Prognostic analysis and validation of lncRNAs in bladder cancer on the basis of neutrophil extracellular traps

• Published in: The journal of gene medicine Vol. 25; no. 10; p. e3525
• Main Authors: Gu, Lan, Guo, Hao, Wu, Long-Xiang, Yuan, Jun-Bin
• Format: Journal Article
• Language: English
• Published: England Wiley Periodicals Inc 01.10.2023
• Subjects: Angiogenesis; Apoptosis; Atrophy; Bladder cancer; Cell activation; Cell cycle; Cell proliferation; Copy number; Gelatinase B; Gene therapy; Genes; Genomes; Leukocytes (neutrophilic); Lymphocytes T; Medical prognosis; Metastases; Neutrophils; Non-coding RNA; Protein-arginine deiminase; Tumor microenvironment; lncRNAs; neutrophil extracellular traps (NETs); tumor-associated neutrophils (TANs); prognostic risk analysis; bladder cancer (BLCA); NKILA
• ISSN: 1099-498X; 1521-2254
• DOI: 10.1002/jgm.3525

Complex interactions in the tumor microenvironment (TME) between bladder cancer (BLCA) and immune cells are critical for cancer progression. However, studies of neutrophil extracellular trap-associated long non-coding RNAs (NET-lncRNAs) in the TME of BLCA have not been reported. This study aims to screen for NET-lncRNAs in BLCA and to preliminarily explore their effects on BLCA development. The correlation of NET-related gene sets, which were identified from the cancer genome atlas (TCGA) BLCA datasets, with lncRNAs was analyzed and the prognosis-related genes were identified through random forest analysis. The least absolute shrinkage and selection operator (LASSO) model was utilized to obtain prognostic risk scores for NET-lncRNAs (NET-Score). We collected clinical BLCA samples, as well as SV-HUC-1 and BLCA cells, to validate the expression of NET-lncRNAs. Survival and independent prognostic analysis were performed. In J82 and UM-UC-3 cells, after NKILA expression was inhibited, cell proliferation and apoptosis levels were detected. NET-related gene sets mainly included CREB5, MMP9, PADI4, CRISPLD2, CD93, DYSF, MAPK3, TECPR2, MAPK1 and PIK3CA. Then, four NET-lncRNAs, MAP 3 K4-AS1, MIR100HG, NKILA and THY1-AS1, were identified. NET-Score had the highest hazard ratio for BLCA. An elevated NET-Score was linked to a significant increase in immune cell infiltration and copy number variation, as well as a notable decrease in survival rate and drug sensitivity. NET-lncRNA-related genes were mainly enriched in the pathways of angiogenesis, immune response, cell cycle and T cell activation. MAP 3 K4-AS1, MIR100HG, NKILA and THY1-AS1 expressions were significantly increased in BLCA tissues. Compared with SV-HUC-1 cells, NKILA expression was elevated in J82 and UM-UC-3 cells. Inhibition of NKILA expression inhibited the proliferation and promoted apoptosis of J82 and UM-UC-3 cells. Several NET-lncRNAs, including MAP 3 K4-AS1, MIR100HG, NKILA and THY1-AS1, were successfully screened in the BLCA. The NET-Score was an independent prognostic factor for BLCA. In addition, inhibition of NKILA expression suppressed BLCA cell development. The above NET-lncRNAs could serve as potential prognostic markers and targets in BLCA.