TMPRSS2, a SARS-CoV-2 Internalization Protease is Downregulated in Head and Neck Cancer Patients.

Abstract

Background: SARS-coronavirus-2 enters host cells through binding of the Spike protein to ACE2 receptor and subsequent S priming by the TMPRSS2 protease. We aim to assess differences in both ACE2 and TMPRSS2 expression in normal tissues from oral cavity, pharynx, larynx and lung tissues as well as neoplastic tissues from the same areas.Methods: The study has been conducted using the TCGA and the Regina Elena Institute databases and validated by experimental model in HNSCC cells. We also included data from one COVID19 patient who went under surgery for HNSCC.Results: TMPRSS2 expression in HNSCC was significantly reduced compared to the normal tissues. It was more evident in women than in men, in TP53 mutated versus wild TP53 tumors, in HPV negative patients compared to HPV positive counterparts. Functionally, we modeled the multivariate effect of TP53, HPV, and other inherent variables on TMPRSS2. All variables had a statistically significant independent effect on TMPRSS2. In particular, in tumor tissues, HPV negative, TP53 mutated status and elevated TP53-dependent Myc-target genes were associated with low TMPRSS2 expression. The further analysis of both TCGA and our institutional HNSCC datasets identified a signature anti-correlated to TMPRSS2. As proof-of-principle we also validated the anti-correlation between microRNAs and TMPRSS2 expression in a SARS-CoV-2 positive HNSCC patient tissues Finally, we did not find TMPRSS2 promoter methylation.Conclusions: Collectively, these findings suggest that tumoral tissues, herein exemplified by HNSCC and lung cancers might be more resistant to SARS-CoV-2 infection due to reduced expression of TMPRSS2. These observations may help to better assess the frailty of SARS-CoV-2 positive cancer patients.

Estimating the viral loads of SARS-CoV-2 in the oral cavity when complicated with periapical lesions

“…Besides, oleic acid and l-lactic acid are known immunomodulators [70] that can downregulate receptor expression. Similar to our results, the expression of TMPRSS2 gene is lower in the oral cavity of the head and neck squamous cell carcinoma [71], confirming that other factors such as inflammatory responses may be involved.…”

Identification of key factors shaping integrated levels of ACE2 and TMPRSS2 expression in head and neck squamous cell carcinoma

“…Mutations in the TP53 tumor suppressor gene are the most frequently detected genetic alterations (about 70-80%) reported in HNSC [62]. Depletion of mutant p53 proteins was found to increase TMPRSS2 expression in HNSC cell lines [22], which supports our hypothesis. CASP8 is a protease involved in the extrinsic apoptotic pathway and also a negative modulator of programmed cell necrosis [63].…”

“…Due to the important roles of ACE2 and TM-PRSS2 in SARS-CoV-2 cell entry, researchers have investigated their expression to identify potential target organs or tissue types and predict the susceptibility to SARS-CoV-2 infection [22,23]. However, current studies based on ACE2 and TMPRSS2 mainly analyze each factor separately.…”

“…However, current studies based on ACE2 and TMPRSS2 mainly analyze each factor separately. For instance, a recent study suggested that HNSCs are less likely to be infected with SARS-CoV-2 than normal tissues for the constant ACE2 but decreased TMPRSS2 [22]. Nevertheless, real individuals present unique combination of the two genes, and the heterogeneity of individual ACE2 and TMPRSS2 expression patterns appears to be ignored by this method.…”

Identification of potential therapeutic targets and mechanisms of COVID-19 through network analysis and screening of chemicals and herbal ingredients

“…Among them, HIV-1 viral infection factor can interact with TP53 to induce G2 cell cycle arrest and positively regulate virus replication [85]. TP53 is significantly related to the expression of TMPRSS2, a key protein of SARS-Cov-2 invasion [86]. NFκB with genetic polymorphisms helps to clear the virus [87]; NFκB also participates in T cell activation and enhances HIV-1 gene expression [88].…”