FMO3 as a novel prognostic biomarker and therapeutic target in non-small cell lung cancer by attenuating endoplasmic reticulum stress

Non-small cell lung cancer (NSCLC) accounts for > 85% of lung malignancies and is characterized by late presentation and limited therapeutic options. While members of the flavin-containing monooxygenase (FMO) family have been implicated in various solid tumors, the expression pattern and biological significance of FMO3 in NSCLC remain undefined. In this study, immunohistochemistry was performed on 10 paired fresh NSCLC-adjacent specimens and a tissue microarray of 115 additional pairs for FMO1-5 and Ki67, with clinicopathological data and 5-year follow-up analyzed. Stable FMO3-overexpressing A549 cells and FMO3-knockdown H1703 cells were generated. Cell proliferation was evaluated by CCK-8, EdU and colony formation assays; apoptosis by Annexin V-FITC/PI flow cytometry; and ER-stress signaling by western blotting of the IRE1α/caspase-12/caspase-3/PARP axis. Results showed FMO3 was selectively upregulated in NSCLC, positively correlated with tumor size and T stage, predicted poorer 5-year survival as an independent prognostic factor. In vitro, FMO3 overexpression promoted proliferation and suppressed apoptosis, while knockdown had the opposite effects, via negative regulation of the IRE1α pathway to attenuate ER-stress. Thus, targeting FMO3 could be a novel NSCLC therapy.