High Endothelin Receptor Type A Expression as an Independent Prognostic Biomarker and Correlated with Immune Infiltrates in Stomach Adenocarcinoma

Yanhua Yan,1 Kechao Nie,2 Junhui Zheng,1 Xiaotao Jiang,1 Yuancheng Huang,1 Zhihua Zheng,1 Yi Wen,3 Peiwu Li3 1The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, 510000, People’s Republic of China; 2Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 3Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510000, People’s Republic of ChinaCorrespondence: Peiwu Li; Yi Wen Email doctorlipw@gzucm.edu.cn; 421491922@qq.comBackground: Stomach adenocarcinoma (STAD) is the most common gastrointestinal cancer and is associated with high mortality worldwide. Endothelin receptor type A (EDNRA) is associated with guanine-nucleotide-binding (G) proteins and plays important roles in cellular processes and various diseases.Purpose: To investigate the prognosis value of EDNRA expression and its correlation with immune infiltrates in patients with STAD.Methods: The association between clinical characteristics and EDNRA expression in STAD was analyzed using the Wilcoxon signed-rank test and logistic regression. The Kaplan–Meier plotter analysis and Cox regression were constructed to evaluate the influence of EDNRA on prognosis, and a receiver operating characteristic (ROC) curve and nomogram were constructed. Gene set enrichment analysis (GSEA) and single-sample gene set enrichment analysis (ssGSEA) were conducted to analyze the correlation between EDNRA and immune infiltrates. In addition, Oncomine, TIMER databases and qRT-PCR of STAD cell lines were used to verify the EDNRA expression in STAD.Results: Our results revealed that EDNRA expression was significantly higher in patients with STAD than normal gastric tissues, and the results have been confirmed by RT-qPCR. KM-plotter analysis revealed that patients with STAD had shorter OS, FP, and PPS (P< 0.001). Multivariate Cox analysis further confirmed that high EDNRA expression was an independent risk factor for OS in patients with STAD. Moreover, other clinicopathologic features were related with worse prognosis in STAD, including age, lymph nodes metastases and primary outcome. More importantly, ROC analysis also confirmed the diagnostic value, and a prognostic nomogram involving age, T, M, N classification, pathologic stage, residual tumor and EDNRA was constructed. GSEA revealed that high EDNRA expression was correlated with immunoregulatory interactions between lymphoid and non lymphoid cells pathways, natural killer cell activation involved in immune response, interleukin 1 receptor binding and pathways in cancer, and ssGSEA showed that EDNRA is correlated with macrophages and NK cells.Conclusion: Collectively, EDNRA can be an independent prognostic biomarker and correlated with immune infiltration in stomach adenocarcinoma.Keywords: EDNRA, STAD, bioinformatics, prognosis