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The nine ADAMs family members serve as potential biomarkers for immune infiltration in pancreatic adenocarcinoma

ABSTRACT: Background The functional significance of ADAMs family members in the immune infiltration of pancreatic adenocarcinoma (PAAD) awaits elucidation. Methods ADAMs family members with significant expression were identified among differentially expressed genes of PAAD based on The Cancer Genome Atlas (TCGA) database followed by a verification based on the Oncomine database. The correlation of ADAMs in PAAD was estimated with the Spearman’s rho value. The pathway enrichment of ADAMs was performed by STRING and GSEALite, respectively. The protein–protein interaction and Gene Ontology analyses of ADAMs and their similar genes were exanimated in STRING and visualized by Cytoscape. Subsequently, the Box-Whisker plot was used to show a correlation between ADAMs and different tumor grade 1/2/3/4 with Student’s t-test. TIMER was applied to estimate a correlation of ADAMs expressions with immune infiltrates and immune checkpoint blockade (ICB) immunotherapy-related molecules. Furthermore, the effect of copy number variation (CNV) of ADAMs genes was assessed on the immune infiltration levels. Result ADAM8/9/10/12/15/19/28/TS2/TS12 were over-expressed in PAAD. Most of the nine ADAMs had a significant correlation. ADAM8/12/15/19 expression was remarkably increased in the comparison between grade 1 and grade 2/3 of PAAD. ADAM8/9/10/12/19/28/TS2/TS12 had a positive correlation with almost five immune infiltrates. ADAM12/19/TS2/TS12 dramatically related with ICB immunotherapy-related molecules. CNV of ADAMs genes potentially influenced the immune infiltration levels. Conclusion Knowledge of the expression level of the ADAMs family could provide a reasonable strategy for improved immunotherapies to PAAD.

SUBMITTER: Qi B

PROVIDER: S-EPMC7532768 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:Background: Pancreatic adenocarcinoma (PDAC) is the most aggressive among all solid malignancies with delayed disease detection and limited effective treatment. However, due to the intricate heterogeneity and exclusive tumor microenvironment (TME), the development of effective therapy has been facing enormous challenges. The lysyl oxidases (LOXs) underpin the shaping of the TME to promote cancer growth, metastasis and modulate response to treatment. Materials and Methods: The mRNA expression, prognostic, and clinicopathological data for LOXs in PDAC from multiple open-access databases were summarized and analyzed. The protein expression was verified by immunohistochemistry (IHC). Co-expressed genes of LOXs were predicted and elaborated by LinkedOmics. Functional enrichment analysis of LOXs co-expressed genes was performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). TIMER and TISIDB were applied to analyze the relationship between LOXs expression and immune infiltration. Results: The mRNA expression levels of LOX, LOXL1 and LOXL2 were significantly higher in PDAC, the expression levels of LOXL3 and LOXL4 were contrary in different databases. High mRNA levels of LOX and LOXL2 were associated with advanced PDAC stage, while elevated LOX and LOXL3 expression correlated with high tumor grade. The IHC staining showed higher expression levels of LOX, LOXL1 and LOXL2, lower expression level of LOXL3 in PDAC tissues, while the protein expression of LOXL4 made no difference. Functional enrichment analysis showed a close relationship with extracellular matrix (ECM) regulation, except that LOXL3 and its ligands were highly associated with immune-related functions. Further analysis suggested that LOX and LOXL3 strongly correlated with tumor-infiltrating lymphocytes (TILs), various immune signatures, and immune checkpoints. Finally, survival analysis revealed high LOX and LOXL2 expression predicted worse overall survival (OS), progression-free interval (PFI), and disease-specific survival (DSS). Conclusion: These findings indicated that the LOX family, especially LOX and LOXL2, might have a prospective value in PDAC oncogenesis, and they may become prognostic biomarkers, revealing a promising field in targeted therapy.

Project description:BackgroundMetabolic reprogramming has been identified as a core hallmark of cancer. Solute carrier family 2 is a major glucose carrier family. It consists of 14 members, and we mainly study solute carrier family 2 member 1 (SLC2A1) and solute carrier family 2 member 2 (SLC2A2) here. SLC2A1, mainly existing in human erythrocytes, brain endothelial cells, and normal placenta, was found to be increased in hepatocellular carcinoma (HCC), while SLC2A2, the major transporter of the normal liver, was decreased in HCC.AimTo identify if SLC2A1 and SLC2A2 were associated with immune infiltration in addition to participating in the metabolic reprogramming in HCC.MethodsThe expression levels of SLC2A1 and SLC2A2 were tested in HepG2 cells, HepG215 cells, and multiple databases. The clinical characteristics and survival data of SLC2A1 and SLC2A2 were examined by multiple databases. The correlation between SLC2A1 and SLC2A2 was analyzed by multiple databases. The functions and pathways in which SLC2A1, SLC2A2, and frequently altered neighbor genes were involved were discussed in String. Immune infiltration levels and immune marker genes associated with SLC2A1 and SLC2A2 were discussed from multiple databases.ResultsThe expression level of SLC2A1 was up-regulated, but the expression level of SLC2A2 was down-regulated in HepG2 cells, HepG215 cells, and liver cancer patients. The expression levels of SLC2A1 and SLC2A2 were related to tumor volume, grade, and stage in HCC. Interestingly, the expression levels of SLC2A1 and SLC2A2 were negatively correlated. Further, high SLC2A1 expression and low SLC2A2 expression were linked to poor overall survival and relapse-free survival. SLC2A1, SLC2A2, and frequently altered neighbor genes played a major role in the occurrence and development of tumors. Notably, SLC2A1 was positively correlated with tumor immune infiltration, while SLC2A2 was negatively correlated with tumor immune infiltration. Particularly, SLC2A2 methylation was positively correlated with lymphocytes.ConclusionSLC2A1 and SLC2A2 are independent therapeutic targets for HCC, and they are quintessential marker molecules for predicting and regulating the number and status of immune cells in HCC.

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The nine ADAMs family members serve as potential biomarkers for immune infiltration in pancreatic adenocarcinoma

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