In this study, we explored the potential relationship between angiotensin converting enzyme 2 (ACE2) and the development of head and neck squamous cell carcinoma (HNSCC) in humans. On the one hand, we used public datasets to analyze the expression level of ACE2 in HNSCC. On the other hand, we constructed a co-expression network of ACE2 and screened several important co-expressed genes and signaling pathways that may significant for the tumor’s progression. Then, the GEO and TCGA databases were analyzed. According to the results, ACE2 expression was significantly upregulated in HNSCC. In addition, ACE2 significantly affects the HNSCC survival time and tumor-associated immune response.
Angiotensin converting enzyme (ACE2) is a structural membrane glycoprotein that participates in the renin-angiotensin reaction; it also an important member of the renin-angiotensin system (RAS). It is known during SARS-CoV-2 infection, the v2irus invades a key receptor in the body. After entering the cell, the virus can induce heterogeneous protein synthesis and the release of inflammatory factors, promoting vasoconstriction, an inflammatory response, hypertension, oxidation, and fibrosis, resulting in multiple organ dysfunction(26). The entry of the coronavirus into the cells depends on the binding of viral spike proteins to the cell receptor and the initiation of S proteins by host cell proteases. Hoffmann et al. (27)demonstrated that SARS-CoV-2 uses ACE2 as a SARS-CoV receptor to enter cells, and the virus also uses the serine protease TMPRSS2 for S protein priming. Sacconi et al. (28) found that the expression of TMPRSS2 in HNSCC cells was significantly lower than in normal tissues, while ACE2 was slightly upregulated in female patients; however, the overall expression levels of ACE2 were comparable to normal tissues. ACE2 hydrolyzes angiotensin I (Ang I) to produce angiotensin II (Ang II). It has been proven that Ang II can promote the invasion and migration of HNSCC cells in an autocrine manner or by triggering stromal tumor-paracrine interactions (3). Narayan et al. (29) performed RT-PCR and a protein analysis on thyroid cancer and normal tissues, respectively, using ACE- and ACE2 specific primers or antibodies. The results showed that the expression of ACE2 in thyroid carcinoma was significantly increased, and the higher the degree of differentiation, the higher the ratio of ACE2/ACE. In addition, Carlos et al. (30)found that ACE2 is significantly associated with epithelial malignancies and can be used as a therapeutic target for malignant epithelial tumors, especially oral squamous cell carcinoma (OSCC).
Through a previous bioinformatics analysis, it was found that ACE2 mainly plays a role in regulating STAT1, and also has a role in bioregulatory and metabolic pathways. STAT1 is an important component of the IFNγ/ STAT1 signaling pathway, which is involved in many cell life activities such as cell growth inhibition and apoptosis promotion. Jiang et al. (31) showed that myotubularin-related protein 2 (MTMR2) can promote the invasion and metastasis of gastric cancer cells by inhibiting the IFNγ/ STAT1 pathway. It has also been shown that the IFNγ/STAT1 pathway promotes tumor cell survival and induces an adaptive immune resistance via CD4 + T cell loss and PD-L1 upregulation (32). Ryan et al. (33)found that in mouse HNSCC, STAT1 could promote a T cell immune response and inhibit myeloid-derived suppressor cell aggregation, thus mediating an anti-tumor immune response. Aldo keto reductase family 1 member C1 (AKR1C1) was positively correlated with cisplatin resistance and was a poor prognostic factor for HNSCC. A transcriptomic analysis by Chang et al. (34)showed that STAT1 and STAT3 could activate an AKR1C1-induced cisplatin resistance, which could be overcome by treatment with ruxolitinib. Metabolic pathways play an important role in regulating tumorigenesis and the development of many tumors. Tumor cells possess new metabolic pathways that enable them to increase the uptake efficiency of nutrients through metabolic reprogramming, in order to meet their requirements for growth and invasion (35). Sur et al. (36) found that oral cancer cells induced the generation of mitochondrial reactive oxygen species (ROS) and inhibited cell apoptosis by altering glycolysis and lipid metabolism pathways. Common reprogramming metabolic pathways include the lKB1-AMP kinase (AMPK) signaling pathways(37). Chen et al.(38)showed that nuclear AMPK recruits PMK2 and β-Catenin by interacting with them, which plays an important role in promoting the cell migration of thyroid cancer. In addition, metabolic pathways are also involved in maintaining tumor stemness. Liu et al. (39)demonstrated that activation of the HSP27/hK2 pathway caused cancer stem cells (CSCs) to exhibit reprogrammed metabolic features and enhanced stem cell phenotypes, such as increased ALDH activity, chemoresistance, and tumor formation. However, the specific relationship between ACE2 and metabolic pathways in tumorigenesis, as well as its role in the pathogenesis, development, and prognosis of HNSCC remains to be further explored.
The tumor microenvironment (TME) and tumor-related immune responses have always been the focus of tumor research, and they have also directed new therapy regimens (40). HNSCC cells can evade the host’s immune system by manipulating their own immunogenicity, producing immunosuppressive mediators, and promoting the creation of immunoregulatory cell types (41). Mandal et al. (42) comprehensively described the immune landscape of HNSCC using the transcriptome data of 280 tumor profiles depicted by The Cancer Genome Atlas (TCGA), and found that both HPV + and HPV-HNSCC tumors were among the most highly immune-infiltrated cancer types. HNSCC has a high level of Treg/CD8 + T cell and NK cell infiltration, which is statistically correlated with its prognosis. ACE2 is an important molecule that participates in TME regulation. Zhang et al. (43) used TCGA to explore the relationship between pan-cancer ACE2 expression and several factors including anti-tumor immunity, immunotherapy responses, the carcinogenic pathway, tumor progression phenotypes, and clinical outcomes. It was found that ACE2 upregulation was associated with increased antitumor immune signatures and increased PD-L1 expression, as well as favorable anti-PD-1/PD-L1/CTLA-4 immunotherapy responses. ACE2 may provide a reference for prognosis following tumor immunotherapy. Previous studies have shown that the expression of ACE2 is negatively correlated with immune cell infiltrates, such as neutrophils and macrophages (44, 45). Cheng et al. (46) showed that overexpression of ACE2 could inhibit the synthesis of vascular endothelial growth factor in TME and it inhibited tumor invasion and inflammation. However, by using the GSE30589 database, Yang et al. (47)found that the expression level of ACE2 was positively correlated with the level of immune infiltration of macrophages, B cells, CD4 + T cells, neutrophils, and dendritic cells in uterine corpus endometrial carcinoma (UCEC). We also found that the expression of ACE2 was positively correlated with the level of immune infiltration of B cells, CD8 + T cells, neutrophils, and dendritic cells. Therefore, the mechanism by which ACE2 participates in the HNSCC immune response warrants further study.