ACE2 and TMPRSS2 Potential Involvement in Genetic Susceptibility to SARS-COV-2 in Cancer Patients

Ravaioli, Sara; Tebaldi, Michela; Fonzi, Eugenio; Angeli, Davide; Mazza, Massimiliano; Nicolini, Fabio; Lucchesi, Alessandro; Fanini, Francesca; Pirini, Francesca; Tumedei, Maria Maddalena; Cerchione, Claudio; Viale, Pierluigi; Sambri, Vittorio; Martinelli, Giovanni; Bravaccini, Sara

doi:10.1177/0963689720968749

Cited by 26 publications

(35 citation statements)

References 43 publications

(57 reference statements)

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“…Notably, the degree of d -dimer elevation positively correlated with mortality in COVID-19 patients [ 40 ]. In addition to arterial thrombotic events and microvascular thrombotic disorders, COVID-19 patients often have mild thrombocytopenia and appear to have increased platelet consumption, together with a corresponding increase in platelet production [ 41 ]. Conversely, if the entry of the SARS-COV-2 into the host cell requires the cleavage of the S protein into the S1 and S2 subunits by TMPRSS2 to promote pathogenicity and myocardial damage reported in COVID-19 patients [ 19 , 20 ], we might speculate that DM vs. Non-DM might over-express these adverse clinical pathways.…”

Section: Discussionmentioning

confidence: 99%

Glycated ACE2 receptor in diabetes: open door for SARS-COV-2 entry in cardiomyocyte

D’Onofrio

Scisciola

Sardu

et al. 2021

Cardiovasc Diabetol

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Rationale About 50% of hospitalized coronavirus disease 2019 (COVID-19) patients with diabetes mellitus (DM) developed myocardial damage. The mechanisms of direct SARS-CoV-2 cardiomyocyte infection include viral invasion via ACE2-Spike glycoprotein-binding. In DM patients, the impact of glycation of ACE2 on cardiomyocyte invasion by SARS-CoV-2 can be of high importance. Objective To evaluate the presence of SARS-CoV-2 in cardiomyocytes from heart autopsy of DM cases compared to Non-DM; to investigate the role of DM in SARS-COV-2 entry in cardiomyocytes. Methods and results We evaluated consecutive autopsy cases, deceased for COVID-19, from Italy between Apr 30, 2020 and Jan 18, 2021. We evaluated SARS-CoV-2 in cardiomyocytes, expression of ACE2 (total and glycosylated form), and transmembrane protease serine protease-2 (TMPRSS2) protein. In order to study the role of diabetes on cardiomyocyte alterations, independently of COVID-19, we investigated ACE2, glycosylated ACE2, and TMPRSS2 proteins in cardiomyocytes from DM and Non-DM explanted-hearts. Finally, to investigate the effects of DM on ACE2 protein modification, an in vitro glycation study of recombinant human ACE2 (hACE2) was performed to evaluate the effects on binding to SARS-CoV-2 Spike protein. The authors included cardiac tissue from 97 autopsies. DM was diagnosed in 37 patients (38%). Fourth-seven out of 97 autopsies (48%) had SARS-CoV-2 RNA in cardiomyocytes. Thirty out of 37 DM autopsy cases (81%) and 17 out of 60 Non-DM autopsy cases (28%) had SARS-CoV-2 RNA in cardiomyocytes. Total ACE2, glycosylated ACE2, and TMPRSS2 protein expressions were higher in cardiomyocytes from autopsied and explanted hearts of DM than Non-DM. In vitro exposure of monomeric hACE2 to 120 mM glucose for 12 days led to non-enzymatic glycation of four lysine residues in the neck domain affecting the protein oligomerization. Conclusions The upregulation of ACE2 expression (total and glycosylated forms) in DM cardiomyocytes, along with non-enzymatic glycation, could increase the susceptibility to COVID-19 infection in DM patients by favouring the cellular entry of SARS-CoV2.

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Section: Discussionmentioning

confidence: 99%

Glycated ACE2 receptor in diabetes: open door for SARS-COV-2 entry in cardiomyocyte

D’Onofrio

Scisciola

Sardu

et al. 2021

Cardiovasc Diabetol

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“…Besides prostate and BC, this concept could be translated also to other AR-expressing tumor types (AR+ TNBC, bladder, kidney, lung, and liver) or to healthy individuals at risk of contracting COVID-19. Despite it has been reported that various tissues express different levels of ACE2 and TMPRSS2 15 , to the best of our knowledge, it is not clear yet if those features are associated to an increased susceptibility, infectivity, and severity of symptoms in those patients. Moreover, it should be better investigated if a tissue-specific damage in COVID-19 patients correlates with the level of ACE2 and/or TMPRSS2 expression in the same tissue.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 90%

“…Moreover, it should be better investigated if a tissue-specific damage in COVID-19 patients correlates with the level of ACE2 and/or TMPRSS2 expression in the same tissue. Due to the pandemic situation, clinicians should pay even more attention to the choice of anti-AR and ER compounds to treat cancer patients given their effects on the regulation of TMPRSS2 expression 15 , since proper treatments could protect from COVID-19 infection and from the severity of its symptoms. We want to stress that for BC patients that can be treated with fulvestrant, tamoxifen or aromatase inhibitors, either tamoxifen or aromatase inhibitors rather than fulvestrant (that could result in TMPRSS2 upregulation), should be preferred.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

“…Moreover, it should be better investigated if a tissue-specific damage in COVID-19 patients correlates with the level of ACE2 and/or TMPRSS2 expression in the same tissue. Due to the pandemic situation, clinicians should pay even more attention to the choice of anti-AR and ER compounds to treat cancer patients given their effects on the regulation of TMPRSS2 expression 15 , since proper treatments could protect from COVID-19 infection and from the severity of its Role of AR and hormonal therapies in TMPRSS2 expression. Comparison of AR gene expression between healthy donor tissues and TCGA cancers according to sex and age categories is shown (A); comparison of AR (B) and TMPRSS2 (C) expression between healthy donor tissues and TCGA cancers in elderly females; and (D) schematic representation of hormonal therapies in prostate and breast tumors and their effects on AR function and TMPRSS2 expression.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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Estrogen and Androgen Receptor Inhibitors: Unexpected Allies in the Fight Against COVID-19

et al. 2021

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Translational Relevance No prophylactic treatments for COVID-19 have been clearly proven and found. In this pandemic context, cancer patients constitute a particularly fragile population that would benefit the best from such treatments, a present unmet need. TMPRSS2 is essential for COVID-19 replication cycle and it is under androgen control. Estrogen and androgen receptor dependent cues converge on TMPRSS2 regulation through different mechanisms of action that can be blocked by the use of hormonal therapies. We believe that there is enough body of evidence to foresee a prophylactic use of hormonal therapies against COVID-19 and this hypothesis can be easily tested on cohorts of breast and prostate cancer patients who follow those regimens. In case of pandemic, if the protective effect of hormonal therapies will be proven on cancer patients, the use of specific hormonal therapies could be extended to other oncological groups and to healthy individuals to decrease the overall risk of infection by SARS-CoV-2. Given the COVID-19 coronavirus emergency, a special focus is needed on the impact of this rapidly spreading viral infection on cancer patients. Androgen receptor (AR) signaling in the transmembrane protease serine 2 (TMPRSS2) regulation is emerging as an important determinant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility. In our study, we analyzed AR and TMPRSS2 expression in 17,352 normal and 9,556 cancer tissues from public repositories and stratified data according to sex and age. The emerging picture is that some patient groups may be particularly susceptible to SARS-CoV-2 infection and may benefit from antiandrogen- or tamoxifen-based therapies. These findings are relevant to choose proper treatments in order to protect cancer patients from concomitant SARS-CoV-2 contagion and related symptoms and put forward the idea that hormonal therapies could be used as prophylactic agents against COVID-19.

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“…Highly expressed entry proteins for SARS‐CoV‐2 may play critical roles for viral infection 22,31‐33 . TMPRSS2‐expressing cell line has been reported to be highly susceptible to SARS‐CoV‐2 infection 34,35 .…”

Section: Discussionmentioning

confidence: 99%

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

Cheng

Zhou

et al. 2021

J Cellular Molecular Medi

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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.

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ACE2 and TMPRSS2 Potential Involvement in Genetic Susceptibility to SARS-COV-2 in Cancer Patients

Cited by 26 publications

References 43 publications

Glycated ACE2 receptor in diabetes: open door for SARS-COV-2 entry in cardiomyocyte

Glycated ACE2 receptor in diabetes: open door for SARS-COV-2 entry in cardiomyocyte

Estrogen and Androgen Receptor Inhibitors: Unexpected Allies in the Fight Against COVID-19

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

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