The pandemic respiratory disease sweeping through 2020 and 2021 is a new type of coronavirus pneumonia (coronavirus disease 2019, COVID-19) caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) (Surkova et al., 2020). Current studies have proven that the invasion of SARS-CoV-2 into host cells mainly depends on the activation of viral spike protein (S protein) by certain proteases (Ward et al., 2020). Transmembrane proteaseserine-2 (TMPRSS2) is a key host protease that mediates S protein activation and initially promotes virus entry into host cells (Hoffmann et al., 2020). Moreover, it is abnormally expressed in a variety of tumors. Hence, cancer has been identified as an individual risk factor for COVID-19 (Stopsack et al., 2020). In 1997, Antonarakis et al. identified the TMPRSS2 gene for the first time and found that the gene encodes a multimeric protein with a serine protease domain (Paoloni-Giacobino et al., 1997). Since then, due to the high expression of the TMPRSS2 gene in the prostate, research on TMPRSS2 has mainly focused on the related diseases of prostate cancer (Hong et al., 2020). Due to the impact of the new coronavirus epidemic, coupled with the expression of TMPRSS2 in the epithelial cells of the respiratory system, enthusiasm for research on TMPRSS2 has further increased (Kimura et al., 2020). However, the systematic analysis of TMPRSS2 aberrations has not been characterized in human cancers. Then, we planned a pan-cancer analysis of TMPRSS2 in malignant tumors.

Our study is the first to explore the TCGA database to perform pan-cancer analysis on TMPRSS2. We also included a set of factors, such as gene expression, survival status, DNA methylation, genetic changes, protein phosphorylation, immune infiltration, and related cell pathways, to study the potential molecular mechanisms of TMPRSS2 in the pathogenesis or clinical prognosis of different cancers.

Previous research evidence has shown that TMPRSS2 plays an important role in monitoring the infection process of severe acute respiratory syndrome (Khoury et al., 2020; Suarez-Farinas et al.) virus and Middle East respiratory syndrome (Lavin et al., 2017) coronavirus (Khan and Khan, 2021). Similarly, in a research report on SARS-CoV-2, TMPRSS2 and angiotensin converting enzyme 2 (ACE2) were coexpressed in human air and alveolar and blood air (Lukassen et al., 2020; Suarez-Farinas et al., 2021). ACE2 has been identified as a functional receptor for pathogenic SARS-CoV-2, which is related to the transport of the virus from the cell membrane to the cytoplasm (Barnes et al., 2020; Liu K. et al., 2021). TMPRSS2 promotes the binding of SARS-CoV-2 to ACE2 in the host cell by activating the S protein and assists the virus in entering the host cell (Kusmartseva et al., 2020). TMPRSS2 may also be the key to SARS-CoV-2 replication, and its expression greatly promotes the replication of the virus and the formation of syncytial virus–infected cells (Buchrieser et al., 2021; Kruger et al., 2021). The expression of TMPRSS2 greatly promoted the replication of the virus and the formation of syncytia (Iwata-Yoshikawa et al., 2019). Another study showed that in the presence of TMPRSS2, the number of SARS coronaviruses entering cells increased by 2.6 times, and the targeted elimination of TMPRSS2 could significantly reduce the number of SARS coronaviruses entering cells (Kawase et al., 2012). In addition, cancer has been identified as a personal factor of COVID-19, so the significance of TMPRSS2 expression in pan-cancers is more likely to be connected to the susceptibility of SARS-CoV-2 to tumor patients (Kuderer et al., 2020; Moris et al., 2020). Some researchers have suggested that although patients with underlying diseases are more susceptible to SARS-CoV-2 infection, patients suffering from head and neck cancer or lung cancer have reduced expression of TMPRSS2 in the body (Sacconi et al., 2020), which makes these patients less susceptible to SARS-CoV-2. Our research has genetically engineered the genetic and epigenetic variation of TMPRSS2 in humans for the first time.

TMRPSS2 expression was overexpressed in seven different types and downregulated in 10 different types (Figure 4). Since COVID-19 is mainly spread through the airway, we are particularly concerned about respiratory tumors. TMRPSS2 was significantly decreased in LUSC but remained unchanged in LUAD (Figure 5). Nine other types of tumors, including BRCA, ESCA, HNSC, KIRC, KIRP, SARC, SKCM, TGCT, and THCA, exhibited downregulation of TMPRSS2. The correlation between genetic diseases and TMRPSS2 expression was also confirmed in this research. In addition, there was no correlation between DNA/RNA mutations and TMRPSS2 expression (Figure 3). Our results implied that there are some differences in the frequency of TMPRSS2 variants in patients with different tumors. The existence of genetic variation does not always affect gene expression. Therefore, the upregulation of TMPRSS2 expression may not be caused by genetic mutations.

Nine probes in the TMRPSS2 promoter were used to detect the DNA methylation level of TMRPSS2 (Figure 10A). The findings verified that three tumors with high expression of TMPRSS2 manifested reduced levels of TMPRSS2 DNA methylation, including COAD, PRAD, and READ (Figure 10B). In other respects, among the nine tumors downregulated by TMPRSS2, BRCA, ESCA, HNSC, KIRP, SARC, SKCM, THCA, and even LUSC showed increased DNA methylation levels (Figure 10C). Since there is no DNA methylation dataset available for KICH normal controls, global DNA methylation levels of KICH cannot be compared. Thus, the DNA methylation levels of KICH at different tumor stages were compared, and the outcomes further found the enhancement of DNA methylation levels. In addition, the level of DNA methylation in other tumors with differential expression of TMPRSS2 remained unchanged, indicating that DNA methylation may not be the only cause of abnormal TMPRSS2 expression, such as histone modification and glycosylation. The high level of methylation in the promoter region can also silence the gene transcription process. Therefore, in some tumors, such as LUSC, the high level of methylation in the TMPRSS2 promoter may lead to a decrease in its transcriptional expression level.

The connection of clinical information with TMPRSS2 expression was monitored by the GEPIA2 database. The disease-free survival of UCES and UCS with high expression of TMPRSS2 was significantly different from that of the low-expression group (Figures 6, 7). The overall survival analysis found that BRCA with high expression of TMPRSS2 was related to poor prognosis. However, low expression of TMPRSS2 was irrelevant to the prognosis of tumor patients (Figures 8, 9). These data suggested that TMPRSS2 may be a double-edged sword in tumor patient prognosis. Therefore, other clinical features should also be fully considered. Second, more in-depth molecular experimental evidence is needed to determine whether the high expression of TMPRSS2 plays an important role in the occurrence of the aforementioned tumors or if it is just the result of normal tissues resisting tumor alterations.

As reported, TMPRSS2 has been shown to be an important regulator of tumorigenesis (Bao et al., 2020). TMPRSS2-ERG gene fusion occurs in approximately 50% of prostate cancer (PCa) cases, and the fusion product is a key driver of prostate cancer. Cell signaling to ablate the TMPRSS2-ERG oncoprotein may be beneficial in the treatment of PCa (Hong et al., 2020). Studies have shown that regardless of the size of the primary tumor, deletion of TMPRSS2 in tumor-bearing mice can significantly reduce metastasis (Kang et al., 2021). This is consistent with the emerging view that metastasis and primary tumor growth are controlled by different factors and suggests that TMPRSS2 may be essential for tumor metastasis behavior. By using a large number of single-cell RNA sequencing datasets, scientists systematically studied the expression of ACE2 and TMPRSS2 in human tumors and normal colorectal tissues and found that these two receptors are highly expressed in colorectal epithelial cells. They further found that patients with colorectal cancer and COVID-19 were more prone to lymphopenia with higher respiratory rates and high-sensitivity C-reactive protein levels than patients with COVID-19 alone (Liu C. et al., 2021). The expression of TMPRSS2 is downregulated in patients with head and neck cancer, which implies more resistance to SARS-CoV-2 infection (Sacconi et al., 2020).

In this research, the potential correlation between tumor-associated fibroblast immune infiltration in all TCGA tumors and TMPRSS2 was explored using the Timer 2.0 database. Information on TMPRSS2 binding components and TMPRSS2 expression–related genes in more than 30 tumors was obtained simultaneously by a series of enrichment analyses. The findings demonstrated that most of these genes were related to endosome membrane, presynapse, Golgi vesicle transport, Ras protein signal transduction, axonogenesis, regulation of neuron projection development, prostate cancer, Rab protein signal transduction, and other related pathways or cell biological functions.

In conclusion, the genetic changes, RNA expression, and DNA methylation of TMPRSS2 were analyzed in more than 30 tumors. These findings suggest the need for priority precautions for COAD, CESC, KICH, PRAD, UCEC, UCS, and READ during the COVID-19 pandemic. In addition, low DNA methylation of TMPRSS2 was also found in most of these tumors with high TMPRSS2 expression. In the end, our study planned the genetic and epigenetic variation of TMPRSS2 in human malignant tumors for the first time. However, the specific molecular mechanism of TMPRSS2 in the formation and development of tumors in vivo has not been clarified. Since our research is a bioinformatics test, it is necessary to conduct further functional and clinical verification.