Nitrogen Metabolism Disorder Accelerates Occurrence and Development of Lung Adenocarcinoma: A Bioinformatic Analysis and In Vitro Experiments

Abstract

BackgroundNitrogen metabolism (NM) plays a pivotal role in immune regulation and the occurrence and development of cancers. The aim of this study was to construct a prognostic model and nomogram using NM-related genes for the evaluation of patients with lung adenocarcinoma (LUAD).MethodsThe differentially expressed genes (DEGs) related to NM were acquired from The Cancer Genome Atlas (TCGA) database. Consistent clustering analysis was used to divide them into different modules, and differentially expressed genes and survival analysis were performed. The survival information of patients was combined with the expressing levels of NM-related genes that extracted from TCGA and Gene Expression Omnibus (GEO) databases. Subsequently, univariate Cox analysis and the least absolute shrinkage and selection operator (LASSO) regression were used to build a prognostic model. GO and KEGG analysis were elaborated in relation with the mechanisms of NM disorder (NMD). Meanwhile, immune cells and immune functions related to NMD were discussed. A nomogram was built according to the univariate and multivariate Cox analysis to identify independent risk factors. Finally, real-time fluorescent quantitative PCR (RT-PCR) and Western bolt (WB) were used to verify the expression level of hub genes.ResultsThere were 138 differential NM-related genes that were divided into two gene modules. Sixteen NM-related genes were used to build a prognostic model and the receiver operating characteristic curve (ROC) showed that the efficiency was reliable. GO and KEGG analysis suggested that NMD accelerated development of LUAD through the Wnt signaling pathway. The level of activated dendritic cells (aDCs) and type II interferon response in the low-risk group was higher than that of the high-risk group. A nomogram was constructed based on ABCC2, HMGA2, and TN stages, which was identified as four independent risk factors. Finally, RT-PCR and WB showed that CDH17, IGF2BP1, IGFBP1, ABCC2, and HMGA2 were differently expressed between human lung fibroblast (HLF) cells and cancer cells.ConclusionsHigh NM levels were revealed as a poor prognosis of LUAD. NMD regulates immune system through affecting aDCs and type II interferon response. The prognostic model with NM-related genes could be used to effectively evaluate the outcomes of patients.

Prognostic and immunotherapeutic implications of bilirubin metabolism‐associated genes in lung adenocarcinoma

“…We could identify a prognostic signature of 15 BMAGs that reliably predicts LUAD outcomes, which was corroborated across five independent GEO datasets. Notably, the linkage of ABCC2 to the prognosis of LUAD has been established, forming the basis of a prognostic nomogram 24 . Moreover, diminished expression of EIF2AK3 in LUAD cells has been implicated in prognostic outcomes 25 .…”

“…Notably, the linkage of ABCC2 to the prognosis of LUAD has been established, forming the basis of a prognostic nomogram. 24 Moreover, diminished expression of EIF2AK3 in LUAD cells has been implicated in prognostic outcomes. 25 The BMAG‐prognostic signature was shown to be an independent factor for prognosis when combined with clinicopathological features, outperforming other indicators.…”

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“…The metabolism of nitrogen affects how malignancies form. According to one study, a malfunction in nitrogen metabolism may use the Wnt signaling pathway to hasten the development of lung adenocarcinoma [20]. Target genes may also be involved in tryptophan metabolism, according to the pathway analysis.…”

Mining toxicogenomic data for dose-responsive pathways: implications in advancing next-generation risk assessment

“…Next, among the overlapping pathways, we have decided to focus on the "nitrogen metabolic processing" pathway (GO: 0006807), since this process plays an extensive role in several carcinogenic and immune-related processes (Kurmi and Haigis, 2020;Zhang et al, 2022). In addition, nitrogen metabolism is essential for the biosynthesis of nucleotides, amino acids, and neurotransmitters (Brosnan, 2003;Wu, 2021).…”