Abstract
NADPH oxidase 4 (NOX4) is deregulated in various cancers and involved in cancer proliferation and metastasis. However, what the role of NOX4 plays during malignant progression of non-small cell lung cancer (NSCLC) remains unknown. Our results show that NOX4 was upregulated in NSCLC cell lines and samples from patients, compared with controls; NOX4 protein levels were closely correlated with clinical disease stage and survival time. Overexpression of NOX4 in A549 and H460 NSCLC cells enhanced cell proliferation and invasion in vitro, and produced larger tumors, shorter survival time, and more lung metastasis in nude mice than control cells. On the contrary, NOX4 depletion inhibited NSCLC cell aggressiveness. Inhibition of PI3K/Akt pathway could sufficiently block the cellular effects of NOX4 overexpression in NSCLC cells both in vitro and in vivo. Specifically, we demonstrated that PI3K/Akt pathway also positively regulated NOX4 expression via NF-κB-mediated manner. Therefore, there existed a mutual positive regulation between NOX4 and PI3K/Akt signaling in NSCLC cells, and NOX4 was confirmed to functionally interplay with PI3K/Akt signaling to promote NSCLC cell proliferation and invasion. In conclusion, the positive feedback loop between NOX4 and PI3K/Akt signaling contributes to NSCLC progression.
Highlights
Lung cancer is the most common cause of cancer death worldwide [1]
The results revealed that NADPH oxidase 4 (NOX4) was markedly higher in Non-small cell lung cancer (NSCLC) cell lines than that in normal lung epithelial cell lines (BEAS2B and NHBE cells)
These findings suggest that stimulation of PI3K/Akt pathway is sufficient to account for NOX4-promoted NSCLC cell aggressiveness in vitro
Summary
Lung cancer is the most common cause of cancer death worldwide [1]. Non-small cell lung cancer (NSCLC) accounts for up to 80% of all lung cancer cases, and patients usually present advanced disease at initial diagnosis [2]. Inhibition of some members of NOX families suppresses tumor growth and leads to cancer cell death [7,8]. In addition to regulation of cancer cell growth, NOXs play important roles in cancer cell progression. To identify the potential role of NOX4 in NSCLC carcinogenesis, we first surveyed the expression of NOX4 in NSCLC patients and found a tight association of NOX4 expression with the poor clinical outcome of NSCLC patients. Such an association was further confirmed in NSCLC cell lines both in vitro and in vivo. We find a positive feedback regulation between NOX4 and PI3K/Akt pathway, which promotes NSCLC cell aggressiveness
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