Essential amino acids as diagnostic biomarkers of hepatocellular carcinoma based on metabolic analysis

Abstract

Metabolomics, defined as the comprehensive identification of all small metabolites in a biological sample, has the power to shed light on phenotypic changes associated with various diseases, including cancer. To discover potential metabolomic biomarkers of hepatocellular carcinoma (HCC), we investigated the metabolomes of tumor and non-tumor tissue in 20 patients with primary HCC using capillary electrophoresis-time-of-flight mass spectrometry. We also analyzed blood samples taken immediately before and 14 days after hepatectomy to identify associated changes in the serum metabolome. Marked changes were detected in the different quantity of 61 metabolites that could discriminate between HCC tumor and paired non-tumor tissue and additionally between HCC primary tumors and colorectal liver metastases. Among the 30 metabolites significantly upregulated in HCC tumors compared with non-tumor tissues, 10 were amino acids, and 7 were essential amino acids (leucine, valine, tryptophan, isoleucine, methionine, lysine, and phenylalanine). Similarly, the serum metabolomes of HCC patients before hepatectomy revealed a significant increase in 16 metabolites, including leucine, valine, and tryptophan. Our results reveal striking differences in the metabolomes of HCC tumor tissue compared with non-tumor tissue, and identify the essential amino acids leucine, valine, and tryptophan as potential metabolic biomarkers for HCC.

Metabolomics-Guided Identification of a Distinctive Hepatocellular Carcinoma Signature

“…Interestingly, contrary to the increase in arginine tissue abundance found in HCC, arginine levels have been shown to be decreased in the sera of HCC patients [37]. Together with metabolomic data from Morine et al and He et al, our findings are complementary in highlighting the important metabolic changes occurring in HCC from the identification of metabolites in liver samples [26,27]. Indeed, our study not only shows that HCC metabolomics has a distinct profile to non-tumoral liver, as suggested in other studies, but 1 H-NMR analysis has also proven that non-cirrhotic liver exhibits very limited metabolomic variability between individuals, highlighting the importance of studying liver tissue metabolomics in HCC among other liver diseases.…”

“…The quest for discovering such metabolic targets for anti-neoplastic treatment begins with a better understanding of HCC pathophysiology. Although some studies have reported metabolomics analyses of fluids from HCC patients, the metabolomics of HCC tissue itself has yet to be better characterized and validated [ 25 , 26 , 27 ]. Nevertheless, metabolomics has become a crucial tool for characterizing cancer cell metabolic behavior [ 22 , 28 ].…”

“…Given the important findings of the reported metabolomics analyses of HCC compared to adjacent normal liver tissues, considered with previous findings of metabolomics in HCC and cirrhosis, studying paramount changes in metabolism occurring during liver disease and hepatocarcinogenesis is bound to lead to paramount discoveries for improving the clinical management of HCC [ 26 , 27 ]. Together with other LC/MS studies of HCC, the main overlapping metabolites considered as altered pathways in liver tumors include alanine, arginine, lactate, succinate, NADH, and NADP metabolites [ 26 , 27 ]. Likewise, convincing evidence of the molecular analysis suggests metabolic reprogramming in HCC [ 19 , 20 , 21 ].…”

Biomarker Discovery for Hepatocellular Carcinoma in Patients with Liver Cirrhosis Using Untargeted Metabolomics and Lipidomics Studies

“…Hepatocellular carcinoma (HCC) is the most common form of liver cancer and ranks third on the list of primary causes of death due to cancer globally [1,2]. By 2025, it is expected that the annual incidence of liver cancer will climb to over a million cases, making HCC one of the leading causes of cancer-related mortality in several developed nations, including the United States [3].…”