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Expressions and significances of the angiotensin-converting enzyme 2 gene, the receptor of SARS-CoV-2 for COVID-19 - PubMed

Expressions and significances of the angiotensin-converting enzyme 2 gene, the receptor of SARS-CoV-2 for COVID-19

Jiewen Fu et al. Mol Biol Rep. 2020 Jun.

Abstract

The ACE2 gene is a receptor of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) for COVID-19 (coronavirus disease 2019). To analyze the expression profiles and clinical significances for this gene in humans, RNA-seq data representing 27 different tissues were analyzed using NCBI; total RNA was extracted from different tissues of mouse and semi-quantitative reverse transcriptional-polymerase chain reaction (Q-RT-PCR) was carried out. Immunohistochemistry expression profiles in normal tissues and cancer tissues and TCGA survival analysis in renal and liver cancer were conducted. ACE2 was highly conserved in different species. In normal tissues, ACE2 expression distributions were organ-specific, mainly in the kidney, male testis and female breast, and cardiovascular and gastrointestinal systems. High level of expression in testis, cardiovascular and gastrointestinal system indicated that SARS-CoV-2 might not only attack the lungs, but also affect other organs, particularly the testes, thus it may severely damage male sexual development for younger male and lead to infertility in an adult male, if he contracted COVID-19. On the other side, high expression of ACE2 was correlated with increased survival rate in renal and liver cancer, indicating that ACE2 is a prognostic marker in both renal cancer and liver cancers. Thus, the ACE2 is a functional receptor for SARS-CoV-2 and has a potential anti-tumor role in cancer. Taken together, this study may not only provide potential clues for further medical pathogenesis of COVID-19 and male fertility, but also indicate the clinical significance of the role of the ACE2 gene in cancer.

Keywords: ACE2 gene; COVID-19; Cancer; Immunohistochemistry (IHC); RNA-sequencing; SARS-CoV-2; Testis.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1

Homologs of the ACE2 proteins. a Conservation for ACE2 in 11 different species. b The indicated two conserved domains. c Multiple sequence alignment results of the N-terminus of ACE2 (RBD located terminal) among indicated different species. “*” indicates the identity whereas “.” and “:” show the similarity. Amino acids from 1 to 418 of human ACE2 are presented

Fig. 2
Fig. 2

The mRNA expression profiles in human and mouse. a The ACE2 expression profiles in the indicated 27 different human tissues. RPKM stands for number reads per kilobase (kB) of transcript per million mapped reads. In RNA-Sequencing, the relative expression of a transcript was proportional to the number of cDNA fragments that originate from it. b The Ace2 gene mRNA expression profile analysis in the different tissues of organisms in the mouse. NC negative control, muscle skeletal muscle

Fig. 3
Fig. 3

Immunohistochemistry (IHC) images of normal tissues (testis and lung) for ACE2. a IHC image of normal testis tissue from a male of age 38 (Patient id: 305). b IHC image of normal testis tissue from a male of age 26 (Patient id: 2254). c IHC image of normal lung tissue from a female of age 49 (Patient id: 2268). Bottom panels, enlarged pictures from top panels. Blue arrows indicate the representative positive results in macrophages, black arrow indicates the representative positive results in type I alveolar epithelial cells, red arrows indicate the representative positive results in type II alveolar epithelial cells (c, red arrow), but dashed red arrows indicate the representative negative staining of type II alveolar epithelial cells. (Color figure online)

Fig. 4
Fig. 4

The protein and mRNA expression overviews for ACE2 in humans. a The ACE2 protein expression overviews. Tissue microarrays are used to show antibody staining for IHC in 20 different types of cancer with total samples of 216 cancer patients. Color-coded bars indicate the percentage of patients with high and medium protein expression levels in each cancer. The types of cancer are color-coded according to which type of normal organ cancer originates from. ACE2 protein expression with low or un-detectable will results in a white bar. b The ACE2 mRNA expression overviews. RNA expression overview shows RNA-seq data from The Cancer Genome Atlas (TCGA) from 17 cancer types representing 21 cancer subtypes with a corresponding major cancer type in the Human Pathology Atlas for comparisons. The FPKMs for each gene were subsequently used for quantification of expression with a detection threshold of the FPKM value of 1. Genes were categorized using the same classification as described above. RPKM stands for number fragments per kilobase of exon per million reads

Fig. 5
Fig. 5

Kaplan–Meier plots for all cancers where high expression of the ACE2 gene has a significant (P < 0.001) association with patient survival are shown in this summary. Prognostic marker is indicated in renal cancer (favorable) and liver cancer (favorable). Whether the prognosis is favorable or unfavorable is indicated in brackets. a Kaplan–Meier plot includes ACE2 expression and survival data for patients with renal cancer. b Kaplan–Meier plot includes ACE2 expression and survival data for patients with liver cancer. Right panels indicate the TCGA RNA-seq dataset for renal and liver cancer respectively

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