COVID-19 disease and malignant cancers: The impact for the furin gene expression in susceptibility to SARS-CoV-2

Abstract

Furin is a proprotein convertase that activates different kinds of regulatory proteins, including SARS-CoV-2 spike protein which contains an additional furin-specific cleavage site. It is essential in predicting cancer patients' susceptibility to SARS-CoV-2 and the disease outcomes due to varying furin expressions in tumor tissues. In this study, we analyzed furin's expression, methylation, mutation rate, functional enrichment, survival rate and COVID-19 outcomes in normal and cancer tissues using online databases, and our IHC. As a result, furin presented with biased expression profiles in normal tissues, showing 12.25-fold higher than ACE2 in the lungs. The furin expression in tumors were significantly increased in ESCA and TGCT, and decreased in DLBC and THYM, indicating furin may play critical mechanistic functions in COVID-19 viral entry into cells in these cancer patients. Line with furin over/downexpression, furin promoter hypo-/hyper-methylation may be the regulatory cause of disease and lead to pathogenesis of ESCA and THYM. Furthermore, presence of FURIN−201 isoform with functional domains (P_proprotein, Peptidase_S8 and S8_pro-domain) is highest in all cancer types in comparison to other isoforms, demonstrating its use in tumorigenesis and SARS-Cov-2 entry into tumor tissues. Furin mutation frequency was highest in UCES, and its mutation might elevate ACE2 expression in LUAD and UCEC, reduce ACE2 expression in COAD, elevate HSPA5 expression in PAAD, and elevate TMPRSS2 expression in BRCA. These results showed that furin mutations mostly increased expression of ACE2, HSPA5, and TMPRSS2 in certain cancers, indicating furin mutations might facilitate COVID-19 cell entry in cancer patients. In addition, high expression of furin was significantly inversely correlated with long overall survival (OS) in LGG and correlated with long OS in COAD and KIRC, indicating that it could be used as a favorable prognostic marker for cancer patients' survival. GO and KEGG demonstrated that furin was mostly enriched in genes for metabolic and biosynthetic processes, retinal dehydrogenase activity, tRNA methyltransferase activity, and genes involving COVID-19, further supporting its role in COVID-19 and cancer metabolism. Moreover, Cordycepin (CD) inhibited furin expression in a dosage dependent manner. Altogether, furin's high expression might not only implies increased susceptibility to SARS-CoV-2 and higher severity of COVID-19 symptoms in cancer patients, but also it highlights the need for cancer treatment and therapy during the COVID-19 pandemic. CD might have a potential to develop an anti-SARS-CoV-2 drug through inhibiting furin expression.

Testicular Germ Cell Tumours and Proprotein Convertases

“…Even if this approach does not eliminate the tumour, it could be combined with other immunotherapeutic strategies to enhance their impact. Combining this information with recent publications confirming furin overexpression in TGCTs, what began as a hypothetical connection is gaining more and more relevance [ 95 , 96 ].…”

“…It is interesting to note that KRAS is linked to TGCT tumour development, so furin could be an interesting molecule to study in this regard [ 53 , 92 ]. In fact, two recent bioinformatic analysis have pointed out a significant increase in furin expression in TGCTs compared to healthy tissue, which only reinforces the notion that this could be a fertile ground for further exploration [ 95 , 96 ].…”

“…There is a need for novel therapeutic approaches that maintain the effectiveness of cisplatin-based chemotherapy but limit the long-term side effects. To date, no research papers have been published with regard to PCs other than PCSK4 in the testis, and only recently have there been references to them in TGCTs [ 95 , 96 ]. We consider that the further study of these fields, with the information we have about the immunological tumour microenvironment and PC substrates, could contribute to the development of much needed new immunotherapies.…”

COVID-19 receptor and malignant cancers: Association of CTSL expression with susceptibility to SARS-CoV-2

“…The methods for immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded lung and breast cancer tissue sections from Chinese patients were described previously 21 , 26 , 27 , 29 . The CTSL antibody (Catalog No.…”

“…CD showed strong binding affinities with SARS-CoV-2 S-protein and Mpro proteins 20 . CD was also reported to inhibit the expression of FURIN, a SARS-CoV-2 receptor, on cancer cell lines in a dose dependent manner 21 . N6,N6-Dimethyladenosine (m 6 2 A) is a modified ribonucleoside previously found in rRNA and also presented in tRNA from mycobacterium bovis Bacille Calmette-Guérin 22 .…”