title: NADPH oxidase 1-dependent ROS is crucial for TLR4 signaling to promote tumor metastasis of non-small cell lung cancer.
abstract: Recent evidence demonstrated an enhanced metastasis of non-small cell lung cancer (NSCLC) cells induced by lipopolysaccharide (LPS) stimulation, which reflected an important role of inflammation in tumor progression. However, the underlying mechanisms still remain unclear. Here, we evaluated the potential role of reactive oxygen species (ROS) in Toll-like receptor 4 (TLR4) signaling enhanced NSCLC metastasis. NSCLC cells were isolated from clinical surgical tissues. We found that LPS stimulation of NSCLC cells facilitates their metastasis that was accompanied by increased ROS production and could be abrogated by ROS inhibition. NADPH oxidase was essential for TLR4 signaling-enhanced NSCLC metastasis. Elevated NADPH oxidase 1 (NOX1) expression by LPS stimulation was observed. Blockade of NOX1 with ML171 alleviated enhanced NSCLC metastasis by TLR4 signaling. Enforced NOX1 expression promoted TLR4 signaling-enhanced NSCLC metastasis, while decreased NOX1 expression inhibited TLR4 signaling-enhanced NSCLC metastasis. Further, NOX1 could regulate the expression of CXCR4 and matrix metallopeptidase 9 (MMP9) in NSCLC cells. NOX1 expression in tumor tissues was correlated with TLR4 expression and clinical stages in NSCLC patients. Finally, inhibition of NOX1/ROS prevented enhanced lung tumor burdens of NSCLC by LPS-induced acute lung infection. Our findings demonstrated a crucial role of NOX1-dependent ROS for TLR4 signaling to enhance the metastasis of NSCLC, which could further the understanding of NSCLC pathogenesis and helpful for developing novel therapeutics for NSCLC.
authors.affiliation: Department of Chest Surgery, The First Bethune Hospital, Jilin University, 71 Xinminda Street, Changchun City, 130021, Jilin, China.
authors.forename: Xiyu
authors.initials: X
authors.lastname: Liu
authors.forename: Changyan
authors.initials: C
authors.lastname: Pei
authors.forename: Song
authors.initials: S
authors.lastname: Yan
authors.forename: Guifeng
authors.initials: G
authors.lastname: Liu
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Wenqing
authors.initials: W
authors.lastname: Chen
authors.forename: Youbin
authors.initials: Y
authors.lastname: Cui
authors.forename: Yahui
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000378:metabolism*; D009362:Neoplasm Metastasis; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human