Genes of the ACE family: Important molecular links between lung cancer and COVID-19 – Zhang – 2021 – Clinical and translational medicine


COVID-19 associated with the SARS-CoV-2 virus is an ongoing global pandemic.1 Although great efforts have been made, the COVID-19 situation is still very serious due to the rapid mutation rate of SARS-COV-2 and the increase in drug resistance.2 Lung cancer patients are more susceptible to COVID-19 due to their immunocompromised state and the fragility of their lung tissue.3, 4 angiotensin-converting enzyme 2 (ACE2) has been confirmed to be the key entry site for the SARS-CoV-2 virus5; however, the roles of AS and TMEM27, the other two genes of the ACE gene family (ACE) with strong homology with ACE2, in lung cancer and COVID-19 have not been fully clarified.

As shown in Figure 1, data for ACEs, SARS-CoV-2 and lung cancer were obtained from several databases. The relationship between the three has been analyzed to provide ideas for the prevention and control of SARS-CoV-2 infection in lung cancer patients. Transcriptional levels of ACEs in 20 cancers were compared to transcription profiles in normal tissues. The dates showed that the transcriptional level of AS was downregulated in four studies, while transcriptional levels of ACE2 and TMEM27 there was only one high study in lung cancer patients (Figure S1, Table S1). And we further revalidated the level of ACE transcription in lung cancer patients in the UALCAN database. It was found that AS was significantly decreased in lung tumor tissue (Figure S2A, B), while ACE2 was at a high transcriptional level in lung tumor tissues (Figure S2C, D). TMEM27 was overexpressed in pulmonary adenocarcinoma (LUAD), while it was downregulated in pulmonary squamous cell carcinoma (LUSC) (Figure S2E, F). We further verified the protein expression levels of ACEs in lung cancer (Figure S3A-C).

A flowchart showing the overall study analysis process. CCEG: Commonly co-expressing ACE genes in lung cancer and COVID-19. ACE: AS, ACE2, TMEM27

Next, the relationship between transcriptional levels of ACEs and clinicopathologic parameters of lung cancer patients was investigated. As shown in Figure S4, the results showed that AS was significantly differentially expressed in histologic subtypes of LUAD patients, as well as lymph node metastases and smoking habits of LUSC patients. ACE2 expression was not only significantly different in age, TP53 mutation status, histological subtypes and smoking habits of LUAD, but also in histological subtypes, smoking habits and stage individual cancer patient LUSC. TMEM27 was significantly differentially expressed in terms of sex, lymph node metastasis status, and smoking habit of LUSC patients, as well as gender, lymph node metastasis status, smoking habit, individual cancer stage, and subtype histology of LUAD patients. Figure S5 reveals that the prognosis of lung cancer patients was remarkably influenced by the mRNA expression levels of most members of the ACE family. Specifically, high expression levels of mRNA from AS, ACE2 and TMEM27 predicts better overall survival in lung cancer patients. Higher expression of ACE mRNA and ACE2 correlated with good first progression in lung cancer patients. Upward regulation of ACE2 correlated with good post-progression survival in lung cancer patients. In the independent prognostic analysis of ACEs, only ACE2 have shown the potential to independently influence the prognosis of patients with lung cancer (Table S2S4).

A comprehensive analysis was performed to assess the association of ACEs with immune cell infiltration. The results showed that AS correlates positively with a total of six types of immune cells in lung cancer tissue. ACE2 was positively linked to only three immune cells in LUAD tissues. TMEM27 was positively correlated with the level of infiltration of six immune cells in LUSC, and negatively connected to neutrophils in LUAD tissues (Figure 2). Analysis of copy number variations showed that ACEs regulate the level of infiltration of immune cells (Figure S6). Further examination revealed that AS was positively correlated with the immune checkpoints PDCD1, LAG3, PDCD1LG2 and CD274 in LUAD and LUSC patients. Especially, ACE2 showed a negative correlation with PDCD1, LAG3, PDCD1LG2 and CD274 in LUAD patients, but a positive correlation with CD274 in LUSC patients (Figure 3). COX multivariate survival analysis revealed that Stage2, Stage3, Stage4 and B cells were independent factors that predict the prognosis of patients with LUAD (Table S5), whereas age, stage3, AS and ACE2 could independently predict the prognosis of patients with CSPU (Table S6).

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Association of transcriptional levels of ACEs with the level of immune infiltration in lung cancer (TIMER database). (A) AS expression was surprisingly positively correlated with six immune cells in a lung tumor. (B) ACE2 was positively related to three immune cells only in LUAD patients. (VS) TMEM27 showed only a negative correlation with neutrophils in LUAD. Filtering criteria: p-value

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Relevance of ACE transcriptional levels to immune checkpoints in lung cancer (TIMER database). (A) AS was positively, while ACE2 was negatively connected to PDCD1, LAG3, PDCD1LG2 and CD274 in LUAD. (B) AS was positively related to PDCD1, LAG3, PDCD1LG2 and CD274, ACE2 showed a positive correlation with CD274 in LUSC. Filtering criteria: p-value

The relevance of ACE expression to immune status was confirmed by the CIBERSORT algorithm6; 22 types of tumor infiltrating immune cells in lung cancer samples were determined (Figure S7). Figures S8 through S9 presented a violin diagram showing the levels of immune cell infiltration in lung cancer samples from the high and low expression group of ACEs. The intersection results of different analyzes and correlation analyzes were obtained as shown in Fig. S10. The results demonstrated that the level of expression of ACEs was strongly related to the infiltration of immune cells.

Finally, a total of 1003 differentially expressed genes (DEG) in COVID-19 were identified (Figure S11). In addition, genes co-expressed in lung cancer have been identified, including 4,325 genes from AS, 325 genes from ACE2 and 451 genes from TMEM27. The area of ​​overlap between ACE genes co-expressed in lung cancer and COVID-19 DEGs was examined. In total, 195 (AS), 27 (ACE2) and 26 (TMEM27) were selected as the commonly co-expressed genes (CCEGs) of ACEs in lung cancer patients with COVID-19. Subsequently, networks of miRNAs and transcription factors targeting CCEGs were constructed (Figure S12). In addition, a functional enrichment analysis of CCEGs of ACEs was performed as shown in Fig. 4. The results implied that CCEGs were extensively enriched in the circulatory system process and P450 pigment metabolism. In addition, CCEGs were enriched in lung, liver and splenic tissue. Table S7 shows that ACEs were correlated with sets of COVID-19 related genes. Several drugs that target CCEGs of ACEs were predicted by the enrichment database (Table S8). Acid red, tetradioxin and etoposide were identified as the drugs with the most significant effect on CCEGs of AS, ACE2, TMEM27, respectively.

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Commonly Co-expressed Genes (CCEGs) Functional Enrichment Analysis Based on Metascape Database. The Ontology of Genes and the Kyoto Encyclopedia of Gene and Genome Analyzes for CCEGs from AS (B), ACE2 (D) and TMEM27(G). PaGenBase analysis of CCEGs of AS (This TMEM27(H). DisGeNET analysis of CCEGs AS (A), ACE2 (E) and TMEM27 (F)

In conclusion, this study shows that ACEs can directly or indirectly affect the development and progression of COVID-19 in lung cancer patients. This discovery can be used to develop effective prevention and treatment strategies for lung cancer patients infected with COVID-19.

CONFLICT OF INTEREST

All authors declare that there is no competing interest.


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