Disease monitoring of hepatocellular carcinoma through metabolomics

Abstract

We elucidate major pathways of hepatocarcinogenesis and accurate diagnostic metabolomic biomarkers of hepatocellular carcinoma (HCC) identified by contemporary HCC metabolomics studies, and delineate a model HCC metabolomics study design. A literature search was carried out on Pubmed for HCC metabolomics articles published in English. All relevant articles were accessed in full text. Major search terms included “HCC”, “metabolomics”, “metabolomics”, “metabonomic” and “biomarkers”. We extracted clinical and demographic data on all patients and consolidated the lead candidate biomarkers, pathways, and diagnostic performance of metabolomic expression patterns reported by all studies in tables. Where reported, we also extracted and summarized the metabolites and pathways most highly associated with the development of cirrhosis in table format. Pathways of lysophospholipid, sphingolipid, bile acid, amino acid, and reactive oxygen species metabolism were most consistently associated with HCC in the cited works. Several studies also elucidate metabolic alterations strongly associated with cirrhosis, with γ-glutamyl peptides, bile acids, and dicarboxylic acids exhibiting the highest capacity for stratifying cirrhosis patients from appropriately matched controls. Collectively, global metabolomic profiles of the referenced works exhibit a promising diagnostic capacity for HCC at a capacity greater than that of conventional diagnostic biomarker alpha-fetoprotein. Metabolomics is a powerful strategy for identifying global metabolic signatures that exhibit potential to be leveraged toward the screening, diagnosis, and management of HCC. A streamlined study design and patient matching methodology may improve concordance among metabolomic datasets in future works.

Metabolomic and transcriptomic profiling of hepatocellular carcinomas in Hras12V transgenic mice

“…Cell death and inflammation induced by BAs are suggested to be the underlying mechanisms . However, other investigations indicate that bile acid tends to be downregulated in clinical human HCC , and a significant negative correlation between bile acid levels and tumor burden was also observed . Consistent with the latter, we find that bile acid biosynthesis was substantially attenuated and that bile acid levels were significantly decreased in hepatic tumors.…”

“…In human HCC, although hyperactivation of Ras/MAPK is a frequent event, a portion of patients do not show signs of hyperactivation . In addition, various metabolic profiles have been reported due to the complicated causes, different grades, or subgroups of human HCC, and there have been different study designs . Similar to the findings on HCC of Ras‐Tg mice, it was suggested that there was a high glycolytic conversion of glucose into pyruvate in the cytosol followed by conversion into acetyl‐CoA and entry into the mitochondrial citric acid cycle with little conversion of pyruvate into lactate or alanine based on a panel of 31 pairs of human HCC tumors and corresponding nontumor liver tissues .…”

Uncovering the anticancer mechanism of Compound Kushen Injection against HCC by integrating quantitative analysis, network analysis and experimental validation

“…Pathway enrichment analysis uncovered the novel anti-HCC mechanisms of CKI, such as the regulation of amino acid metabolism and FRS2-mediated cascade. Metabolic disorders are involved in the pathogenesis of HCC 5 , 6 . Therefore, metabolomics was used to detect the differential metabolites and metabolic pathways regulated by CKI.…”

“…Approximately three-quarters of HCC cases are attributed to chronic HBV and HCV infections 2 . In recent years, substantial evidence has shown that genetic alterations 3 , 4 and metabolic disorders 5 , 6 also play critical roles in the pathogenesis of HCC. Most HCC patients are diagnosed at an advanced stage with few therapeutic measures.…”

Serum microRNA signatures and metabolomics have high diagnostic value in hepatocellular carcinoma

“…Compared with other metabolomic techniques, such as nuclear magnetic resonance (NMR) and liquid chromatography/mass spectrometry (LC/MS), GC/MS has a more robust result and is widely used in metabolite identification based on its high sensitivity, peak resolution, and reproducibility [ 16 ]. Several studies have reported the diagnostic value of metabolomics in HCC [ 17 ]. We further validated the diagnostic accuracy of GC/MS analysis and compared the most frequently used statistical methods.…”