Integrated Bioinformatic Analysis of SARS-CoV-2 Infection Related Genes ACE2, BSG and TMPRSS2 in Aerodigestive Cancers

Abstract

Background: Cancer patients are more vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection than the general population, with lung epithelial cells or enterocytes being the main targets. However, the expressions of SARS-CoV-2 entry-related genes in aerodigestive cancers have not been fully elucidated.

Methods: In this study, the expressions of SARS-CoV-2 receptors and cofactors, including angiotensin I-converting enzyme 2 (ACE2), basigin (BSG) and transmembrane serine protease 2 (TMPRSS2), were comprehensively assessed. We compared BSG and TMPRSS2 expressions between aerodigestive cancers and matched normal tissues through Gene Expression Profiling Interactive Analysis 2 (GEPIA2). Furthermore, expressions in healthy colon tissues at different anatomical locations were explored using the Genotype-Tissue Expression (GTEx) dataset. In addition, expressions among different tumor stages and the prognostic values were detected through GEPIA2. Moreover, the correlation between gene expression and immune infiltration was explored via Tumor Immune Estimation Resource (TIMER). Finally, expressions in primary colorectal cancer (CRC), lung metastasis and liver metastasis were investigated using the Gene Expression Omnibus (GEO) dataset GSE41258.

Results: Similar to ACE2, TMPRSS2 and BSG were also highly expressed in the digestive tracts. Intriguingly, BSG/TMPRSS2 expression in adjacent normal colon tissue or lung tissue was higher than that in corresponding healthy tissue, whereas they varied not among different tumor stages and correlated not with prognosis in aerodigestive cancers. Moreover, ACE2 was expressed at higher levels in lung metastases from CRC than in normal lung tissues.

Conclusion: SARS-CoV-2 entry genes were highly expressed in CRC, and we reported for the first time higher expression of ACE2 in lung metastases from CRC than in normal lung, indicating that these patients may be more susceptible to extrapulmonary or pulmonary SARS-CoV-2 infection. Since our study is a bioinformatic analysis, further experimental evidences and clinical data are urgently needed.

Keywords: ACE2; BSG; COVID-19; TMPRSS2; aerodigestive cancers.

Figure 1

BSG and TMPRSS2 expressions in normal human tissues and cancers. (A and B) Difference in BSG or TMPRSS2 expression between men and women from GTEx data. The y-axis represents transformed log2 (FPKM+1). (C and D) Overview of BSG or TMPRSS2 expression in different cancers from TCGA, as obtained from GEPIA2. (E and F) Box plot showing the mRNA expression levels of BSG or TMPRSS2 in human cancer cell lines from the CCLE database. Within each box, the median is a solid line, while the mean is a dashed line. Unpaired t-test were performed.

Figure 2

Differential expressions of BSG or TMPRSS2 among aerodigestive cancers, adjacent normal tissues and healthy tissues. (A and B) Boxplot showing differential BSG or TMPRSS2 expression between human digestive cancer and matched normal tissue (TCGA normal + GTEx normal), as obtained from GEPIA2. (C and D) Boxplot showing differential BSG or TMPRSS2 expression between lung cancer and matched normal lung (TCGA normal + GTEx normal), as obtained from GEPIA2. |log2 (fold change)| cutoff, 0.5; p-value cutoff, 0.05; jitter size, 0.4 (red color: cancer; gray color: normal). (E and F) Differential BSG or TMPRSS2 expression among COAD, adjacent normal colon and healthy colon (including transverse and sigmoid colon). (G and H) Differential BSG or TMPRSS2 expression among lung cancer, adjacent normal lung and healthy lung. Kruskal–Wallis tests with post hoc using Dunn’s method were performed.

Figure 3

Correlation between BSG or TMPRSS2 expression and tumor purity or immune infiltration in COAD, LUAD or LUSC through TIMER. (A and B) Scatter plots showing the correlations between BSG/TMPRSS2 expression and tumor purity or immune cell infiltration in COAD. (C and D) Scatter plots showing the correlations between BSG/TMPRSS2 expression and tumor purity or immune cell infiltration in LUAD. (E and F) Scatter plots showing the correlations between BSG/TMPRSS2 expression and tumor purity or immune cell infiltration in LUSC.

Figure 4

The correlations between BSG expression and tumor stages in aerodigestive cancers through GEPIA2. (A–G) Violin plots showing BSG expression at different stages of CHOL, COAD, ESCA, LIHC, PAAD, READ and STAD (cancers of the digestive tracts). (H–I) Violin plots showing BSG expression at different stages of lung cancers, including LUAD and LUSC.

Figure 5

The correlations between TMPRSS2 expression and tumor stages in aerodigestive cancers through GEPIA2. (A–G) Violin plots showing TMPRSS2 expression at different stages of CHOL, COAD, ESCA, LIHC, PAAD, READ and STAD (cancers of the digestive tracts). (H–I) Violin plots showing TMPRSS2 expression at different stages of lung cancers, including LUAD and LUSC.

Figure 6

Prognostic value of BSG or TMPRSS2 in aerodigestive cancers. (A and B) Survival significance map of BSG showed the survival analysis results, including OS and DFS, in aerodigestive cancers through GEPIA2 (the red or blue blocks denote higher or lower risks; the rectangles with frames indicate p < 0.05). (C and D) Kaplan-Meier plots of OS and DFS in LIHC and LUAD. Median BSG expression values were adopted as the cutoff. (E and F) Survival significance map of TMPRSS2 showed the survival analysis results in aerodigestive cancers.

Figure 7

ACE2, BSG and TMPRSS2 expressions in CRC, liver metastasis, normal liver, lung metastasis and normal lung. (A–F) Differential expression of ACE2, BSG or TMPRSS2 among CRC at different anatomical locations, using data from TCGA (A–C) or GSE41258 (D–F). (G–I) Differential expression of ACE2, BSG or TMPRSS2 among primary CRC, liver metastasis, normal liver, lung metastasis and normal lung. All samples were taken from CRC patients. Kruskal–Wallis tests with post hoc using Dunn’s method were performed.