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. 2022 Nov 22:13:1286-1298.
doi: 10.18632/oncotarget.28306.

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

Yuji Morine  1 , Tohru Utsunomiya  1 , Hisami Yamanaka-Okumura  2 , Yu Saito  1 , Shinichiro Yamada  1 , Tetsuya Ikemoto  1 , Satoru Imura  1 , Shohei Kinoshita  3   4 , Akiyoshi Hirayama  3   4 , Yasuhito Tanaka  5 , Mitsuo Shimada  1
Affiliations

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

Yuji Morine et al. Oncotarget. .

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.

Keywords: diagnostic biomarker; essential amino acid; hepatocellular carcinoma; metabolomics.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1. Discrimination between tumor and non-tumor tissues from HCC patients by metabolomics.
OPLS-DA of HCC tumor and non-tumor tissues could clearly distinguished.
Figure 2
Figure 2. Metabolic analysis of primary and metastatic liver tumors from patients with HCC and colorectal cancer.
(A) PCA of components of tumor tissues from patients with HCC (HCC-pt), CRLM (CLRM-pt), and HCC of viral (HBV, HCV) and non-viral etiology (non-B/C). (B) PCA of components of non-tumor liver tissues from patients as described for (A).
Figure 3
Figure 3. Identification and quantification of metabolites in tumor and non-tumor tissues from HCC patients.
(A) Hierarchical clustering of metabolites present at different levels in HCC tumor tissue compared with non-tumor tissue. (B) Quantification of the indicated 10 amino acids in HCC tumor tissue compared with non-tumor tissue.
Figure 4
Figure 4. Discrimination between HCC patients before and after hepatectomy by serum metabolomics.
OPLS-DA of serum metabolites from HCC patients before and after hepatectomy.
Figure 5
Figure 5. Identification and quantification of serum metabolites in HCC patients before and after hepatectomy.
(A) Hierarchical clustering of metabolites in sera from HCC patients after hepatectomy compared with before hepatectomy. (B) Quantification of EAAs in sera from HCC patients after hepatectomy compared with before hepatectomy. (C) Quantification of EAAs in HCC tumor tissues of patients stratified according to HCC staging.
See this image and copyright information in PMC

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