Differential Expression of the TLR4 Gene in Pan-Cancer and Its Related Mechanism

Abstract

Previous studies have revealed the relationship between toll-like receptor 4 (<i>TLR4</i>) polymorphisms and cancer susceptibility. However, the relationship between <i>TLR4</i> and prognosis and immune cell infiltration in pan-cancer patients is still unclear. Through the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases, the distinct expression of the <i>TLR4</i> gene in 24 tumors and normal tissues was analyzed. Univariate Cox proportional hazards regression analysis was used to identify the cancer types whose <i>TLR4</i> gene expression was related to prognosis. The relationship between <i>TLR4</i> and tumor cell immune invasion was studied. Spearman's rank correlation coefficient was used to analyze the relationship among <i>TLR4</i> and immune neoantigens, tumor mutation burden (TMB), microsatellite instability (MSI), DNA repair genes, and DNA methylation. Gene Set Enrichment Analysis (GSEA) was used to identify the tumor-related pathways that the <i>TLR4</i> gene was highly expressed in; the expression of the <i>TLR4</i> gene was verified with the Human Protein Atlas (HPA) database. Low expression of <i>TLR4</i> was associated with an inferior prognosis in kidney renal clear cell carcinoma (KIRC), skin cutaneous melanoma (SKCM), and uterine corpus endometrial carcinoma (UCEC), while high expression was related to a poor prognosis in head and neck squamous cell carcinoma (HNSC), prostate adenocarcinoma (PRAD), stomach adenocarcinoma (STAD), and testicular germ cell tumor (TGCT). The expression of <i>TLR4</i> was negatively correlated with the expression of B cells in STAD. The expression of <i>TLR4</i> was positively correlated with the infiltration of B cells, CD4 and CD8 T cells, neutrophils, macrophages, and dendritic cells in STAD, KIRC, UCEC, TGCT, and SKCM. The expression of the <i>TLR4</i> gene in KIRC, SKCM, STAD, TGCT, and UCEC was highly correlated with inducible T-cell costimulator (<i>ICOS</i>), cytotoxic T lymphocyte-associated molecule 4 (<i>CTLA4</i>), and <i>CD28</i> immune checkpoints. Spearman's rank correlation coefficient showed that the expression of <i>TLR4</i> gene was significantly correlated with TMB in STAD and UCEC and was prominently correlated with MSI in TGCT, STAD, and SKCM. The expression of the <i>TLR4</i> gene was highly correlated with MLH1, MSH2, and MSH6 in KIRC, SKCM, and STAD. The expression of the <i>TLR4</i> gene was remarkably correlated with the methyltransferases DNA methyltransferase 2 (DNMT2) and DNA methyltransferase 3-beta (DNMT3B) in SKCM and STAD. Enrichment analysis showed that <i>TLR4</i> was highly expressed in the chemokine signaling pathway and the cell adhesion molecule and cytokine receptor interaction pathway. In summary, the expression of <i>TLR4</i> is linked to the prognosis of KIRC, SKCM, STAD, TGCT, and UCEC patients and the level of immune infiltration of CD4, CD8 T cells, macrophages, neutrophils, and dendritic cells.