Lipocalin-2 promotes NSCLC progression by activating the JAK2/STAT3 signaling pathway.

BACKGROUND: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Lipocalin-2 (LCN2), a pleiotropic protein implicated in tumorigenesis and cancer progression, has been associated with multiple malignancies. However, its precise role in NSCLC and the underlying molecular mechanisms remain incompletely understood. This study aimed to elucidate the function of LCN2 in NSCLC, with a particular focus on its involvement in the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway. METHODS: LCN2 expression in NSCLC tissues was comprehensively analyzed using bioinformatics tools, including the Universal Analysis of Cancer (UALCAN), The Cancer Genome Atlas (TCGA), UCSC-XENA, and Gene Expression Omnibus (GEO) databases. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were employed to assess LCN2 expression levels in NSCLC cell lines. The functional impact of LCN2 on NSCLC cells, including proliferation, apoptosis, and metastasis, were assessed through a series of in vitro assays, such as Cell Counting Kit-8 (CCK-8), EdU, wound healing, and transwell migration and invasion assays. An in vivo xenograft model was established to investigate the effects of LCN2 on tumor growth and metastasis. Additionally, the involvement of the JAK2/STAT3 signaling pathway was examined using western blotting and pharmacological inhibition with AG490. RESULTS: LCN2 was significantly upregulated in NSCLC tissues and cell lines, and its elevated expression correlated with poor prognosis. Functional analyses demonstrated that LCN2 knockdown suppressed NSCLC cell proliferation, migration, and invasion while promoting apoptosis. Mechanistically, LCN2 was found to activate the JAK2/STAT3 pathway by interacting with SOCS3, and pharmacological blockade of this pathway effectively abrogated the oncogenic effects of LCN2 overexpression. CONCLUSIONS: This study identifies LCN2 as a potential oncogene in NSCLC, driving tumor progression through activation of the JAK2/STAT3 signaling pathway. These findings suggest that targeting LCN2 or its downstream signaling components may represent a promising therapeutic strategy for NSCLC.