Construction and experimental validation of a necroptosis-related lncRNA signature as a prognostic model and immune-landscape predictor for lung adenocarcinoma.

ABSTRACT

Necroptosis is a new form of cell death. Since the discovery that long non-coding RNAs can affect the proliferation of lung adenocarcinoma, much has been learned about it, yet those of necroptosis-related long non-coding RNAs (NRlncRNAs) in lung adenocarcinoma (LUAD) remain enigmatic. This study aims to explore novel biomarkers and therapeutic targets for LUAD. The LUAD data was downloaded from The Cancer Genome Atlas, and necroptosis-related genes were retrieved from published literature. Co-expression analysis, univariate Cox analysis, least absolute shrinkage and selection operator regression analysis were used to identify necroptosis-related prognostic long non-coding RNAs. A comprehensive evaluation of tumor immunity for necrosis-related features was performed, and we identified a 9-NRlncRNA signature. Kaplan-Meier and Cox regression analyses confirmed that the signature was an independent predictor of LUAD outcome in the test and train sets (all P < 0.05). The areas of 1-, 2-, and 3-year overall survival under the time-dependent receiver operating characteristics (ROC) curve (AUC) were 0.754, 0.746, and 0.720, respectively. The GSEA results showed that 9 NRlncRNAs were associated with multiple malignancy-associated and immunoregulatory pathways. Based on this model, we found that the immune status and level of response to chemotherapy and targeted therapy were significantly different in the low-risk group compared with the high-risk group. qRT-PCR assay revealed that 9 NRlncRNAs were involved in the regulation of tumor cell proliferation and may affect the expression of programmed cell death 1 (PD1) and CD28 at human immune checkpoints. Our results indicated that the novel signature involving 9 NRlncRNAs (AL031600.2, LINC01281, AP001178.1, AL157823.2, LINC01290, MED4-AS1, AC026355.2, AL606489.1, FAM83A-AS1) can predict the prognosis of LUAD and are associated with the immune response. This will provide new insights into the pathogenesis and development of therapies for LUAD.