RATIONALE: CARD recruited membrane associated protein 3 (CARMA3) is a novel scaffold protein that regulates NF-kappaB activation; however, the underlying mechanism of CARMA3 in lung cancer stemness and metastasis remains largely unknown. OBJECTIVES: To investigate the molecular mechanisms underlying the involvement of CARMA3 in non-small cell lung cancer progression. METHODS: The expression levels of CARMA3 and NME2 in a cohort of lung cancer patients (n = 91) were examined by immunohistochemistry staining and assessed by Kaplan-Meier survival analysis. The effects of CARMA3, 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-kappaB-driven miR-182 expression and NME2 regulation. MEASUREMENTS AND MAIN RESULTS: We observed that CARMA3 inversely correlated with NME2 expression in lung cancer patients (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 lung cancer patients 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-kappaB/miR-182 pathway and by increasing cancer stem cell properties and metastasis in lung cancer. CONCLUSIONS: We identified a novel mechanism of CARMA3 in lung cancer stemness and metastasis through the negative regulation of NME2 by NF-kappaB-dependent induction of miR-182. Our findings provide an attractive strategy for targeting the CARMA3/NF-kappaB/miR-182 pathway as a potential treatment for lung cancer.
Date:
2015-07
Relation:
American Journal of Respiratory and Critical Care Medicine. 2015 Jul;192(1):64-75.
