AMPKα2 promotes tumor immune escape by inducing CD8+ T-cell exhaustion and CD4+ Treg cell formation in liver hepatocellular carcinoma
Abstract Background Adenosine monophosphate-activated protein kinase (AMPK) is associated with the development of liver hepatocellular carcinoma (LIHC). AMPKα2, an α2 subunit of AMPK, is encoded by PRKAA2, and functions as the catalytic core of AMPK. However, the role of AMPKα2 in the LIHC tumor imm...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-03-01
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| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12885-024-12025-y |
| _version_ | 1827327176475672576 |
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| author | Yan Ouyang Yan Gu Xinhai Zhang Ya Huang Xianpeng Wei Fuzhou Tang Shichao Zhang |
| author_facet | Yan Ouyang Yan Gu Xinhai Zhang Ya Huang Xianpeng Wei Fuzhou Tang Shichao Zhang |
| author_sort | Yan Ouyang |
| collection | DOAJ |
| description | Abstract Background Adenosine monophosphate-activated protein kinase (AMPK) is associated with the development of liver hepatocellular carcinoma (LIHC). AMPKα2, an α2 subunit of AMPK, is encoded by PRKAA2, and functions as the catalytic core of AMPK. However, the role of AMPKα2 in the LIHC tumor immune environment is unclear. Methods RNA-seq data were obtained from the Cancer Genome Atlas and Genotype-Tissue Expression databases. Using the single-cell RNA-sequencing dataset for LIHC obtained from the China National Genebank Database, the communication between malignant cells and T cells in response to different PRKAA2 expression patterns was evaluated. In addition, the association between PRKAA2 expression and T-cell evolution during tumor progression was explored using Pseudotime analysis, and the role of PRKAA2 in metabolic reprogramming was explored using the R “scMetabolis” package. Functional experiments were performed in LIHC HepG2 cells. Results AMPK subunits were expressed in tissue-specific and substrate-specific patterns. PRKAA2 was highly expressed in LIHC tissues and was associated with poor patient prognosis. Tumors with high PRKAA2 expression displayed an immune cold phenotype. High PRKAA2 expression significantly promoted LIHC immune escape. This result is supported by the following evidence: 1) the inhibition of major histocompatibility complex class I (MHC-I) expression through the regulation of interferon-gamma activity in malignant cells; 2) the promotion of CD8+ T-cell exhaustion and the formation of CD4+ Treg cells in T cells; 3) altered interactions between malignant cells and T cells in the tumor immune environment; and 4) induction of metabolic reprogramming in malignant cells. Conclusions Our study indicate that PRKAA2 may contribute to LIHC progression by promoting metabolic reprogramming and tumor immune escape through theoretical analysis, which offers a theoretical foundation for developing PRKAA2-based strategies for personalized LIHC treatment. |
| first_indexed | 2024-03-07T14:56:16Z |
| format | Article |
| id | doaj.art-3e6e7efc7fde4f358e4731934a2e130c |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-03-07T14:56:16Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-3e6e7efc7fde4f358e4731934a2e130c2024-03-05T19:23:56ZengBMCBMC Cancer1471-24072024-03-0124111710.1186/s12885-024-12025-yAMPKα2 promotes tumor immune escape by inducing CD8+ T-cell exhaustion and CD4+ Treg cell formation in liver hepatocellular carcinomaYan Ouyang0Yan Gu1Xinhai Zhang2Ya Huang3Xianpeng Wei4Fuzhou Tang5Shichao Zhang6Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Guizhou Medical UniversityKey Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Guizhou Medical UniversityKey Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Guizhou Medical UniversityImmune Cells and Antibody Engineering Research Center of Guizhou Province, Key Laboratory of Biology and Medical Engineering, Guizhou Medical UniversityKey Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Guizhou Medical UniversityImmune Cells and Antibody Engineering Research Center of Guizhou Province, Key Laboratory of Biology and Medical Engineering, Guizhou Medical UniversityImmune Cells and Antibody Engineering Research Center of Guizhou Province, Key Laboratory of Biology and Medical Engineering, Guizhou Medical UniversityAbstract Background Adenosine monophosphate-activated protein kinase (AMPK) is associated with the development of liver hepatocellular carcinoma (LIHC). AMPKα2, an α2 subunit of AMPK, is encoded by PRKAA2, and functions as the catalytic core of AMPK. However, the role of AMPKα2 in the LIHC tumor immune environment is unclear. Methods RNA-seq data were obtained from the Cancer Genome Atlas and Genotype-Tissue Expression databases. Using the single-cell RNA-sequencing dataset for LIHC obtained from the China National Genebank Database, the communication between malignant cells and T cells in response to different PRKAA2 expression patterns was evaluated. In addition, the association between PRKAA2 expression and T-cell evolution during tumor progression was explored using Pseudotime analysis, and the role of PRKAA2 in metabolic reprogramming was explored using the R “scMetabolis” package. Functional experiments were performed in LIHC HepG2 cells. Results AMPK subunits were expressed in tissue-specific and substrate-specific patterns. PRKAA2 was highly expressed in LIHC tissues and was associated with poor patient prognosis. Tumors with high PRKAA2 expression displayed an immune cold phenotype. High PRKAA2 expression significantly promoted LIHC immune escape. This result is supported by the following evidence: 1) the inhibition of major histocompatibility complex class I (MHC-I) expression through the regulation of interferon-gamma activity in malignant cells; 2) the promotion of CD8+ T-cell exhaustion and the formation of CD4+ Treg cells in T cells; 3) altered interactions between malignant cells and T cells in the tumor immune environment; and 4) induction of metabolic reprogramming in malignant cells. Conclusions Our study indicate that PRKAA2 may contribute to LIHC progression by promoting metabolic reprogramming and tumor immune escape through theoretical analysis, which offers a theoretical foundation for developing PRKAA2-based strategies for personalized LIHC treatment.https://doi.org/10.1186/s12885-024-12025-yAMPKα2Cell communicationCD8+ T-cell exhaustionTumor immune escapeImmunotherapyLiver hepatocellular carcinoma |
| spellingShingle | Yan Ouyang Yan Gu Xinhai Zhang Ya Huang Xianpeng Wei Fuzhou Tang Shichao Zhang AMPKα2 promotes tumor immune escape by inducing CD8+ T-cell exhaustion and CD4+ Treg cell formation in liver hepatocellular carcinoma BMC Cancer AMPKα2 Cell communication CD8+ T-cell exhaustion Tumor immune escape Immunotherapy Liver hepatocellular carcinoma |
| title | AMPKα2 promotes tumor immune escape by inducing CD8+ T-cell exhaustion and CD4+ Treg cell formation in liver hepatocellular carcinoma |
| title_full | AMPKα2 promotes tumor immune escape by inducing CD8+ T-cell exhaustion and CD4+ Treg cell formation in liver hepatocellular carcinoma |
| title_fullStr | AMPKα2 promotes tumor immune escape by inducing CD8+ T-cell exhaustion and CD4+ Treg cell formation in liver hepatocellular carcinoma |
| title_full_unstemmed | AMPKα2 promotes tumor immune escape by inducing CD8+ T-cell exhaustion and CD4+ Treg cell formation in liver hepatocellular carcinoma |
| title_short | AMPKα2 promotes tumor immune escape by inducing CD8+ T-cell exhaustion and CD4+ Treg cell formation in liver hepatocellular carcinoma |
| title_sort | ampkα2 promotes tumor immune escape by inducing cd8 t cell exhaustion and cd4 treg cell formation in liver hepatocellular carcinoma |
| topic | AMPKα2 Cell communication CD8+ T-cell exhaustion Tumor immune escape Immunotherapy Liver hepatocellular carcinoma |
| url | https://doi.org/10.1186/s12885-024-12025-y |
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