An asparagine metabolism-based classification reveals the metabolic and immune heterogeneity of hepatocellular carcinoma
Abstract Introduction and objectives hepatocellular carcinoma (HCC) is the major form of liver cancer with a poor prognosis. Amino acid metabolism has been found to alter in cancers and contributes to malignant progression. However, the asparagine metabolism status and relevant mechanism in HCC were...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-10-01
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| Series: | BMC Medical Genomics |
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| Online Access: | https://doi.org/10.1186/s12920-022-01380-z |
| _version_ | 1811257101450739712 |
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| author | Jianguo Bai Ruifeng Tang Keyu Zhou Jialei Chang Hongyue Wang Qixin Zhang Jiahui Shi Chao Sun |
| author_facet | Jianguo Bai Ruifeng Tang Keyu Zhou Jialei Chang Hongyue Wang Qixin Zhang Jiahui Shi Chao Sun |
| author_sort | Jianguo Bai |
| collection | DOAJ |
| description | Abstract Introduction and objectives hepatocellular carcinoma (HCC) is the major form of liver cancer with a poor prognosis. Amino acid metabolism has been found to alter in cancers and contributes to malignant progression. However, the asparagine metabolism status and relevant mechanism in HCC were barely understood. Methods By conducting consensus clustering and the least absolute shrinkage and selection operator regression of HCC samples from three cohorts, we classified the HCC patients into two subtypes based on asparagine metabolism level. The Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analyses and Gene Set Enrichment Analysis of the differentially expressed genes between two subgroups were conducted. Immune cell infiltration was evaluated using CIBERSORT algorithm. The prognostic values of genes were analyzed by univariate and multivariate cox regression, ROC curve and Kaplan–Meier survival estimate analyses. Cell types of sing-cell RNA sequencing (scRNA-seq) data were clustered utilizing UMAP method. Results HCC patients with higher asparagine metabolism level have worse prognoses. Moreover, we found the distinct energy metabolism patterns, DNA damage response (DDR) pathway activating levels, drug sensitivities to DDR inhibitors, immune cell compositions in the tumor microenvironment and responses to immune therapy between two subgroups. Further, we identified a potential target gene, glutamic-oxaloacetic transaminase 2 (GOT2). GOT2 downregulation was associated with worse HCC prognosis and increased infiltration of T regulatory cells (Tregs). ScRNA-seq revealed the GOT2 downregulation in cancer stem cells compared with HCC cells. Conclusions Taken together, HCC subtype which is more reliant on asparagine and glutamine metabolism has a worse prognosis, and a core gene of asparagine metabolism GOT2 is a potential prognostic marker and therapeutic target of HCC. Our study promotes the precision therapy of HCC and may improve patient outcomes. |
| first_indexed | 2024-04-12T17:52:14Z |
| format | Article |
| id | doaj.art-dfff6ee83e6d4ce58f292303979cff31 |
| institution | Directory Open Access Journal |
| issn | 1755-8794 |
| language | English |
| last_indexed | 2024-04-12T17:52:14Z |
| publishDate | 2022-10-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medical Genomics |
| spelling | doaj.art-dfff6ee83e6d4ce58f292303979cff312022-12-22T03:22:29ZengBMCBMC Medical Genomics1755-87942022-10-0115111810.1186/s12920-022-01380-zAn asparagine metabolism-based classification reveals the metabolic and immune heterogeneity of hepatocellular carcinomaJianguo Bai0Ruifeng Tang1Keyu Zhou2Jialei Chang3Hongyue Wang4Qixin Zhang5Jiahui Shi6Chao Sun7Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical UniversityDepartment of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical UniversityDepartment of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical UniversityDepartment of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical UniversityDepartment of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical UniversityDepartment of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical UniversityDepartment of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical UniversityDepartment of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical UniversityAbstract Introduction and objectives hepatocellular carcinoma (HCC) is the major form of liver cancer with a poor prognosis. Amino acid metabolism has been found to alter in cancers and contributes to malignant progression. However, the asparagine metabolism status and relevant mechanism in HCC were barely understood. Methods By conducting consensus clustering and the least absolute shrinkage and selection operator regression of HCC samples from three cohorts, we classified the HCC patients into two subtypes based on asparagine metabolism level. The Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analyses and Gene Set Enrichment Analysis of the differentially expressed genes between two subgroups were conducted. Immune cell infiltration was evaluated using CIBERSORT algorithm. The prognostic values of genes were analyzed by univariate and multivariate cox regression, ROC curve and Kaplan–Meier survival estimate analyses. Cell types of sing-cell RNA sequencing (scRNA-seq) data were clustered utilizing UMAP method. Results HCC patients with higher asparagine metabolism level have worse prognoses. Moreover, we found the distinct energy metabolism patterns, DNA damage response (DDR) pathway activating levels, drug sensitivities to DDR inhibitors, immune cell compositions in the tumor microenvironment and responses to immune therapy between two subgroups. Further, we identified a potential target gene, glutamic-oxaloacetic transaminase 2 (GOT2). GOT2 downregulation was associated with worse HCC prognosis and increased infiltration of T regulatory cells (Tregs). ScRNA-seq revealed the GOT2 downregulation in cancer stem cells compared with HCC cells. Conclusions Taken together, HCC subtype which is more reliant on asparagine and glutamine metabolism has a worse prognosis, and a core gene of asparagine metabolism GOT2 is a potential prognostic marker and therapeutic target of HCC. Our study promotes the precision therapy of HCC and may improve patient outcomes.https://doi.org/10.1186/s12920-022-01380-zHepatocellular carcinomaAsparagine metabolismTumor microenvironmentDNA damage responseGOT2 |
| spellingShingle | Jianguo Bai Ruifeng Tang Keyu Zhou Jialei Chang Hongyue Wang Qixin Zhang Jiahui Shi Chao Sun An asparagine metabolism-based classification reveals the metabolic and immune heterogeneity of hepatocellular carcinoma BMC Medical Genomics Hepatocellular carcinoma Asparagine metabolism Tumor microenvironment DNA damage response GOT2 |
| title | An asparagine metabolism-based classification reveals the metabolic and immune heterogeneity of hepatocellular carcinoma |
| title_full | An asparagine metabolism-based classification reveals the metabolic and immune heterogeneity of hepatocellular carcinoma |
| title_fullStr | An asparagine metabolism-based classification reveals the metabolic and immune heterogeneity of hepatocellular carcinoma |
| title_full_unstemmed | An asparagine metabolism-based classification reveals the metabolic and immune heterogeneity of hepatocellular carcinoma |
| title_short | An asparagine metabolism-based classification reveals the metabolic and immune heterogeneity of hepatocellular carcinoma |
| title_sort | asparagine metabolism based classification reveals the metabolic and immune heterogeneity of hepatocellular carcinoma |
| topic | Hepatocellular carcinoma Asparagine metabolism Tumor microenvironment DNA damage response GOT2 |
| url | https://doi.org/10.1186/s12920-022-01380-z |
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