TESPA1, a key gene in thymocyte development, is a rare and potentially pathogenic variant in 14 systemic diseases, such as rheumatoid arthritis, and plays an important role in the pathogenesis of these diseases, such as autoimmune arthritis[8, 29, 30]. In the process of double-positive (DP) thymocytes become mature single-positive CD4+ and CD8+ T cells, TESPA1 have been reported as a necessary gatekeeper of thymic-specific TCR signaling regulator that are able to improve the sensitivity of the TCR signal to facilitate positive selection[8, 9, 31–33],The mechanism of Tespa1 in T cell development and the regulation of TCR is that Tespa1 interacts with a transmembrane Ca2+ channel protein in endoplasmic reticulum inositol 1,4,5-trisphosphate receptor (IP3R), then induced subsequent calcium signaling and MAPK activation[11, 34]. Interestingly, Tespa1 protein is phosphorylated in response to store-operated calcium entry. For B cells, Tespa1 is essential for T cell-dependent (TD) B cell responses. However, Tespa1 does not influence the development of B cells, but Tespa1-deficient has a significant reduced impact on antibody concentrations in serum due to inhibit the activation and proliferation of B cells induced by TD antigens. Mast cell is also activated by Tespa1, which orchestrates by tuning the balance of LAT1 and LAT2 signalosome assembly. Tespa1 also participate in mitochondrial Ca2+ uptake in the MAM compartment. Owing to the close relationship between TESPA1 and immune system, more and more attention focused on the role of TESPA1 in cancer. Novelty, TESPA1 has been discovered credible prognostic value in evaluating the survival/prognosis of patients, invasion and progression of tumors in LUAD patients. Whether TESPA1 plays a role in the pathogenesis of different tumors through some common molecular mechanisms remains unclear. Therefore, based on TCGA, CPTAC and GEO database data, as well as molecular characteristics of gene expression, genetic changes, DNA methylation or protein phosphorylation, we comprehensively examined TESPA1 genes in a total of 33 different tumors.
TESPA1 expression level is aberrantly high or aberrantly low in different tumors. However, the survival prognostic analysis data of TESPA1 gene showed that there were significant differences among different tumors. Our study first used four independent datasets in PrognoScan, and TCGA data in GEPIA and Kaplan-Meier plotter approach to explore the expression of TESPA1 and its prognostic value across pan-cancers for a more rigorous conclusion. For breast cancer and liver hepatocellular carcinoma, the expression of TESPA1 shown no difference in cancers compared with normal tissues. But in TCGA data in GEPIA and Kaplan-Meier plotter displayed consistently TESPA1 was beneficial to OS, DFS and RFS. Overexpressed TESPA1 gene may be a new target for breast cancer and liver hepatocellular carcinoma treatment. For skin cutaneous melanoma, high expressed TESPA1 was correlated with OS, DFS but not RFS. Kaplan-Meier plotter approach shown that in skin cancers, high expressed TESPA1 was correlated with OS. The expression of TESPA1 in different stage of skin cutaneous melanoma is also shown obvious difference. TESPA1 may play an important role in the development and treatment of. For the three cancers in kidney, TESPA1was all highly expressed. High expressed TESPA1 was related to good OS and RFS in kidney renal clear cell carcinoma and DFS of kidney chromophobe, but had a detrimental effect on prognosis kidney renal papillary cell carcinoma. This contradictory conclusion needs to be unified in a large number of samples. For tumor of reproductive system, including cervical squamous cell carcinoma, Ovarian serous cystadenocarcinoma, uterine carcinosarcoma and uterine corpus endometrial carcinoma. TESPA1 expressed lowly compared with controls. OS and RFS of Ovarian serous cystadenocarcinoma, cervical squamous cell carcinoma and uterine corpus endometrial carcinoma benefit from high expressed TESPA1. The contradiction also exists in testicular germ cell tumors, TESPA1 was beneficial to RFS of TGCT, but was detrimental to OS of TGCT. For eye cancers, uveal melanoma, contradictory conclusion that higher TESPA1 was beneficial DMFS of eye cancer via Prognoscan, but higher TESPA1 was related to poor survival of uveal melanoma via GEPIA 2. For lung cancer, we analyzed the datasets of the TCGA-LUSC and TCGA-LUAD projects and found a correlation between TESPA1 high expression and good overall survival prognosis of lung adenocarcinoma but not lung squamous cell carcinoma. The expression of TESPA1 in every stage of lung adenocarcinoma is also shown obvious difference. Previous study has obtained the consistent results and proposed prognostic value of TESPA1. Our results demonstrated the prognostic value of TESPA1 in lung adenocarcinoma, and the possible of its value in lung adenocarcinoma treatment. Larger sample sizes and experiments are required to confirm these results. In blood cancers, results from Oncomine and TIMER2 consistently shown that TESPA1 is high expressed in leukemia, but the survival analysis by Prognoscan has demonstrated that higher TESPA1 expression could led to poor survival in blood cancers. The prognostic value of TESPA1 in blood cancer is prospective. For tumor of digestive system, TESPA1 is has no different expression in cholangiocarcinoma esophageal carcinoma, stomach adenocarcinoma compared with controls. But the expression level of TESPA1 had an influence on the survival of tumor of digestive system. Moreover, TESPA1 has been demonstrated to be associated with the development of gastric carcinoma. For brain cancers, TESPA1 expression is reduced in glioblastoma and low-grade glioma, The Prognoscan demonstrated high-expressed TESPA1 is related the good OS of brain cancer. Up-regulated TESPA1 maybe a new treatment of brain cancers. In summary, considering the above contradiction between TESPA1 expression level and the prognosis of some cancers. There are three possible reasons. First, a larger sample size is needed to further verify the above conclusions. Second, other clinical features should also be fully considered. Finally, further in vitro and in vivo molecular experimental evidence is needed to determine whether the high expression of TESPA1 plays an important role cancer mentioned above or is merely an accompanying result of the immune response.
We found a previously uncharacterized and closed correlation between TESPA1 expression and immune cell infiltration across pan-cancers and reveal its critical mechanisms and immunological role in tumor microenvironment. After the analysis by TIMER2, TESPA1 expression levels in cancers were significant positively correlated with infiltration of immune cells, including CD8 + T cells, CD4 + T cells, B cells, macrophages, mast cells, CAF, Treg, monocytes and dendritic cells. Particularly, TESPA1 correlation with B cells, T cells, dendritic cells are almost comparable high, which confirmed that TESPA1 possibly involved in tumor antigen presentation and tumor killing critically. Not only B cells, T cells, dendritic cells, but macrophage and Treg is also correlated with expression level of TESPA1. Due to the complex of tumor microenvironment, the mechanism of TESPA1 affects cancers through the regulation of the immune microenvironment is unclear, which is need further research to explore.
Furthermore, we integrated the information on TESPA1-binding components and TESPA1 expression-related genes across all tumors for a series of enrichment analyses and identified the potential impact of “coagulation”, “hemostasis” and “blood coagulation” in the etiology or pathogenesis of cancers. Interestingly, previous studies have demonstrated that cancer and the hemostatic system interact with each other and trigger coagulation abnormalities. Hemostatic factors have been reported play a critical role tumor progression, growth and metastasis through effecting on the key event of neovascularization[37–39]. But the mechanism is not clear, our study may provide a new sight to solve this problem. Also, the treatments of cancer aimed at hemostatic system are bifunctional therapeutic approaches that are both able to attack the malignant process and resolve the coagulation impairment. Last but not least, the coagulation disorders of tumor patients are different from those of other diseases. Finding cancer specific biomarkers can better guide the treatment of tumor patients.
We also found significant differences in TESPA1 DNA methylation compared with normal tissues, and different levels of TESPA1 DNA methylation were also associated with different survival outcomes, including OS, DFI and PFI. It’s a pity that the data of total protein of TESPA1 is not clear. We only used the CPTAC dataset to analyzed of the TESPA1 phosphorylated protein in breast cancer, clear cell renal cell carcinoma, lung adenocarcinoma. We observed high expression level of phosphorylated TESPA1 protein level at the S311 locus in the primary tumors compared with normal controls in breast cancer and clear cell renal cell carcinoma, but low expression level in lung adenocarcinoma. We also found that S454 phosphorylation of TESPA1 is increased in primary tumor. Additional experiments are required to further evaluate the total protein level of TESPA1 and more phosphorylated locus in other types of cancer, and their role in tumorigenesis.
There are some limitations still exist in our study. Firstly, systematic bias may be introduced into our analysis given that the data were collected by analysis of a large number of tumor tissues from different types of gene chip and methods of sequencing. Higher-resolution methods such as single-cell RNA sequencing is very necessary[3, 41–43]. Secondly, due to the complex disease-related clinicopathological characteristics of cancers, more clinical data need to be involved into the correlation analysis between TESPA1 expression and clinical outcome. Finally, in vivo or in vitro experiments were essential to validate the results of the prognostic value and immunological role in cancer obtained by bioinformatics analysis. Finally, owing to the complexity of tumor microenvironment and hallmarks of cancer, we just observed a phenomenon of the close correlation between TESPA1 expression and immune cell infiltration and patient survival in cancer, we could not directly conclude whether TESPA1 affects patient survival via immune cell infiltration. Our study laid the foundation for further exploration of the mechanism of interactions between the expression of TESPA1 and the infiltration of tumor immune cells. Future studies on up or down TESPA1 expression and immune cell infiltration in cancer populations will help to provide a clear answer to this question.