Prostate adenocarcinoma and COVID-19: The possible impacts of TMPRSS2 expressions in susceptibility to SARS-CoV-2

Abstract

TMPRSS2 (OMIM: 602060) is a cellular protease involved in many physiological and pathological processes, and it facilitates entry of viruses such as SARS-CoV-2 into host cells. It is important to predict the prostate's susceptibility to SARS-CoV-2 infection in cancer patients and the disease outcome by assessing TMPRSS2 expression in cancer tissues. In this study, we conducted the expression profiles of the TMPRSS2 gene for COVID-19 in different normal tissues and PRAD (prostate adenocarcinoma) tumour tissues. TMPRSS2 is highly expressed in normal tissues including the small intestine, prostate, pancreas, salivary gland, colon, stomach, seminal vesicle and lung, and is increased in PRAD tissues, indicating that SARS-CoV-2 might attack not only the lungs and other normal organs, but also in PRAD cancer tissues. Hypomethylation of TMPRSS2 promoter may not be the mechanism for TMPRSS2 overexpression in PRAD tissues and PRAD pathogenesis. TMPRSS2 expresses eleven isoforms in PRAD tissues, with the TMPRSS2-001 isoform expressed highest and followed by TMPRSS2-201. Further isoform structures prediction showed that these two highly expressed isoforms have both SRCR_2 and Trypsin (Tryp_SPc) domains, which may be essential for TMPRSS2 functional roles for tumorigenesis and entry for SARS-CoV-2 in PRAD patients. Analyses of functional annotation and enrichment in TMPRSS2 showed that TMPRSS2 is mostly enriched in regulation of viral entry into host cells, protein processing and serine-type peptidase activity. TMPRSS2 is also associated with prostate gland cancer cell expression, different complex(es) formation, human influenza and carcinoma, pathways in prostate cancer, influenza A, and transcriptional misregulation in cancer. Altogether, even though high expression of TMPRSS2 may not be favourable for PRAD patient's survival, increased expression in these patients should play roles in susceptibility of the SARS-CoV-2 infection and clinical severity for COVID-19, highlighting the value of protective actions of PRAD cases by targeting or androgen-mediated therapeutic strategies in the COVID-19 pandemic.

Keywords: COVID-19; SARS-CoV-2; TMPRSS2 gene; prostate adenocarcinoma; susceptibility.

FIGURE 1

Homologs of the TMPRSS2 proteins and its expression in normal tissues and cells. A, Conservation for TMPRSS2 in eleven of different species. B, TMPRSS2 mRNA expression in normal tissues. RNA expression overview shows RNA of consensus NX (Normalized eXpression) levels from 55 types of tissues and 6 types of blood cells, created by combining three different transcriptomics sources: RNA‐seq data from HPA, RNA‐seq data from GTEx and CAGE data from FANTOM5. Colour‐coding is based on tissue groups with common functional features. HPA, Human Protein Atlas. GTEx, Genotype‐Tissue Expression

FIGURE 2

TMPRSS2 expression and its promoter methylation status in tumour tissues of prostate adenocarcinoma (PRAD) and corresponding normal tissues. A, Expression profile for TMPRSS2 in 32 different tumour tissues and their corresponding normal tissues (TCGA normal and GTEx data). Tissue‐wise expression using profiles. B, Expression profile for TMPRSS2 in PRAD tumour tissues and the corresponding normal tissues (TCGA normal and GTEx data) (*: P <.01). Tissue‐wise expression using box plots. C, The promoter methylation status for the regulating TMPRSS2 expression from PRAD. D, Pearson analysis for correlation between the mRNA expression and the methylation status for TMPRSS2 from PRAD. E, Spearman analysis for correlation between the mRNA expression and the methylation status for the TMPRSS2 gene from PRAD

FIGURE 3

Isoform usage and isoform structures for TMPRSS2. A, Isoform usage for TMPRSS2. In this panel, the profiles for the expression distribution (violin plot, upper panel) and isoform usage (bar plot, lower panel) of TMPRSS2 in PRAD are presented. X: isoforms, Y: cancer type (PRAD). B, Isoform structures for TMPRSS2. Multiple isoforms and their protein domain structures are shown in an interactive plot. Note: 5 isoforms' information is missing from Figure 3A: TMPRSS2‐004, TMPRSS2‐005, TMPRSS2‐006, TMPRSS2‐011, TMPRSS2‐002. Trysin, Tryp_SPc domain

FIGURE 4

Survival analysis for the gene of TMPRSS2 from PRAD patients for overall survival (A) and disease‐free survival (B). The GENT2 databases are used to assess on the TCGA‐COAD cohort data and plot Kaplan‐Meier curves

FIGURE 5

GO enrichment analysis results. The enriched information for biological process (A), molecular function (B), cellular component (C), associations between gene TMPRSS2 and tissues (D), associations between gene TMPRSS2 and cellular compartments (E), associations between gene TMPRSS2 and human disease (F) in GO analysis, and KEGG pathway (G) were obtained from the database of Enrichr, based on the TMPRSS2‐correlated genes. GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes