ABSTRACT
Neutrophiltolymphocyte ratio (NLR) is commonly considered a useful prognostic index for many cardiovascular diseases; however, it has limited sensitivity and specificity. Factors associated with elevated NLR may aid in the prediction of prognosis with heart failure (HF) in combination with NLR. The present study sought to identify decisive factors associated with NLR in HF patients and investigate their association with elevated NLR. The gene expression profile for blood samples from 197 individuals with chronic heart failure (CHF), with corresponding hematological parameters and clinical data were obtained from the public database, GSE77343. Differentially expressed genes (DEGs) were identified, and Gene Ontology and pathway enrichment analyses were performed. The proteinprotein interaction network was constructed with the Search Tool for the Retrieval of Interacting Genes along with Cytoscape. Receiver operating characteristic curves for predictive power, sensitivity and specificity were constructed. The present study identified specific associated DEGs by using Pearson linear correlation and logistic regression analysis. A mean NLR of 3.96 was determined as the cutoff value in the analysis. In total, 31 genes were initially identified as DEGs associated with elevated NLR. They were mainly enriched in neutrophil activation and neutrophil mediated immunity, in fluid shear stress and atherosclerosis, and transcriptional misregulation in cancer. Three focused DEGs, solute carrier family 22 member 4 (SLC22A4), interleukin1 receptor 2 (IL1R2) and vanin 3 (VNN3), were finally revealed to be independently associated with elevated NLR in CHF patients. The present study demonstrated that the three genes SLC22A4, IL1R2 and VNN3 may be independently associated with elevated NLR in CHF patients as potential decisive factors of NLR.
Subject(s)
Amidohydrolases/genetics , Cell Adhesion Molecules/genetics , Heart Failure/genetics , Lymphocytes/metabolism , Neutrophils/metabolism , Organic Cation Transport Proteins/genetics , Receptors, Interleukin-1 Type II/genetics , Aged , Amidohydrolases/immunology , Annexin A3/genetics , Annexin A3/immunology , Biomarkers , Cell Adhesion Molecules/immunology , Chronic Disease , Databases, Genetic , Female , GPI-Linked Proteins/genetics , GPI-Linked Proteins/immunology , Gene Expression Regulation , Gene Ontology , Gene Regulatory Networks , Heart Failure/diagnosis , Heart Failure/immunology , Heart Failure/pathology , Humans , Leukocyte Count , Lymphocytes/immunology , Lymphocytes/pathology , Male , Middle Aged , Molecular Sequence Annotation , Neutrophils/immunology , Neutrophils/pathology , Organic Cation Transport Proteins/immunology , Protein Interaction Mapping , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/immunology , Receptors, Interleukin-1 Type I/genetics , Receptors, Interleukin-1 Type I/immunology , Receptors, Interleukin-1 Type II/immunology , SymportersABSTRACT
Cancer stem-like cells/cancer-initiating cells (CSCs/CICs) are considered to represent a small population of cancer cells that is resistant to conventional cancer treatments and responsible for tumor recurrence and metastasis. The aim of this study was to establish CSC/CIC-targeting immunotherapy. In this study, we found that Annexin A3 (ANXA3) was preferentially expressed in CSCs/CICs derived from hepatocellular carcinoma (HCC) cells compared to non-CSCs/CICs. In HCC samples, high levels of ANXA3 correlated with expansion of CD133(+) tumor cells representing CSCs/CICs in HCC; the combination of high levels of ANXA3 and CD133 was associated with progression of HCC. Overexpression of ANXA3 increased the proportion of CD133(+) cells, enhancing their tumorigenicity. On the contrary, knockdown of ANXA3 decreased CD133(+) cells and inhibited tumorigenicity. The mechanistic study revealed that ANXA3-mediated maintenance of HCC CSCs/CICs activity was likely involved with the HIF1A/Notch pathway. Using ANXA3 as a target, ANXA3-transfected dendritic cells could induce more functionally active T cells and these effector T cells could superiorly kill CD133(+) HCC CSCs/CICs in vitro and in vivo. Taken together, our findings suggest that ANXA3 plays a role in HCC CSC/CIC maintenance, and that ANXA3 may represent a potential CSC/CIC-specific therapeutic target for improving the treatment of HCC.
