ObjectivesTwo of the main target tissues of SARS-coronavirus MESHD
2 are the oral cavity pharynx-larynx epithelium, the main virus entry site, and the lung epithelium. The virus enters host cells through binding of the Spike protein PROTEIN
to ACE2 HGNC
receptor and subsequent S priming by the HGNC
protease. Herein we aim to assess differences in both ACE2 HGNC
expression in normal tissues from oral cavity-pharynx-larynx and lung tissues as well as neoplastic tissues from the same histological areas. The information provided in this study may contribute to better understanding of SARS-coronavirus MESHD
2 ability to interact with different biological systems and contributes to cumulative knowledge on potential mechanisms to inhibit its diffusion.
Materials and MethodsThe study has been conducted using The Cancer Genome Atlas (TCGA) and the Regina Elena Institute (IRE) databases and validated by experimental model in HNSCC and Lung cancer cells. Data from one COVID19 MESHD
positive patient who was operated on for HNSCC was also included. We have analyzed 478 tumor samples and 44 normal samples from TCGA HNSCC cohort for whom both miRNA and mRNA sequencing was available. The dataset included 391 HPV- and 85 HPV+ cases, with 331 P53 HGNC
mutated and 147 P53 HGNC
wild type cases respectively. 352 out of 478 samples were male and 126 female. In IRE cohort we analyzed 66 tumor samples with matched normal sample for miRNA profiling and 23 tumor\normal matched samples for mRNA profiling. 45 out of 66 tumors from IRE cohort were male and 21 female, 38 were P53 HGNC
mutated and 27 wild type. Most patients (63 of 66) in IRE cohort were HPV negative. Normalized TCGA HNSCC gene expression and miRNA expression data were obtained from Broad Institute TCGA Genome Data Analysis Center (http://gdac.broadinstitute.org/). mRNA expression data from IRE cohort used in this study has been deposited to NCBIs Gene Expression Omnibus and is accessible through GEO series accession number GSE107591. In order to inference about potential molecular modulation of HGNC
, we also included miRNAs expression for the 66 IRE cohort matched tumor and normal samples from Agilent platform. DNA methylation data for TCGA tumors were obtained from Wanderer (http://maplab.imppc.org/wanderer/). We used miRWalk and miRNet web tools for miRNA-target interaction prediction and pathway enrichment analysis. The correlation and regression analyses as well as the miRNA and gene modulation and the survival analysis were conducted using Matlab R2019.
ResultsTMPRSS2 expression in HNSCC was significantly reduced compared to the normal tissues and had a prognostic value in HNSCC patients. Reduction of HGNC
expression was more evident in women than in men, in TP53 HGNC
mutated versus wild TP53 HGNC
tumors as well as in HPV negative patients compared to HPV positive counterparts. Functionally, we assessed the multivariate effect on HGNC
in a single regression model. We observed that all variables had an independent effect on HGNC
in HNSCC patients with HPV negative, TP53 HGNC
mutated status and with elevated TP53 HGNC
-dependent Myc HGNC
-target genes associated with low HGNC
expression. Investigation of the molecular modulation of HGNC
in both HNSCC and lung cancers revealed that expression of microRNAs targeting HGNC
anti-correlated in both TCGA and IRE HNSCC datasets, while there was not evidence of HGNC
promoter methylation in both tumor cohorts. Interestingly, the anti-correlation between microRNAs and HGNC
expression was corroborated by testing this association in a SARS-CoV-2 positive HNSCC patient.
ConclusionsCollectively, these findings suggest that tumoral tissues, herein exemplified by HNSCC and lung cancers might be more resistant to SARS-CoV-2 infection MESHD
due to reduced expression of HGNC
. The protective mechanism might occur, at least partially, through the aberrant activation of HGNC
targeting microRNAs; thereby providing strong evidence on the role of non-coding RNA molecule in host viral infection. These observations may help to better assess the frailty of SARS-CoV-2 positive cancer patients.