Dataset Information

The Potential Role of IL1RAP on Tumor Microenvironment-Related Inflammatory Factors in Stomach Adenocarcinoma.

ABSTRACT: This study was performed to investigate the role of interleukin-1 receptor accessory protein (IL1RAP) in stomach carcinoma in vitro and in vivo, determine whether IL1RAP knockdown could regulate the development of stomach carcinoma, and elucidate the relationship between IL1RAP knockdown and inflammation by tumor microenvironment-related inflammatory factors in stomach carcinoma. We first used TCGA and GEPIA systems to predict the potential function of IL1RAP. Second, western blot and RT-PCR were used to analyze the expression, or mRNA level, of IL1RAP at different tissue or cell lines. Third, the occurrence and development of stomach carcinoma in vitro and in vivo were observed by using IL1RAP knockdown lentivirus. Finally, the inflammation of stomach carcinoma in vitro and in vivo was observed. Results show that in GEPIA and TCGA systems, IL1RAP expression in STAD tumor tissue was higher than normal, and high expression of IL1RAP in STAD patients had a worse prognostic outcome. Besides, GSEA shown IL1RAP was negative correlation of apopopsis, TLR4 and NF-?B signaling pathway. We also predicted that IL1RAP may related to IL-1 s, IL-33, and IL-36 s in STAD. The IL1RAP expression and mRNA level in tumor, or MGC803, cells were increased. Furthermore, IL1RAP knockdown by lentivirus could inhibit stomach carcinoma development in vitro and in vivo through weakening tumor cell proliferation, migration, invasion, therefore reducing tumor volume, weight, and biomarker levels, and increasing apoptotic level. Finally, we found IL1RAP knockdown could increase inflammation of tumor microenvironment-related inflammatory factors of stomach carcinoma, in vitro and in vivo. Our study demonstrates that IL1RAP is possibly able to regulate inflammation and apoptosis in stomach carcinoma. Furthermore, TLR4, NF-?B, IL-1 s, IL-33, and IL-36 s maybe the downstream target factor of IL1RAP in inflammation. These results may provide a new strategy for stomach carcinoma development by regulating inflammation.

SUBMITTER: Lv Q

PROVIDER: S-EPMC7897808 | biostudies-literature | 2021 Jan-Dec

REPOSITORIES: biostudies-literature

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The Potential Role of IL1RAP on Tumor Microenvironment-Related Inflammatory Factors in Stomach Adenocarcinoma.

Lv Qing Q Xia Qinghua Q Li Anshu A Wang Zhiyong Z

Technology in cancer research & treatment 20210101

This study was performed to investigate the role of interleukin-1 receptor accessory protein (IL1RAP) in stomach carcinoma in vitro and in vivo, determine whether IL1RAP knockdown could regulate the development of stomach carcinoma, and elucidate the relationship between IL1RAP knockdown and inflammation by tumor microenvironment-related inflammatory factors in stomach carcinoma. We first used TCGA and GEPIA systems to predict the potential function of IL1RAP. Second, western blot and RT-PCR wer ...[more]

PMID: 33602046

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Project description:N6-methylandrostenedione (m6A) methylation plays a very important role in the development of malignant tumors. The immune system is the key point in the progression of tumors, particularly in terms of tumor treatment and drug resistance. Tumor immunotherapy has now become a hot spot and a new approach for tumor treatment. However, as far as the stomach adenocarcinoma (STAD) is concerned, the in-depth research is still a gap in the m6A-associated immune markers. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases is extremely important for our research, where we obtained gene mutation, gene expression data and relevant clinical information of STAD patients. Firstly, the samples from GEO were used as external validation groups, while the TCGA samples were divided into a training group and an internal validation group randomly. Using the way of Single factor COX-LASSO- and multi-factor Cox to construct the prognostic model. Then, all samples were subjected to cluster analysis to generate high and low expression groups of immune gene. Meanwhile, we also collected the correlation between these types and tumor microenvironment. On this basis, a web version of the dynamic nomogram APP was developed. In addition, we performed microenvironmental correlation, copy number variation and mutation analyses for model genes. The prognostic model for STAD developed here demonstrated a very strong predictive ability. The results of cluster analysis manifested that the immune gene low expression group had lower survival rate and higher degree of immune infiltration. Therefore, the immune gene low expression group was associated with lower survival rates and a higher degree of immune infiltration. Gene set enrichment analysis suggested that the potential mechanism might be related to the activation of immunosuppressive functions and multiple signaling pathways. Correspondingly, the web version of the dynamic nomogram APP produced by the DynNom package has successfully achieved rapid and accurate calculation of patient survival rates. Finally, the multi-omics analysis of model genes further enriched the research content. Interference of RAB19 was confirmed to facilitate migration of STAD cells in vitro, while its overexpression inhibited these features. The prognostic model for STAD constructed in this study is accurate and efficient based on multi-omics analysis and experimental validation. Additionally, the results of the correlation analysis between the tumor microenvironment and m6Ascore are the basics of further exploration of the pathophysiological mechanism in STAD.

Project description:BackgroundGastric cancer (GC) represents a major global clinical problem with very limited therapeutic options and poor prognosis. Necroptosis, a recently discovered inflammatory form of cell death, has been implicated in carcinogenesis and inducing necroptosis has also been considered as a therapeutic strategy.ObjectiveWe aim to evaluate the role of this pathway in gastric cancer development, prognosis and immune aspects of its tumor microenvironment.Methods and resultsIn this study, we evaluated the gene expression of 55 necroptosis-related genes (NRGs) that were identified via carrying out a comprehensive review of the medical literature. Necroptosis pathway was deregulated in gastric cancer samples (n=375) as compared to adjacent normal tissues (n=32) obtained from the "The Cancer Genome Atlas (TCGA)". Based on the expression of these NRGs, two molecular subtypes were obtained through consensus clustering that also showed significant prognostic difference. Differentially expressed genes between these two clusters were retrieved and subjected to prognostic evaluation via univariate cox regression analysis and LASSO cox regression analysis. A 13-gene risk signature, termed as necroptosis-related genes prognostic index (NRGPI), was constructed that comprehensively differentiated the gastric cancer patients into high- and low-risk subgroups. The prognostic significance of NRGPI was validated in the GEO cohort (GSE84437: n=408). The NRGPI-high subgroup was characterized by upregulation of 10 genes (CYTL1, PLCL1, CGB5, CNTN1, GRP, APOD, CST6, GPX3, FCN1, SERPINE1) and downregulation of 3 genes (EFNA3, E2F2, SOX14). Further dissection of these two risk groups by differential gene expression analysis indicated involvement of signaling pathways associated with cancer cell progression and immune suppression such as WNT and TGF-β signaling pathway. Para-inflammation and type-II interferon pathways were activated in NRGPI-high patients with an increased infiltration of Tregs and M2 macrophage indicating an exhausted immune phenotype of the tumor microenvironment. These molecular characteristics were mainly driven by the eight NRGPI oncogenes (CYTL1, PLCL1, CNTN1, GRP, APOD, GPX3, FCN1, SERPINE1) as validated in the gastric cancer cell lines and clinical samples. NRGPI-high patients showed sensitivity to a number of targeted agents, in particular, the tyrosine kinase inhibitors.ConclusionsNecroptosis appears to play a critical role in the development of gastric cancer, prognosis and shaping of its tumor immune microenvironment. NRGPI can be used as a promising prognostic biomarker to identify gastric cancer patients with a cold tumor immune microenvironment and poor prognosis who may response to selected molecular targeted therapy.

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Project description:BackgroundLung adenocarcinoma (LUAD) is the most common histological type of lung cancers, which is the primary cause of cancer-related mortality worldwide. Growing evidence has suggested that tumor microenvironment (TME) plays a pivotal role in tumorigenesis and progression. Hence, we investigate the correlation of TME related genes with LUAD prognosis.MethodThe information of LUAD gene expression data was obtained from The Cancer Genome Atlas (TCGA). According to their immune/stromal scores calculated by the ESTIMATE algorithm, differentially expressed genes (DEGs) were identified. Then, we performed univariate Cox regression analysis on DEGs to obtain genes that are apparently bound up with LUAD survival (SurGenes). Functional annotation and protein-protein interaction (PPI) was also conducted on SurGenes. By validating the SurGenes with data sets of lung cancer from the Gene Expression Omnibus (GEO), 106 TME related SurGenes were generated. Further, intersection analysis was executed between the 106 TME related SurGenes and hub genes from PPI network, PTPRC and CD19 were obtained. Gene Set Enrichment Analysis and CIBERSORT analysis were performed on PTPRC and CD19. Based on the TCGA LUAD dataset, we conducted factor analysis and Step-wise multivariate Cox regression analysis for 106 TME related SurGenes to construct the prognostic model for LUAD survival prediction. The LUAD dataset in GEO (GSE68465) was used as the testing dataset to confirm the prognostic model. Multivariate Cox regression analysis was used between risk score from the prognostic model and clinical parameters.ResultA total of 106 TME related genes were collected in our research totally, which were markedly correlated with the overall survival (OS) of LUAD patient. Bioinformatics analysis suggest them mainly concentrated on immune response, cell adhesion, and extracellular matrix. More importantly, among 106 TME related SurGenes, PTPRC and CD19 were highly interconnected nodes among PPI network and correlated with immune activity, exhibiting significant prognostic potential. The prognostic model was a weighted linear combination of the 106 genes, by which the low-OS LUAD samples could be separated from the high-OS samples with success. This model was also able to rebustly predict the situation of survival (training set: p-value < 0.0001, area under the curve (AUC) = 0.649; testing set: p-value = 0.0009, AUC = 0.617). By combining with clinical parameters, the prognostic model was optimized. The AUC achieved 0.716 for 3 year and 0.699 for 5 year.ConclusionA series of TME-related prognostic genes were acquired in this research, which could reflect immune disorders within TME, and PTPRC and CD19 show the potential to be an indicator for LUAD prognosis and tumor microenvironment modulation. The prognostic model constructed base on those prognostic genes presented a high predictive ability, and may have clinical implications in the overall survival prediction of LUAD.

Dataset Information

The Potential Role of IL1RAP on Tumor Microenvironment-Related Inflammatory Factors in Stomach Adenocarcinoma.

Publications

The Potential Role of IL1RAP on Tumor Microenvironment-Related Inflammatory Factors in Stomach Adenocarcinoma.

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