The Correlation Between Immune Invasion and SARS-COV-2 Entry Protein ADAM17 in Cancer Patients by Bioinformatic Analysis

Abstract

SARS-Cov-2 caused the COVID-19 pandemic worldwide. ADAM17 functions as a disintegrin and transmembrane metalloproteinase domain protein involved in the regulation of SARS-CoV-2 receptor ACE2. However, its impact on cancer patients infected with COVID-19 and its correlation with immune cell infiltration is unclear. This study compared ADAM17 expression between normal and tumor tissues based on GEPIA. The correlations between ADAM17 expression and immune cell infiltration and immunomodulators were investigated. Besides, treated drugs for targeting ADAM17 were searched in the TISDB database. We found that ADAM17 was highly conserved in many species and was mainly expressed in lung, brain, female tissues, bone marrow and lymphoid tissues. It was also highly expressed in respiratory epithelial cells of rhinitis and bronchus. ADAM17 expression in tumors was higher than that in several paired normal tissues and was negatively correlated with the prognosis of patients with malignant tumors. Interestingly, ADAM17 expression significantly correlated with immunomodulators and immune cell infiltration in normal and tumor tissues. Moreover, eight small molecules targeting ADAM17 only demonstrate therapeutic significance. These findings imply important implications for ADAM17 in cancer patients infected with COVID-19 and provide new clues for development strategy of anti-COVID-19.

Immunomodulatory role of metalloproteinase ADAM17 in tumor development

“…ADAM17 is a widely distributed transmembrane protein that is involved in different physiological processes such as inflammation, cell proliferation and apoptosis by its hydrolysis of various precursor membrane proteins, such as TNF-a, TNFRII, HB-EGF, IL-1R1, etc. It is localized in the membranes and cytoplasm of normal and tumor tissues and expressed in human lung, bronchus, nasopharynx, placenta, and lymphoid tissues (20,21). In lung or respiratory tissues, activation of ADAM17 may contribute to the shedding of the collectrin-like part of ACE2, leading to the formation of soluble ACE2 (sACE2) (22,23) and the development of inflammatory response (24).…”

“…In lung or respiratory tissues, activation of ADAM17 may contribute to the shedding of the collectrin-like part of ACE2, leading to the formation of soluble ACE2 (sACE2) (22,23) and the development of inflammatory response (24). Furthermore, in distinct cells from the lung, ADAM17 expression is relatively high in pneumocytes and endothelial cells (20), suggesting that ADAM17 may be participating in the cleavage and shedding of key proteins in lung tissues. Activation of ADAM17 promotes the release of soluble fms-like tyrosine kinase 1 (sFlt1) in the placenta and induces preeclampsia (25).…”

“…ADAM17 is lowly expressed in NK cells and its activation by IL-15 obstructs the proliferation of NK cells (19). Among multiple immune cells, ADAM17 is relatively high expressed in granulocytes and monocytes (20). ADAM17 mediates IL-6R shedding from neutrophils and induces apoptosis (27), which may be associated with a pro-inflammatory response mediated by the sIL-6R/IL-6 trans-signaling pathway (28).…”

Impact of TMPRSS2 Expression, Mutation Prognostics, and Small Molecule (CD, AD, TQ, and TQFL12) Inhibition on Pan-Cancer Tumors and Susceptibility to SARS-CoV-2

“…The human TMPRSS2 gene expression levels in cancers were evaluated in The Cancer Genome Atlas (TCGA) database (accessed on date for this link, e.g., , accessed on 1 September 2022), and the correlation of TMPRSS2 gene expression levels with cancer survival was evaluated by Gene Expression Profiling Interactive Analysis (GEPIA 2, , accessed on 1 September 2022) [ 43 , 44 , 45 ]. Mutation and survival analyses for TMPRSS2 in pan-cancers were performed using cBioPortal ( , accessed on 1 September 2022) in TCGA [ 46 , 47 ].…”

The regulation of ISG20 expression on SARS-CoV-2 infection in cancer patients and healthy individuals

“…Immunohistochemistry (IHC) in formalin-fixed, paraffinembedded breast cancer tissue sections from Chinese patients was performed as described previously (17,(25)(26)(27). The ISG20 antibody (C-12, cat #: sc-514979) for IHC and western blotting was purchased from Santa Cruz Biotechnology, Inc., USA.…”