Abstract
Lung adenocarcinoma (LUAD) is a major cause of cancer-related mortality worldwide. Understanding the mechanism of LUAD progression will aid in the development of therapeutic approaches targeting this malignancy. Hypoxia is characteristic of solid tumors and contributes significantly to LUAD progression, although the molecular mechanisms involved have not been fully elucidated. Long noncoding RNAs (lncRNAs) are key regulators of cancer progression. Here, we identify SLC9A3-AS1 as a previously unrecognized hypoxia-induced lncRNA that is aberrantly upregulated in LUAD tissues. Functional analyses demonstrated that SLC9A3-AS1 promotes LUAD cell proliferation, migration, and invasion in vitro, as well as tumor growth in vivo. Mechanistically, SLC9A3-AS1 acts as a competing endogenous RNA (ceRNA) by binding to miR-506-5p, alleviating the post-transcriptional repression of aspartate β-hydroxylase (ASPH) and activating NOTCH1 signaling. ASPH overexpression or miR-506-5p inhibition counteracts the effects of SLC9A3-AS1 knockdown, restoring LUAD cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) capacity. Furthermore, we report that SLC9A3-AS1 is a hypoxia-responsive gene that is transcriptionally activated by hypoxia-inducible factor-1α (HIF-1α) in LUAD cells. Collectively, these results identify SLC9A3-AS1 as a key hypoxia-induced regulator of LUAD progression and reveal a miR-506-5p/ASPH/NOTCH1 signaling pathway that drives oncogenic activity. These findings provide new insights for the diagnosis and treatment of LUAD.