformation of hepatic cells.
abstract: The observation that prolonged inflammation plays a causative role in cancer development has been well documented. However, an incremental process that leads from healthy to malignant phenotypes has not yet been described. Experimentally induced hepatocellular carcinoma is considered one of the representative laboratory models for studying this process. Hepatic exposure to viral infection or toxic reagents leads to chronic inflammation and gradual transformation into hepatocellular carcinoma. Here we present metabolomic profiles of hepatic cells at different stages during inflammation-induced cellular transformation by N-nitrosodiethylamine. Using gas chromatography-mass spectrometry, we quantitatively assessed the changes in cellular metabolites during the transformation process in hepatitis and liver cirrhosis. Further pathway analysis of the differentially expressed metabolites showed that carbohydrate metabolism and lipid metabolism were greatly altered in hepatitis and liver cirrhosis, respectively. Additionally, the enhanced inflammation in cirrhosis was associated with a shift from carbohydrate metabolism to lipid and amino acid metabolism. Among the differentially expressed metabolites found in diseased mouse livers, d-glucose and d-mannitol showed the most significant changes, highlighting them as potential early-diagnostic biomarkers of hepatocellular carcinoma development. Taken together, these investigations into the dynamic metabolic changes that occur during the precancerous stages of hepatocellular carcinoma add to and refine understanding of how chronic inflammation ultimately leads to cancer. Furthermore, the findings set the stage for identifying metabolites that may serve as early-diagnostic indicators of these unfolding events.
authors.affiliation: Department of Basic Medicine, Medical College of Xiamen University/Cancer Research Center of Xiamen University, Xiamen 361102, PR China; Lawrence Berkeley National Laboratory, Berkeley, CA 94720-8197, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Peng
authors.affiliation: Zhongshan Hospital, Medical College of Xiamen University, Xiamen 361004, PR China; Department of Basic Medicine, Medical College of Xiamen University/Cancer Research Center of Xiamen University, Xiamen 361102, PR China.
authors.forename: Fan
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Basic Medicine, Medical College of Xiamen University/Cancer Research Center of Xiamen University, Xiamen 361102, PR China.
authors.forename: Rong
authors.initials: R
authors.lastname: Han
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.
authors.forename: George
authors.initials: G
authors.lastname: Luo
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Cathopoulis
authors.affiliation: Department of Basic Medicine, Medical College of Xiamen University/Cancer Research Center of Xiamen University, Xiamen 361102, PR China.
authors.forename: Kun
authors.initials: K
authors.lastname: Lu
authors.affiliation: Department of Basic Medicine, Medical College of Xiamen University/Cancer Research Center of Xiamen University, Xiamen 361102, PR China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Basic Medicine, Medical College of Xiamen University/Cancer Research Center of Xiamen University, Xiamen 361102, PR China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.affiliation: Zhongshan Hospital, Medical College of Xiamen University, Xiamen 361004, PR China.
authors.forename: Guo-Yan
authors.initials: GY
authors.lastname: Liu
authors.affiliation: Zhongshan Hospital, Medical College of Xiamen University, Xiamen 361004, PR China. Electronic address: 103753999@qq.com.
authors.forename: Jian-Chun
authors.initials: JC
authors.lastname: Cai
authors.affiliation: Zhongshan Hospital, Medical College of Xiamen University, Xiamen 361004, PR China; Department of Basic Medicine, Medical College of Xiamen University/Cancer Research Center of Xiamen University, Xiamen 361102, PR China. Electronic address: shisonglin@xmu.edu.cn.
authors.forename: Song-Lin
authors.initials: SL
authors.lastname: Shi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D016000:Cluster Analysis; D004052:Diethylnitrosamine; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D055442:Metabolome / Q000187:drug effects; D055432:Metabolomics / Q000379:methods*; D008810:Mice, Inbred C57BL; D011759:Pyrrolidines; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013859:Thiocarbamates
chemical_list: D008070:Lipopolysaccharides; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D004052:Diethylnitrosamine
keywords: Biomarker; Chronic inflammation; Hepatocellular carcinoma; Mass spectrometry; Metabolomics