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Comprehensive analysis of the amino acid metabolism-related gene signature for prognosis, tumor immune microenvironment, and candidate drugs in hepatocellular carcinoma
INTRODUCTION: Metabolic rewiring satisfies increased nutritional demands and modulates many oncogenic processes in tumors. Amino acid metabolism is abnormal in many malignancies. Metabolic reprogramming of amino acids not only plays a crucial role in sustaining tumor cell proliferation but also infl...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9792509/ https://www.ncbi.nlm.nih.gov/pubmed/36582227 http://dx.doi.org/10.3389/fimmu.2022.1066773 |
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author | Li, Yue Mo, Huanye Jia, Siying Wang, Jun Ma, Ying Liu, Xin Tu, Kangsheng |
author_facet | Li, Yue Mo, Huanye Jia, Siying Wang, Jun Ma, Ying Liu, Xin Tu, Kangsheng |
author_sort | Li, Yue |
collection | PubMed |
description | INTRODUCTION: Metabolic rewiring satisfies increased nutritional demands and modulates many oncogenic processes in tumors. Amino acid metabolism is abnormal in many malignancies. Metabolic reprogramming of amino acids not only plays a crucial role in sustaining tumor cell proliferation but also influences the tumor immune microenvironment. Herein, the aim of our study was to elucidate the metabolic signature of amino acids in hepatocellular carcinoma (HCC). METHODS: Transcriptome profiles of HCC were obtained from the TCGA and ICGC databases. Based on the expression of amino acid metabolism-related genes (AAMRGs), we clustered the HCC samples into two molecular subtypes using the non-negative matrix factorization algorithm. Then, we constructed the amino acid metabolism-related gene signature (AAMRGS) by Cox regression and LASSO regression. Afterward, the clinical significance of the AAMRGS was evaluated. Additionally, we comprehensively analyzed the differences in mutational profiles, immune cell infiltration, immune checkpoint expression, and drug sensitivity between different risk subgroups. Furthermore, we examined three key gene expressions in liver cancer cells by quantitative real-time PCR and conducted the CCK8 assay to evaluate the influence of two chemotherapy drugs on different liver cancer cells. RESULTS: A total of 81 differentially expressed AAMRGs were screened between the two molecular subtypes, and these AAMRGs were involved in regulating amino acid metabolism. The AAMRGS containing GLS, IYD, and NQO1 had a high value for prognosis prediction in HCC patients. Besides this, the two AAMRGS subgroups had different genetic mutation probabilities. More importantly, the immunosuppressive cells were more enriched in the AAMRGS-high group. The expression level of inhibitory immune checkpoints was also higher in patients with high AAMRGS scores. Additionally, the two AAMRGS subgroups showed different susceptibility to chemotherapeutic and targeted drugs. In vitro experiments showed that gemcitabine significantly reduced the proliferative capacity of SNU449 cells, and rapamycin remarkedly inhibited Huh7 proliferation. The five HCC cells displayed different mRNA expression levels of GLS, IYD, and NQO1. CONCLUSIONS: Our study explored the features of amino acid metabolism in HCC and identified the novel AAMRGS to predict the prognosis, immune microenvironment, and drug sensitivity of HCC patients. These findings might help to guide personalized treatment and improve the clinical outcomes of HCC. |
format | Online Article Text |
id | pubmed-9792509 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-97925092022-12-28 Comprehensive analysis of the amino acid metabolism-related gene signature for prognosis, tumor immune microenvironment, and candidate drugs in hepatocellular carcinoma Li, Yue Mo, Huanye Jia, Siying Wang, Jun Ma, Ying Liu, Xin Tu, Kangsheng Front Immunol Immunology INTRODUCTION: Metabolic rewiring satisfies increased nutritional demands and modulates many oncogenic processes in tumors. Amino acid metabolism is abnormal in many malignancies. Metabolic reprogramming of amino acids not only plays a crucial role in sustaining tumor cell proliferation but also influences the tumor immune microenvironment. Herein, the aim of our study was to elucidate the metabolic signature of amino acids in hepatocellular carcinoma (HCC). METHODS: Transcriptome profiles of HCC were obtained from the TCGA and ICGC databases. Based on the expression of amino acid metabolism-related genes (AAMRGs), we clustered the HCC samples into two molecular subtypes using the non-negative matrix factorization algorithm. Then, we constructed the amino acid metabolism-related gene signature (AAMRGS) by Cox regression and LASSO regression. Afterward, the clinical significance of the AAMRGS was evaluated. Additionally, we comprehensively analyzed the differences in mutational profiles, immune cell infiltration, immune checkpoint expression, and drug sensitivity between different risk subgroups. Furthermore, we examined three key gene expressions in liver cancer cells by quantitative real-time PCR and conducted the CCK8 assay to evaluate the influence of two chemotherapy drugs on different liver cancer cells. RESULTS: A total of 81 differentially expressed AAMRGs were screened between the two molecular subtypes, and these AAMRGs were involved in regulating amino acid metabolism. The AAMRGS containing GLS, IYD, and NQO1 had a high value for prognosis prediction in HCC patients. Besides this, the two AAMRGS subgroups had different genetic mutation probabilities. More importantly, the immunosuppressive cells were more enriched in the AAMRGS-high group. The expression level of inhibitory immune checkpoints was also higher in patients with high AAMRGS scores. Additionally, the two AAMRGS subgroups showed different susceptibility to chemotherapeutic and targeted drugs. In vitro experiments showed that gemcitabine significantly reduced the proliferative capacity of SNU449 cells, and rapamycin remarkedly inhibited Huh7 proliferation. The five HCC cells displayed different mRNA expression levels of GLS, IYD, and NQO1. CONCLUSIONS: Our study explored the features of amino acid metabolism in HCC and identified the novel AAMRGS to predict the prognosis, immune microenvironment, and drug sensitivity of HCC patients. These findings might help to guide personalized treatment and improve the clinical outcomes of HCC. Frontiers Media S.A. 2022-12-13 /pmc/articles/PMC9792509/ /pubmed/36582227 http://dx.doi.org/10.3389/fimmu.2022.1066773 Text en Copyright © 2022 Li, Mo, Jia, Wang, Ma, Liu and Tu https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Li, Yue Mo, Huanye Jia, Siying Wang, Jun Ma, Ying Liu, Xin Tu, Kangsheng Comprehensive analysis of the amino acid metabolism-related gene signature for prognosis, tumor immune microenvironment, and candidate drugs in hepatocellular carcinoma |
title | Comprehensive analysis of the amino acid metabolism-related gene signature for prognosis, tumor immune microenvironment, and candidate drugs in hepatocellular carcinoma |
title_full | Comprehensive analysis of the amino acid metabolism-related gene signature for prognosis, tumor immune microenvironment, and candidate drugs in hepatocellular carcinoma |
title_fullStr | Comprehensive analysis of the amino acid metabolism-related gene signature for prognosis, tumor immune microenvironment, and candidate drugs in hepatocellular carcinoma |
title_full_unstemmed | Comprehensive analysis of the amino acid metabolism-related gene signature for prognosis, tumor immune microenvironment, and candidate drugs in hepatocellular carcinoma |
title_short | Comprehensive analysis of the amino acid metabolism-related gene signature for prognosis, tumor immune microenvironment, and candidate drugs in hepatocellular carcinoma |
title_sort | comprehensive analysis of the amino acid metabolism-related gene signature for prognosis, tumor immune microenvironment, and candidate drugs in hepatocellular carcinoma |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9792509/ https://www.ncbi.nlm.nih.gov/pubmed/36582227 http://dx.doi.org/10.3389/fimmu.2022.1066773 |
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