• Yi-Wen Chang, Ching-Feng Chiu, Kang-Yun Lee, Chih-Chen Hong, Yi-Yun Wang, Ching-Chia Cheng, Yi-Hua Jan, Ming-Shyan Huang, Michael Hsiao, Jui-Ti Ma, and Jen-Liang Su.
• 1 National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
• Am. J. Respir. Crit. Care Med. 2015 Jul 1;192(1):64-75.

RationaleCARD-recruited membrane-associated protein 3 (CARMA3) is a novel scaffold protein that regulates nuclear factor (NF)-κB activation; however, the underlying mechanism of CARMA3 in lung cancer stemness and metastasis remains largely unknown.ObjectivesTo investigate the molecular mechanisms underlying the involvement of CARMA3 in non-small cell lung cancer progression.MethodsThe expression levels of CARMA3 and NME2 in a cohort of patients with lung cancer (n = 91) were examined by immunohistochemistry staining and assessed by Kaplan-Meier survival analysis. The effects of CARMA3, microRNA-182 (miR-182), and NME2 on cancer stemness and metastasis were measured in vitro and in vivo. Chromatin immunoprecipitation and luciferase reporter assays were performed to determine the mechanisms of NF-κB-driven miR-182 expression and NME2 regulation.Measurements And Main ResultsWe observed that CARMA3 inversely correlated with NME2 expression in patients with lung cancer (Pearson correlation coefficient: R = -0.24; P = 0.022). NME2 levels were significantly decreased in tumor tissues compared with adjacent normal lung tissues (P < 0.001), and patients with lung cancer with higher levels of NME2 had longer survival outcomes (overall survival, P < 0.01; disease-free survival, P < 0.01). Mechanistically, CARMA3 promoted cell motility by reducing the level of NME2 through the NF-κB/miR-182 pathway and by increasing cancer stem cell properties and metastasis in lung cancer.ConclusionsWe identified a novel mechanism of CARMA3 in lung cancer stemness and metastasis through the negative regulation of NME2 by NF-κB-dependent induction of miR-182. Our findings provide an attractive strategy for targeting the CARMA3/NF-κB/miR-182 pathway as a potential treatment for lung cancer.

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