In the current study, we attempted to identify prognostic GPLs-related genes involved in tumor-microenvironment in endometrial cancer. LPCAT1 has been confirmed to be associated with the immune activities. Importantly, ssGSEA analysis indicated that LPCAT1 might serve as an indicator for TME statement in UCEC patients.
Obesity, hypertension and diabetes are clearly recognized as risk factors of endometrial cancer. And the metabolic changes of endometrial tumors themselves compared with their nonmalignant counterparts have been gradually recognized. Studies have shown glucose transport which is mediated by GLUT-6 and glycolytic-lipogenic metabolism may be responsible for tumor cell survival[16]. Significant elevation in the expression of SREBP1 and subsequent enhancement of lipid synthesis are the main characteristics of EC[17]. Poor diagnosis has been proved to be associated with overexpression of FASN in endometrial cancer[18]. Despite increasing metabolic genes were found responsible for endometrial cancer, there are few studies on glycerophospholipids-related metabolites. GPLs are necessary for cells to maintain homeostasis and normal physiological functions. Disorder of GPLs is obviously involved in benign disease and cancers[19–22]. Identification of dysregulated GPLs-related genes may provide a novel perspective for the therapies of EC.
More and more studies have shown that metabolic changes can affect tumor microenvironment (TME), especially immune cells. The study of Ringel et al demonstrated that free fatty acid (FFA) was decreased in tumor microenvironment of mice fed with high-fat diet, and the exhaustion of free fatty acid not only inhibited the function of CD8 + T cells but also reduced the number of it[23]. TME components played an indispensable role in the initiation and development of tumorigenesis. Targeting TME remodeling may provide a potential therapy strategy to inhibit tumor progression. Several studies have demonstrated that immune microenvironment influence the tumor biological behavior[9, 24, 25]. Lack of Tumor-killing immune cells have been shown to associated with poor diagnosis of various malignancies.
Focusing on GPLs metabolism influence endometrial cancer TME. We systematically investigated the expression of 77 GPLs-related genes in UCEC tumor tissues and their prognostic values. 23 out of 77 genes were differentially expressed, and the expression of 11 genes was related to prognosis of UCEC patients. These results significantly indicated the potential role of GPLs metabolism in EC and the possibility of targeting GPLs-related genes as therapy. To identify core prognostic genes playing essential role in EC, two machine learning algorithm and PPI analysis were used. Finally, we select four significant genes. Then, Patients were divided into high-expression group and low-expression group by median expression of four significant genes, respectively. ImmuneScore, StromalScore and ESTIMATEScore were calculated by estimate R package to estimate the immune and stromal proportion of each patients. The higher the ImmuneScore and the StromalScore, the larger respective components were in TME. Scores were compared between high-expression group and low-expression group and the results revealed that only LPCAT1 was related to tumor microenvironment. Scores of high expression group of LPCAT1 was significantly lower than low expression group, suggesting that the high concentration of immune cells was in the TME of low expression group of LPCAT1. Here, we embarked from the transcriptomic analysis of UCEC in TCGA database, which revealed that the increased expression of LPCAT1 was significantly associated with the advanced, specific subtypes and poor prognosis. Chen et al. had demonstrated that the immune and stromal scores positively correlated with clinical outcomes of EC patients[10]. It might represent one of the mechanisms contributing to better prognosis of low expression group of LPCAT1. Accordingly, it suggested that LPCAT1 might be a potential prognostic marker and a therapeutic target of TME in UCEC.
LPCAT1 is a membership of lysophosphatidylcholine acyltransferases (LPCATs) family which regulate phospholipid metabolism in the Lands cycle. It catalyzes the transformation of lysophosphatidylcholine (LPC) into phosphatidylcholine (PC) by incorporating fatty acyl chains into phosphatidy lcholine[26]. LPCAT1 was initially isolated from alveolar type II cells and involved in the synthesis of alveolar surfactant[27]. Recently, LPCAT1 has been found overexpressed and acted as an oncogene in a variety of tumors[28]. However, no study demonstrated the relationship of LPCAT1 in endometrial cancer and tumor microenvironment.
To further investigate the functions of LPCAT1 in EC, DEGs analysis were performed, which were further subjected to GO and KEGG enrichment analysis.
Our results showed that salivary secretion in KEGG and receptor ligand activity, endopeptidase inhibitor activity, hormone activity, transmembrane transporter complex, ion channel complex, motile cilium, pattern specification process, regionalization, anterior/posterior pattern specification in GO were enriched.
Those all suggested that the underlying mechanism of LPCAT1 served as a potential prognostic molecular marker and therapeutic target in EC.
Another important aspect of this study was the correlation between LPCAT1 expression and the level of immune infiltration, which closely tied to the microenvironment of EC. As many studies have reported that various of immune cells, including different kinds of lymphocytes and macrophages, could form an immune microenvironment of EC, which consequently influenced EC patients outcomes[29–31]. Thus, we analyzed the relationship between LPCAT1 genomic alterations and immune infiltration in EC. Our results demonstrate that the upregulation of LPCAT1 was along with the increase of activated CD4 T cell, effector memory CD4 T cell, memory B cell and Type 2 T helper cell, which were positively correlated with LPCAT1 expression. While the upregulation of LPCAT1 was also along with the reduction of activated B cell, activated CD8 T cell, CD56dim natural killer cell, central memory CD4 T cell, effector memory CD8 T cell, eosinophil, macrophage, mast cell, MDSC, monocyte, T follicular helper cell which were negatively correlated with expression of LPCAT1. Meanwhile, LPCAT1 might act as a predictor estimating immunotherapy responses. Together these findings suggested that the LPCAT1 played an important role in recruitment and regulation of immune infiltrating cells in UCEC.
However, lack of experimental proof is the limitation of this study. Although IHC assay proved the LPCAT1 expression was significantly higher in EC than in adjacent normal tissues, the potential role of LPCAT1 and its relationship with immune cells is not sufficient without further in vivo or in vitro experiments to support. Better understanding of the functions and underlying mechanism of LPCAT1 in EC will be recognized by more verifying experiments and clinical trials which might improve accuracy of diagnosis and therapy strategy. Therefore, further studies should be conducted to verify the accuracy of a combined analysis of LPCAT1 expression, GPLs and the amounts of tumor-infiltrating immune cells for UCEC patients.