LAUSR

Lung cancer poses severe threats to human health. It is indispensable to discover more druggable molecular targets. We identified a novel dysregulated long non‐coding RNA (lncRNA), LINC00669, in lung adenocarcinoma (LUAD) by analyzing the TCGA and GEO databases. Pan‐cancer analysis indicated significantly upregulated LINC00669 across 33 cancer types. GSEA revealed a tight association of LINC00669 with the cell cycle. We next attempted to improve the prognostic accuracy of this lncRNA by establishing a risk signature in reliance on cell cycle genes associated with LINC00669. The resulting risk score combined with LINC00669 and stage showed an AUC of 0.746. The risk score significantly stratified LUAD patients into low‐ and high‐risk subgroups, independently predicting prognosis. Its performance was verified by nomogram (C‐index = 0.736) and decision curve analysis. Gene set variation analysis disclosed the two groups' molecular characteristics. We also evaluated the tumor immune microenvironment by dissecting 28 infiltrated immune cells, 47 immune checkpoint gene expressions, and immunophenoscore within the two subgroups. Furthermore, the risk signature could predict sensitivity to immune checkpoint inhibitors and other anticancer therapies. Eventually, in vitro and in vivo experiments were conducted to validate LINC00669's function using qRT‐PCR, CCK8, flow cytometry, western blot, and immunofluorescence staining. The gain‐ and loss‐of‐function study substantiated LINC00669's oncogenic effects, which stimulated non‐small cell lung cancer cell proliferation but reduced apoptosis via activating the Wnt/β‐catenin pathway. Its oncogenic potentials were validated in the xenograft mouse model. Overall, we identified a novel oncogenic large intergenic non‐coding RNA (lincRNA), LINC00669. The resulting signature may facilitate predicting prognosis and therapy responses in LUAD.