More recent studies have shown the expression and biological roles of WTAP in human malignancies [12–18]. WTAP functions as an oncogene in tumorigenesis of several malignant tumors, and its enhanced expression is associated with poor prognosis as well [12–18]. As far as we known, the expression of WTAP and its potential effect on regulation of biological behaviors involved in EC pathogenesis, as well as its prognostic value in EC have not yet been investigated. Our present research provided more insights into the functions of WTAP in carcinogenesis, development, prognostic evaluation as well as therapeutic regimen of EC.
In this research, bioinformatic analysis utilizing RNA sequencing data as reported by the TCGA revealed an increased expression of WTAP in EC, and its over-expression was associated with unfavorable clinical features, such as high-grade tumor and high-risk histology. This finding suggested that EC patients with high WTAP expression were more prone to contributing to progression compared with those with low WTAP expression. Furthermore, WTAP high expression was correlated with short survival time, poor OS and RFS. To further explore the biological roles of WTAP in EC, we carried out GSEA using data from TCGA. GSEA showed that wnt/β-catenin signaling pathway was differentially enriched in the WTAP high expression phenotype. This finding implicated that WTAP might act as a novel diagnostic and prognostic biomarker for EC and offer more treatment choices.
Studies have reported that embryonic stem cells and embryos with mutant WTAP fail to differentiate into mesoderm and endoderm during embryonic development, revealing the indispensable role of WTAP in keeping normal growth and differentiation in mouse embryo [20, 21]. We demonstrated that WTAP was correlated with differentiation in EC tumor tissues in our present analysis. A similar association between WTAP and tumor differentiation has also recently been reported, including malignant glioma, pancreatic ductal adenocarcinoma and acute myelogenous leukemia [14, 15, 17]. However, the molecular mechanisms underlying differentiation still remain largely unexplored.
It is widely believed that the majority of EC patients are classified as type I EEC linked with unopposed estrogen stimulation and favorable prognosis or type II non-endometrioid tumor with poor outcomes [5, 22, 23]. In this study, we demonstrated that WTAP was significantly over-expressed in EC tissues, especially in type II non-endometrioid tumors, suggesting that WTAP, like p53, acted as a useful biomarker to distinguish non-EEC from EEC [24–26]. This finding indicated that WTAP might serve as an underlying marker for pre-operative identification of EC patients needing aggressive treatment.
EEC represents a range of carcinomas, from poorly to well differentiated tumors (such as high to low grade), whereas non-EEC is a high-grade tumor by definition. This may be explained to some extent by the enhanced expression of WTAP in non-EEC groups compared with EEC groups considering the association of high WTAP expression with poor differentiation in EC tissues as demonstrated in our present study. Additionally, high expression of WTAP in EEC might also contribute to the poor differentiation in EEC tissues. However, this need to be further studied in future research.
In this report, we observed that WTAP high expression phenotype was associated with wnt/β-catenin signaling pathway by GSEA. A few reports have proposed that wnt/β-catenin signaling pathway is involved in multiple cellular functions. Previous studies have revealed a critical role of wnt/β-catenin signaling pathway in cell proliferation in liver regeneration [27, 28]. Aberrant activation of wnt/β-catenin signaling pathway is correlated with tumorigenesis of several cancers as well, such as EC and prostate cancer [29–31]. Furthermore, wnt/β-catenin signaling pathway has been shown to be crucial in the process of invasion and migration in laryngeal squamous cell carcinoma and non-small cell lung cancer [32, 33]. Additionally, literature has reported that WTAP can enhance malignant potential of tumor cells in several cancers [12–18], including inhibiting apoptosis, promoting proliferation, and accelerating invasion and migration of cancer cells. Zhang et al. have reported that WTAP exerts its cancer-promoting role by regulating wnt/β-catenin signaling pathway via WTAP– WT1–TBL1 axis in colorectal cancer . However, whether WTAP exerts its effects on EC through wnt/β-catenin signaling pathway as demonstrated by GSEA in this current study needs to be further elucidated.
There are limitations in the present study. On the one hand, the association between the WTAP expression at the mRNA and protein levels could not be clearly evaluated in this report due to the limitations in our research design. On the other hand, only small amount of data regarding recurrence sites and distant metastasis were available, which were not enough for further analysis, therefore limiting the clinical outcome evaluation of this study. Consequently, further study is required.
Collectively, over-expression of WTAP in EC tumor tissues suggested its potential role as a diagnostic biomarker for EC. In addition, WTAP could function as a promising target for therapeutic utility due to its potential effects on EC. Besides, high expression of WTAP might be an underlying prognostic biomarker of poor OS and RFS in EC. Moreover, the wnt/β-catenin signaling pathway could be the critical signaling pathway regulated by WTAP in EC. However, further experimental validation should be conducted to elucidate the biological effects of WTAP.