Risk factors and actionable molecular signatures in COVID-19-associated lung adenocarcinoma and lung squamous cell carcinoma patients.

The molecular mechanism of the pathological impact of COVID-19 in lung cancer patients remains poorly understood to date. In this study, we used differential gene expression pattern analysis to try to figure out the possible disease mechanism of COVID-19 and its associated risk factors in patients with the two most common types of non-small-cell lung cancer, namely, lung adenocarcinoma and lung squamous cell carcinoma. We also used network-based approaches to identify potential diagnostic and molecular targets for COVID-19-infected lung cancer patients. Our study showed that lung cancer and COVID-19 patients share 36 genes that are expressed differently and in common. Most of these genes are expressed in lung tissues and are mostly involved in the pathogenesis of different respiratory tract diseases. Additionally, we also found that COVID-19 may affect the expression of several cancer-associated genes in lung cancer patients, such as the oncogenes JUN, TNC, and POU2AF1. Moreover, our findings suggest that COVID-19 may predispose lung cancer patients to other diseases like acute liver failure and respiratory distress syndrome. Additionally, our findings, in concert with published literature, suggest that molecular signatures, such as hsa-mir-93-5p, CCNB2, IRF1, CD163, and different immune cell-based approaches could help both diagnose and treat this group of patients. Altogether, the scientific findings of this study will help formulate appropriate management measures and guide the development of diagnostic and therapeutic measures for COVID-19-infected lung cancer patients.

Effect of Cepharanthine on the Stemness of Lung Squamous Cell Carcinoma Based on Network Pharmacology and Bioinformatics.

Background: Lung squamous cell carcinoma (LUSC) has poor survival prognosis and few clinical treatment options. We urgently need to explore new therapeutic drugs in clinical practice. Cepharanthine (CEP) has been shown to have anticancer effects in several tumors, but the mechanism of CEP in treating LUSC has not been reported. Methods: SwissTargetPrediction, PharmMapper, and GeneCards were used to identify targets of CEP and LUSC. Further topological analysis was used to obtain hub genes via Cytoscape. Molecular docking was carried out to verify the combination of CEP with hub targets. Based on bioinformatics, we first analyzed the expression and survival of hub targets in LUSC and further analyzed the correlation between hub targets and cancer stemness, immune cell infiltration, and tumor mutation burden (TMB). Results: A total of 41 targets were identified. Further topological analysis identified 6 hub genes: AURKA, CCNA2, CCNE1, CDK1, CHEK1, and PLK1. Molecular docking analysis showed that CEP had stable binding to all these 6 target proteins. In-depth bioinformatics analysis of these 6 targets showed that high expression of these targets were positively correlated with cancer stemness index and negatively correlated with tumor infiltrating immune cells. In immune subtype analysis, the expressions of these targets were significantly decreased in inflammatory tumors. In addition, we also found that the expressions of these targets were positively correlated with TMB. Conclusion: Based on multidisciplinary analysis, we preliminarily identified potential targets of CEP for LUSC treatment and suggested that CEP may play a role in regulating LUSC stemness.

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

Objectives: To quantify the integrated levels of ACE2 and TMPRSS2, the two well-recognized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry-related genes, and to further identify key factors contributing to SARS-CoV-2 susceptibility in head and neck squamous cell carcinoma (HNSC). Methods: We developed a metric of the potential for tissue infected with SARS-CoV-2 ("TPSI") based on ACE2 and TMPRSS2 transcript levels and compared TPSI levels between tumor and matched normal tissues across 11 tumor types. For further analysis of HNSC, weighted gene co-expression network analysis (WGCNA), functional analysis, and single sample gene set enrichment analysis (ssGSEA) were conducted to investigate TPSI-relevant biological processes and their relationship with the immune landscape. TPSI-related factors were identified from clinical and mutational domains, followed by lasso regression to determine their relative effects on TPSI levels. Results: TPSI levels in tumors were generally lower than in the normal tissues. In HNSC, the genes highly associated with TPSI were enriched in viral entry-related processes, and TPSI levels were positively correlated with both eosinophils and T helper 17 (Th17) cell infiltration. Furthermore, the site of onset, human papillomaviruses (HPV) status, and nuclear receptor binding SET domain protein 1 (NSD1) mutations were identified as the most important factors shaping TPSI levels. Conclusions: This study identified the infection risk of SARS-CoV-2 between tumor and normal tissues, and provided evidence for the risk stratification of HNSC.

Expression profile of SARS-CoV-2 cellular entry proteins in normal oral mucosa and oral squamous cell carcinoma.

OBJECTIVE: Besides angiotensin converting enzyme 2 (ACE2), an active involvement of proteases (FURIN and/or TMPRSS2) is important for cellular entry of SARS-CoV-2. Therefore, a simultaneous expression profiling of entry proteins in a tissue might provide a better risk assessment of SARS-CoV-2 infection as compared to individual proteins. In an attempt to understand the relative susceptibility of oral squamous cell carcinoma (OSCC) lesions as compared to the normal oral mucosa (NOM) for SARS-CoV-2 attachment/entry, this study examined the mRNA and protein expression profiles of ACE2, FURIN, and TMPRSS2 in the corresponding tissues using public transcriptomic and proteomics datasets. METHODS AND METHODS: Public transcriptomic and proteomics datasets (the Cancer Genome Atlas (TCGA)/the Genotype-Tissue Expression (GTEx), the Human Protein Atlas (HPA), and two independent microarray datasets) were used to examine the expression profiles of ACE2, TMPRSS2 and FURIN in NOM and OSCC. RESULTS: ACE2, TMPRSS2, and FURIN mRNAs were detected in NOM, however, at lower levels as compared to other body tissues. Except for moderate up-regulation of FURIN, expression levels of ACE2 and TMPRSS2 mRNA were unchanged/down-regulated in OSCC as compared to the NOM. CONCLUSIONS: These results indicate that NOM may serve as a possible site for SARS-CoV-2 attachment, however, to a lesser extent as compared to organs with higher expression levels of the SARS-CoV-2 entry proteins. However, the evidence is lacking to suggest that expression status of entry proteins predisposes OSCC lesions to additional risk for SARS-CoV-2 attachment/entry as compared to NOM.

Epigenetic regulation in the pathogenesis of non-melanoma skin cancer.

Understanding of cancer with the help of ever-expanding cutting edge technological tools and bioinformatics is revolutionizing modern cancer research by broadening the space of discovery window of various genomic and epigenomic processes. Genomics data integrated with multi-omics layering have advanced cancer research. Uncovering such layers of genetic mutations/modifications, epigenetic regulation and their role in the complex pathophysiology of cancer progression could lead to novel therapeutic interventions. Although a plethora of literature is available in public domain defining the role of various tumor driver gene mutations, understanding of epigenetic regulation of cancer is still emerging. This review focuses on epigenetic regulation association with the pathogenesis of non-melanoma skin cancer (NMSC). NMSC has higher prevalence in Caucasian populations compared to other races. Due to lack of proper reporting to cancer registries, the incidence rates for NMSC worldwide cannot be accurately estimated. However, this is the most common neoplasm in humans, and millions of new cases per year are reported in the United States alone. In organ transplant recipients, the incidence of NMSC particularly of squamous cell carcinoma (SCC) is very high and these SCCs frequently become metastatic and lethal. Understanding of solar ultraviolet (UV) light-induced damage and impaired DNA repair process leading to DNA mutations and nuclear instability provide an insight into the pathogenesis of metastatic neoplasm. This review discusses the recent advances in the field of epigenetics of NMSCs. Particularly, the role of DNA methylation, histone hyperacetylation and non-coding RNA such as long-chain noncoding (lnc) RNAs, circular RNAs and miRNA in the disease progression are summarized.

Interferons and viruses induce a novel truncated ACE2 isoform and not the full-length SARS-CoV-2 receptor.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, utilizes angiotensin-converting enzyme 2 (ACE2) for entry into target cells. ACE2 has been proposed as an interferon-stimulated gene (ISG). Thus, interferon-induced variability in ACE2 expression levels could be important for susceptibility to COVID-19 or its outcomes. Here, we report the discovery of a novel, transcriptionally independent truncated isoform of ACE2, which we designate as deltaACE2 (dACE2). We demonstrate that dACE2, but not ACE2, is an ISG. In The Cancer Genome Atlas, the expression of dACE2 was enriched in squamous tumors of the respiratory, gastrointestinal and urogenital tracts. In vitro, dACE2, which lacks 356 amino-terminal amino acids, was non-functional in binding the SARS-CoV-2 spike protein and as a carboxypeptidase. Our results suggest that the ISG-type induction of dACE2 in IFN-high conditions created by treatments, an inflammatory tumor microenvironment or viral co-infections is unlikely to increase the cellular entry of SARS-CoV-2 and promote infection.

Identification of angiotensin-converting enzyme 2 (ACE2) protein as the potential biomarker in SARS-CoV-2 infection-related lung cancer using computational analyses.

COVID-19 is a pandemic that began to spread worldwide caused by SARS-CoV-2. Lung cancer patients are more susceptible to SARS-CoV-2 infection. The SARS-CoV-2 enters into the host by the ACE2 receptor. Thus, ACE2 is the key to understand the mechanism of SARS-CoV-2 infection. However, the lack of knowledge about the biomarker of COVID-19 warrants the development of ACE2 biomarkers. The analysis of ACE2 expression in lung cancer was performed using The Cancer Genome Atlas (TCGA). Therefore, we investigated the prognosis, clinical characteristics, and mutational analysis of lung cancer. We also analyzed the shared proteins between the COVID-19 and lung cancer, protein-protein interactions, gene-miRNAs, gene-transcription factors (TFs), and the signaling pathway. Finally, we compared the mRNA expression of ACE2 and its co-expressed proteins using the TCGA. The up-regulation of ACE2 in lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) was found irrespective of gender and age. We found the low survival rate in high expression of ACE2 in lung cancer patients and 16 mutational positions. The functional assessment of targeted 12,671, 3107, and 29 positive genes were found in COVID-19 disease, LUAD, and LUSC, respectively. Then, we identified eight common genes that interact with 20 genes, 219 miRNAs, and 16 TFs. The common genes performed the mRNA expression in lung cancer, which proved the ACE2 is the best potential biomarker compared to co-expressed genes. This study uncovers the relationship between COVID-19 disease and lung cancer. We identified ACE2 and also its co-expressed proteins are the potential biomarker and therapy as the current COVID-19 disease and lung cancer.

Structural variations and expression profiles of the SARS-CoV-2 host invasion genes in lung cancer.

Recent days have seen growing evidence of cancer's susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and of the effect of genomic differences on the virus' entrance genes in lung cancer. Genetic confirmation of the hypotheses regarding gene expression and mutation pattern of target genes, including angiotensin-converting enzyme-2 (ACE2), transmembrane serine protease 2 (TMPRSS2), basigin (CD147/BSG) and paired basic amino acid cleaving enzyme (FURIN/PCSK3), as well as correlation analysis, was done in relation to lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) using in silico analysis. Not only were gene expression and mutation patterns detected, but also there were correlation and survival analysis between ACE2 and other target genes expression levels. The total genetic anomaly carrying rate of target genes, including ACE2, TMPRSS2, CD147/BSG, and FURIN/PCSK3, was determined as 8.1% and 21 mutations were detected, with 7 of these mutations having pathogenic features. p.H34N on the RBD binding residues for SARS-CoV-2 was determined in our LUAD patient group. According to gene expression analysis results, though the TMPRSS2 level was statistically significantly decreased in the LUSC patient group compared to healthy control, the ACE2 level was determined to be high in LUAD and LUSC groups. There were no meaningful differences in the expression of CD147 and FURIN genes. The challenge for today is building the assessment of genomic susceptibility to COVID-19 in lung cancer, requiring detailed experimental laboratory studies, in addition to in silico analyses, as a way of assessing the mechanism of novel virus invasion that can be used in the development of effective SARS-CoV-2 therapy.

Analysis of the susceptibility of lung cancer patients to SARS-CoV-2 infection.

Recent studies have reported that COVID-19 patients with lung cancer have a higher risk of severe events than patients without cancer. In this study, we investigated the gene expression of angiotensin I-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) with prognosis in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Lung cancer patients in each age stage, subtype, and pathological stage are susceptible to SARS-CoV-2 infection, except for the primitive subtype of LUSC. LUAD patients are more susceptible to SARS-CoV-2 infection than LUSC patients. The findings are unanimous on tissue expression in gene and protein levels.