Abstract
Angiotensin-converting enzyme 2 (ACE2) has been implicated as an oncogene in certain cancer types; however, there is a lack of analysis on the role of ACE2 in the predictive value for prognosis and immunotherapy response in various tumor types. This study used data from the Cancer Genome Atlas (TCGA), Tumor Immune Estimation Resource (TIMER 2.0), cBioPortal, and ROC Plotter databases to analyze the expression, prognosis, and immune cell infiltration of ACE2 in various tumor types. Furthermore, we analyzed the correlation between the expression of ACE2 and clinicopathological characteristics in 119 pairs of colorectal cancer (CRC) tissues using immunohistochemistry analysis, and then conducted the in vitro experiments to verify the role of ACE2 in the migration and proliferation of CRC cells. We found that ACE2 was highly expressed in CRC tissues compared with adjacent normal tissues, and that CRC patients with high ACE2 expression levels showed poor survival. Additionally, combined bioinformatics and qRT-PCR analysis identified a strong negative correlation between ACE2 expression and natural killer cell infiltration in CRC. Meanwhile, ACE2 expression was significantly elevated in patients resistant to anti-CTLA-4 and anti-PD-L1 therapy and was linked to poor prognosis. In vitro experiments showed that silencing ACE2 inhibits the proliferation and invasion of CRC cells. These results highlight ACE2’s involvement in CRC pathogenesis and cancer-immune interactions, positioning it as a promising prognostic and therapeutic biomarker in CRC.
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Data availability
The original datasets used in this study are available in the TCGA (https://portal.gdc.cancer.gov/) and Gene Expression Omnibus repository (https://www.ncbi.nlm.nih.gov/geo). The analyzed data sets generated during the research are available from the corresponding author upon reasonable request.
Abbreviations
- ACE2:
-
Angiotensin converting enzyme 2
- AngI:
-
Angiotensin I
- AngII:
-
Angiotensin II
- RAS:
-
Renin-angiotensin system
- CCLE:
-
Cancer Cell Line Encyclopedia
- TCGA:
-
The Cancer Genome Atlas
- PPI:
-
protein protein interaction
- GO:
-
Gene ontology
- KEGG:
-
Kyoto Encyclopedia of Genes and Genomes
- TIMER:
-
Tumor Immune Estimation Resource
- TAMs:
-
Tumor-associated macrophages
- BEST:
-
The Biomarker exploration of solid tumors
- IHC:
-
Immunohistochemistry
- qRT-PCR:
-
Quantitative real-time polymerase chain reaction
- TME:
-
Tumor microenvironment
- GDSC:
-
Cancer Drug Sensitivity Genomics
- IC50 :
-
Semi-maximum inhibitory concentration
- PD-1:
-
Programmed death 1
- MSI-H:
-
Microsatellite instability high
- MSI-L:
-
Microsatellite instability low
References
"Acharya, K. R. et al. Advances in the structural basis for angiotensin-1 converting enzyme (ACE) inhibitors.Bioscience Reports. 44(8) ,BSR20240130 (2024).
Gheblawi, M. et al. Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System. Circul. Res. 126 (10), 1456–1474 (2020).
Domińska, K. Involvement of ACE2/Ang-(1–7)/MAS1 Axis in the Regulation of Ovarian Function in Mammals. International J. Mol. Sciences 21(13) 4572 (2020).
Rizopoulos, T. et al. Angiotensin-converting enzyme 2 expression in human tumors: Implications for prognosis and therapy (Review). Oncol. Rep. 54 (3), 1–18 (2025).
Perlot, T. et al. ACE2 – From the renin–angiotensin system to gut microbiota and malnutrition. Microbes Infect. 15 (13), 866–873 (2013).
Yang, J-K. et al. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol. 47 (3), 193–199 (2009).
Zhang, Q. et al. ACE2 inhibits breast cancer angiogenesis via suppressing the VEGFa/VEGFR2/ERK pathway. Journal Experimental & Clin. Cancer Research 38(1),173 (2019).
Chen, S. et al. Causal linkage between angiotensin-converting enzyme 2 and risk of lung cancer: a bidirectional two-sample Mendelian randomization study. Frontiers Medicine 111419612 (2024).
Jedrzej Grzegrzolka, K. S. ACE and ACE2 expression in normal and malignant skin lesions. Folia Histochem. Cytobiol 50(3 ) 232-8 (2013).
Xu, J. et al. The ACE2/Angiotensin-(1–7)/Mas Receptor Axis: Pleiotropic Roles in Cancer. Frontiers Physiology 8276 (2017).
Xu, H. et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. International J. Oral Science 12(1) 8 (2020).
Narayan, S. S. et al. Angiotensin converting enzymes ACE and ACE2 in thyroid cancer progression. Neoplasma 67 (02), 402–409 (2020).
Bernardi, S. et al. Characterization and significance of ACE2 and Mas receptor in human colon adenocarcinoma. J. Renin-Angiotensin-Aldosterone Syst. 13 (1), 202–209 (2011).
Siegel, R. L. et al. Cancer statistics, CA: Cancer J. Clin. 75(1), 10–45(2025).
Zhou, M. et al. Plasma-derived exosomal tRF-3004a as a diagnostic biomarker for colorectal cancer. Scientific Reports 15(1) 45558 (2025).
Zhang, Y. et al. Associations between pathological features and risk of metachronous colorectal cancer. Int. J. Cancer. 155 (6), 1023–1032 (2024).
Zheng, W. et al. Increasing coverage in cervical and colorectal cancer screening by leveraging attendance at breast cancer screening: A cluster-randomised, crossover trial. PLOS Medicine 21(8) ,e1004431 (2024).
Hang, D. et al. Development and evaluation of a risk prediction tool for risk-adapted screening of colorectal cancer in China. Cancer Letters 597217057 (2024).
Li, J. et al. A phase IV study to evaluate the safety of fruquintinib in Chinese patients in real-world clinical practice. Oncologist 29 (8), e1012–e1019 (2024).
Tamraz, M. et al. Optimization of colorectal cancer screening strategies: New insights. World J. Gastroenterol. 30 (28), 3361–3366 (2024).
Qiao, X. et al. Discovery of novel and potent dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment via structure-based pharmacophore modelling, virtual screening, and molecular docking, molecular dynamics simulation studies, and biological evaluation. Journal Enzyme Inhib. Med. Chemistry 39(1) 2295241 (2023).
Tang, Z. et al. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 45 (W1), W98–W102 (2017).
Liang, Y. et al. In silico analyses of pan-squamous cell carcinoma unveiled the immunological implications of MRPL13, which had previously been under-recognized. Heliyon 10(1) e23582 (2024).
Chandrashekar, D. S. et al. UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses. Neoplasia 19 (8), 649–658 (2017).
Li, J-R. et al. Cancer RNA-Seq Nexus: a database of phenotype-specific transcriptome profiling in cancer cells. Nucleic Acids Res. 44 (D1), D944–D951 (2016).
Yang, X. et al. Comprehensive analysis of prognostic value and immune infiltration of IAPs family in hepatocellular carcinoma. J. Cancer. 14 (15), 2848–2866 (2023).
Cerami, E. et al. The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discov. 2 (5), 401–404 (2012).
Szklarczyk, D. et al. The STRING database in 2023: protein–protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 51 (D1), D638–D646 (2023).
Puig, R. R. et al. Network Building with the Cytoscape BioGateway App Explained in Five Use Cases. Current Protocols Bioinformatics 72(1) e106 (2020).
Yuan, H. et al. CancerSEA: a cancer single-cell state atlas. Nucleic Acids Res. 47 (D1), D900–D908 (2019).
Modhukur, V. et al. MethSurv: A Web Tool to Perform Multivariable Survival Analysis Using DNA Methylation Data. Epigenomics 10 (3), 277–288 (2017).
Shen, W. et al. Sangerbox: A comprehensive, interaction-friendly clinical bioinformatics analysis platform. iMeta 1(3) e36 (2022).
Li, T. et al. TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res. 77 (21), e108–e110 (2017).
Homayounfar, K. et al. Metastatic recurrence after complete resection of colorectal liver metastases: impact of surgery and chemotherapy on survival. Int. J. Colorectal Dis. 28 (7), 1009–1017 (2013).
Ou, C. et al. Targeting YAP1/LINC00152/FSCN1 Signaling Axis Prevents the Progression of Colorectal Cancer. Advanced Science 7(3)1901380 (2019).
Yu, X. et al. Immunological role and prognostic value of somatostatin receptor family members in colon adenocarcinoma. Frontiers Pharmacology 141255809 (2023).
Gajewski, T. F. et al. Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 14 (10), 1014–1022 (2013).
Palmeri, M. et al. Real-world application of tumor mutational burden-high (TMB-high) and microsatellite instability (MSI) confirms their utility as immunotherapy biomarkers. ESMO Open 7(1)100336 (2022).
Flores-Monroy, J. et al. Ang (1–7) is a modulator of the vasoconstrictor actions of Ang I and Ang II. J. Renin-Angiotensin-Aldosterone Syst. 16 (2), 254–259 (2015).
Geng, Y-L. et al. The role of angiotensin-(1–7) on acquired platinum resistance-induced angiogenesis in non-small cell lung cancer in vitro and in vivo. Neoplasma 68 (04), 770–779 (2021).
Qian, Y-R. et al. Angiotensin-converting enzyme 2 attenuates the metastasis of non-small cell lung cancer through inhibition of epithelial-mesenchymal transition. Oncol. Rep. 29 (6), 2408–2414 (2013).
He, C. et al. Integrated Bioinformatic Analysis of SARS-CoV-2 Infection Related Genes ACE2, BSG and TMPRSS2 in Aerodigestive Cancers. Journal Inflamm. Research Volume. 14, 791–802 (2021).
Royce, G. H. et al. The potential role of necroptosis in inflammaging and aging. GeroScience 41 (6), 795–811 (2019).
Zhuang, T. et al. Current status and future perspectives of platelet-derived extracellular vesicles in cancer diagnosis and treatment. Biomarker Research 12(1) 88 (2024).
Wang, D. et al. Crosstalk between N6-methyladenosine (m6A) modification and noncoding RNA in tumor microenvironment. Int. J. Biol. Sci. 19 (7), 2198–2219 (2023).
Sodhi, C. P. et al. Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration. Am. J. Physiology-Lung Cell. Mol. Physiol. 314 (1), L17–L31 (2018).
Cheng, Q. et al. ACE2 overexpression inhibits acquired platinum resistance-induced tumor angiogenesis in NSCLC. Oncol. Rep. 36 (3), 1403–1410 (2016).
Chen, Q. et al. Dendritic cells-derived extracellular vesicles in tumourigenesis: From biological roles to clinical implications. Cancer Letters 633218034 (2025).
Lisi, L. et al. Clinical experience with CTLA-4 blockade for cancer immunotherapy: From the monospecific monoclonal antibody ipilimumab to probodies and bispecific molecules targeting the tumor microenvironment. Pharmacological Research 175105997 (2022).
Acknowledgements
The authors would like to thank TCGA projects and KEGG platform for providing their platform and contributors for uploading their meaningful datasets.
Funding
This study was supported by the Central South University Innovation-Driven Research Programme (2023CXQD075).
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Guoqian Liu and Xiaoqian Yu conducted experimental operations, sample processing, and data analysis, and performed the experiments. All authors participated in writing the paper. Hui Nie and Chunlin Ou conceived and designed the experiments. All authors read and approved the final manuscript.
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This retrospective study was carried out using the opt-out method for the case series of our hospital. We have confirmed that all experiments were conducted in accordance with the relevant guidelines and regulations. This study was approved by the Ethics Committee of Xiangya Hospital (Approval No. 202308166) and was conducted in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was waived by our Institutional Review Board (Medical Ethics Committee of Xiangya Hospital, Central South University) because of the retrospective nature of our study. Research still conducts to comply with ethical norms.
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Liu, G., Yu, X., Jiang, W. et al. Angiotensin‑converting enzyme 2 as an immune and prognostic biomarker in colorectal cancer. Sci Rep (2026). https://doi.org/10.1038/s41598-026-43588-4
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DOI: https://doi.org/10.1038/s41598-026-43588-4
