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. 2022 May 18:13:903461.
doi: 10.3389/fimmu.2022.903461. eCollection 2022.

Distinct Roles of Adenosine Deaminase Isoenzymes ADA1 and ADA2: A Pan-Cancer Analysis

Zhao-Wei Gao  1 , Lan Yang  1 , Chong Liu  1 , Xi Wang  1 , Wen-Tao Guo  1 , Hui-Zhong Zhang  1 , Ke Dong  1
Affiliations

Distinct Roles of Adenosine Deaminase Isoenzymes ADA1 and ADA2: A Pan-Cancer Analysis

Zhao-Wei Gao et al. Front Immunol. .

Abstract

Objective: Adenosine deaminase (ADA) plays an important role in immune response, which includes two isoenzymes: ADA1 and ADA2. This study aims to explore the roles of ADA1 and ADA2 in cancers.

Methods: Human Protein Atlas (HPA) and Gene Expression Profiling Interactive Analysis (GEPIA2) databases were used to analyze the mRNA expression of ADA1 and ADA2 in human normal cells and tumor tissues. The enzyme assay was used to detect the ADA1 and ADA2 activities in serum from cancer patients. The Kaplan-Meier (KM) plotter was used to analyze the prognostic value of ADA1 and ADA2. TIMER2.0 was used to explore how ADA1 and ADA2 correlate with immune infiltration and immune checkpoints. cBioPortal database was used to investigate the mutations of ADA1 and ADA2. LinkedOmics was used to screen the ADA1 and ADA2 expression-related genes.

Results: ADA1 was significantly increased in several tumor tissues, including cholangiocarcinoma (CHOL), lymphoid neoplasm diffuse large B-cell lymphoma (DLBC), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), thymoma (THYM), and uterine carcinosarcoma (UCS). ADA2 expression was significantly increased in esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), acute myeloid leukemia (LAML), OV, PAAD, skin cutaneous melanoma (SKCM), and stomach adenocarcinoma (STAD). There were no significant changes in serum ADA1 activities in most cancers, while serum ADA2 activities were increased in most cancers. For prognosis, high ADA1 expression was associated with the poor survival in several cancers, including esophageal squamous cell carcinoma (ESCC), HNSC, KIRC, kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), and uterine corpus endometrial carcinoma (UCEC). However, high ADA2 expression showed a favorable prognosis in breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), HNSC, KIRC, KIRP, LUAD, OV, PAAD, sarcoma, and THYM. ADA1 showed a moderate positive correlation with multiple infiltrating immune cells in most cancers. ADA2 was positively correlated with B cells, CD8 T cells, monocytes/macrophages, and dendritic cells (DCs) and was strongly negatively correlated with myeloid-derived suppressor cells. Function analysis showed that ADA1 expression-related genes were mainly enriched in cell division biological progression. However, ADA2-related genes were mainly associated with immune response.

Conclusion: As isoenzymes, ADA1 and ADA2 showed opposite prognostic values and different correlative patterns with immune infiltrating. These data demonstrated the distinct roles of ADA1 and ADA2 in cancer. ADA2 might act as a protective factor in cancer.

Keywords: ADA1; ADA2; cancer; immune infiltration; prognosis.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
ADA1 and ADA2 expression profiles in human tissues. (A, B) HPA database showed the ADA1 and ADA2 expression in normal human tissues. (C, D) Comparisons of ADA1 and ADA2 expression levels between tumor and non-tumor control tissues based on TCGA and GTEx database (black, expression levels showed no significant difference between tumor and normal; red, expression levels were increased in tumor; green, expression levels were decreased in tumor). HPA, Human Protein Atlas; TCGA, The Cancer Genome Atlas; GTEx, Genotype-Tissue Expression.
Figure 2
Figure 2
Prognostic value of ADA1 in different cancers. (A) Forest plots showed the relation between ADA1 expression and OS of cancer patients. (B–I) Survival curves of ESCC, HNSC, KIRC, KIRP, LIHC, LUAD, THYM, and UCEC. *p < 0.05, ***p < 0.001. OS, overall survival; ESCC, esophageal squamous cell carcinoma; HNSC, head and neck squamous cell carcinoma; KIRC, kidney renal clear cell carcinoma; KIRP, kidney renal papillary cell carcinoma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; THYM, thymoma; UCEC, uterine corpus endometrial carcinoma.
Figure 3
Figure 3
Prognostic value of ADA2 in different cancers. (A) Forest plots showed the relation between ADA2 expression and OS of cancer patients. (B–K) Survival curves of BRCA, CESC, HNSC, KIRC, KIRP, LUAD, OV, PAAD, SARC, and THYM. *p < 0.05, **p < 0.01, ***p < 0.001. OS, overall survival; BRCA, breast invasive carcinoma; CESC, cervical squamous cell carcinoma and endocervical adenocarcinoma; HNSC, head and neck squamous cell carcinoma; KIRC, kidney renal clear cell carcinoma; KIRP, kidney renal papillary cell carcinoma; LUAD, lung adenocarcinoma; OV, ovarian serous cystadenocarcinoma; PAAD, pancreatic adenocarcinoma; SARC, sarcoma; THYM, thymoma.
Figure 4
Figure 4
Associations of ADA1 and ADA2 expression with immune infiltration. (A) The correlations between ADA1 expression and immune infiltration in cancers. (B) The correlations between ADA2 expression and immune infiltration in cancers.
Figure 5
Figure 5
The correlations between ADA1, ADA2, and immune checkpoints. (A) The correlations between ADA1 and confirmed immune checkpoints in multiple cancers. (B) The correlations between ADA2 and confirmed immune checkpoints in multiple cancers. *p < 0.05, **p < 0.01, ***p < 0.001.
Figure 6
Figure 6
ADA1 and ADA2 mutation landscape. (A, B) ADA1 and ADA2 mutation frequency in multiple TCGA pan-cancer studies according to the cBioPortal database. (C, D) The general mutation count of ADA1 and ADA2 in various TCGA cancer types by the cBioPortal database. (E, F) Mutation diagram of ADA1 and ADA2 in different cancer types across protein domains. TCGA, The Cancer Genome Atlas.
Figure 7
Figure 7
ADA1 and ADA2 expression-related genes and function analysis. (A) The shared gene signature positively correlated to ADA1 expression among LUAD, KIRP, and KIRC. (B) The shared gene signature positively correlated to ADA2 expression among LUAD, KIRP, and KIRC. (C) Function enrichment analysis of shared ADA1-related genes (n = 20). (D–G) Function enrichment analysis of shared ADA2-related genes (n = 403). TCGA, The Cancer Genome Atlas; LUAD, lung adenocarcinoma; KIRP, kidney renal papillary cell carcinoma; KIRC, kidney renal clear cell carcinoma.
Figure 8
Figure 8
The activities of ADA1 and ADA2 in serum from cancer patients. (A) Serum ADA1 activity in cancers. (B) Serum ADA2 activity in cancers. *p < 0.05, **p < 0.01, ***p < 0.001. ns, no significant.
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