It is imperative to advance the understanding of lung cancer biology. The Cancer Genome Atlas (TCGA) dataset was used for bioinformatics analysis. CCK-8 assay, flow cytometry, and western blot were performed in vitro, followed by in vivo study. We found that lncRNA Highly Accelerated Region 1A (HAR1A) is significantly downregulated in lung adenocarcinoma (LUAD) and negatively associated with prognosis. We improved the prognostic accuracy of HAR1A in LUAD by combining genes regulating cell apoptosis and cell cycle to generate a 23-gene signature. Nomogram and decision curve analysis (DCA) confirmed that the gene signature performed robustly in predicting overall survival. Gene set variation analysis (GSVA) demonstrated several significantly upregulated malignancy-related events in the high-risk group, including DNA replication, DNA repair, glycolysis, hypoxia, MYC targets v2, and mTORC1. The risk signature distinguished LUAD patients suitable for chemotherapies or targeted therapies. Additionally, the knockdown of HAR1A accelerated NSCLC cell proliferation but inhibited apoptosis and vice versa. HAR1A regulated cellular activities through the STAT3 signaling pathway. The tumor-suppressing role of HAR1A was verified in the mouse model. Overall, the gene signature was robustly predictive of prognosis and sensitivity to anti-tumor drugs. HAR1A functions as a tumor suppressor in NSCLC by regulating the STAT3 signaling pathway.
Keywords: LUAD; STAT3; lncRNA HAR1A; prognostic signature; proliferation.