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Association Between EphA1 and Tumor Microenvironment in Gastric Carcinoma and its Clinical Significance.

ABSTRACT: BACKGROUND With the growing global burden of gastric carcinoma (GC) and the urgent need for biomolecular targeted therapies, this study aimed to elucidate the relationship between EphA1 and the tumor microenvironment (focusing primarily on the key inflammatory cytokines IL-6 and tumor angiogenic cytokine VEGF) to identify a new potential therapeutic target. MATERIAL AND METHODS IHC and qRT-PCR were performed to quantify the protein and gene expression levels of EphA1, IL-6, and VEGF in normal mucosal tissues, carcinoma tissues, and paracarcinomatous tissues from 57 GC patients. Spearman's rank correlation test was performed to determine the relationship between EphA1, IL-6, and VEGF expression levels. The relationships of EphA1 with clinicopathologic parameter and survival in GC patients were also evaluated. RESULTS The protein and gene expression levels of EphA1 were all attenuated gradually from carcinoma tissues to paracarcinomatous tissues and then to normal mucosal tissues in GC patients. Additionally, significant correlations between the overexpression of EphA1 with aggressive clinicopathological features and shorter survival time of GC patients were verified. In particular, we found a significant positive correlation between the expression of EphA1 and tumor microenvironment hallmark proteins IL-6 and VEGF in carcinoma tissues and paracarcinomatous tissues. CONCLUSIONS EphA1 can promote the occurrence and development of GC by its selective high expression in cancer tissues and its relationship with malignant clinical features and prognosis of GC patients. The underlying potential mechanism appears to involve enhancement of the tumor microenvironment, which via drives the expression of tumor microenvironment hallmark proteins IL-6 and VEGF.

SUBMITTER: Wang YC

PROVIDER: S-EPMC7133419 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Association Between EphA1 and Tumor Microenvironment in Gastric Carcinoma and its Clinical Significance.

Wang Yong-Cang YC Dai Yin Y Xu Ge-Liang GL Yu Wei W Quan Rui-Liang RL Zhao Ya-Jun YJ

Medical science monitor : international medical journal of experimental and clinical research 20200327

BACKGROUND With the growing global burden of gastric carcinoma (GC) and the urgent need for biomolecular targeted therapies, this study aimed to elucidate the relationship between EphA1 and the tumor microenvironment (focusing primarily on the key inflammatory cytokines IL-6 and tumor angiogenic cytokine VEGF) to identify a new potential therapeutic target. MATERIAL AND METHODS IHC and qRT-PCR were performed to quantify the protein and gene expression levels of EphA1, IL-6, and VEGF in normal mu ...[more]

PMID: 32218416

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Project description:Background: Gastric carcinoma (GC) is a carcinoma with a high incidence rate, and it is a deadly carcinoma globally. An effective tool, that is, able to predict different survival outcomes for GC patients receiving individualized treatments is deeply needed. Methods: In total, data from 975 GC patients were collected from TCGA-STAD, GSE15459, and GSE84437. Then, we performed a comprehensive unsupervised clustering analysis based on 54 TGFβ-pathway-related genes and correlated these patterns with tumor microenvironment (TME) cell-infiltrating characteristics. WGCNA was then applied to find the module that had the closest relation with these patterns. The least absolute shrinkage and selection operator (LASSO) algorithm was combined with cross validation to narrow down variables and random survival forest (RSF) was used to create a risk score. Results: We identified two different TGFβ regulation patterns and named them as TGFβ Cluster 1 and Cluster 2. TGFβ Cluster 1 was linked to significantly poorer survival outcomes and represented an inflamed TME subtype of GC. Using WGCNA, a module (magenta) with the closest association with the TGFβ clusters was identified. After narrowing down the gene list by univariate Cox regression analysis, the LASSO algorithm and cross validation, four of the 243 genes in the magenta module were applied to build a risk score. The group with a higher risk score exhibited a considerably poorer survival outcome with high predictive accuracy. The risk score remained an independent risk factor in multivariate Cox analysis. Moreover, we validated this risk score using GSE15459 and GSE84437. Furthermore, we found that the group with a higher risk score represented an inflamed TME according to the evidence that the risk score was remarkably correlated with several steps of cancer immunity cycles and a majority of the infiltrating immune cells. Consistently, the risk score was significantly related to immune checkpoint genes and T cell-inflamed gene expression profiles (GEPs), indicating the value of predicting immunotherapy. Conclusions: We have developed and validated a TGFβ-associated signature, that is, capable of predicting the survival outcome as well as depicting the TME immune characteristics of GC. In summary, this signature may contribute to precision medicine for GC.

Project description:Programmed death-ligand 1 (PD-L1) is a crucial negative costimulatory molecule expressed on both tumor and immune cells. It binds to programmed death-1, facilitating tumor escape. Tumor-infiltrating immune cells play a vital role in this process. However, the clinical relationship between PD-L1 expression and tumor-infiltrating immune cells remains uncertain. Immunohistochemistry (IHC) was utilized to assess PD-L1 expression and TIIC markers (CD3, CD4, CD8, CD19, CD31, CD68, CD11c, CD56, and α-smooth muscle actin) in gastric adenocarcinoma tissues from 268 patients. The aim was to explore the prognostic significance of PD-L1 and the infiltration of different immune cell types. The study analyzed overall survival and the correlations between PD-L1 expression, immune cell infiltration, and clinicopathological characteristics. Among the 268 patients, 52 (19.40%) exhibited high PD-L1 expression on tumor cells (TPD-L1), while 167 (62.31%) displayed high PD-L1 expression on immune cells (IPD-L1). Patients with high IPD-L1 expression showed improved survival compared to those with low IPD-L1 expression (P = .028). High TPD-L1 expression associated with various clinicopathological features, such as larger tumor size, poorer differentiation, deeper invasion depth, and higher tumor stage. Conversely, patients with high IPD-L1 expression exhibited shallower tumor invasion and lower mortality rates. Univariate analysis indicated that superficial tumor infiltration, absence of lymph node and distant metastasis, low tumor stage, high IPD-L1 expression, and elevated CD8 and CD19 expression were associated with a reduced risk of tumor progression. Multivariate analysis revealed that patients with high IPD-L1 and CD8 expression or high TPD-L1 and low CD31 expression experienced significantly better overall survival than patients with other combinations. The findings indicate that patients with high PD-L1 expression in immune cells have a substantially improved prognosis. Additionally, the combination of PD-L1 with CD8 or CD31 expression status can serve as an indicator of prognosis in patients with gastric adenocarcinoma.

Dataset Information

Association Between EphA1 and Tumor Microenvironment in Gastric Carcinoma and its Clinical Significance.

Publications

Association Between EphA1 and Tumor Microenvironment in Gastric Carcinoma and its Clinical Significance.

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