title: CARMA3 Represses Metastasis Suppressor NME2 to Promote Lung Cancer Stemness and Metastasis.
abstract: BACKGROUND
  CARD-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.
  
  
  OBJECTIVE
  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 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: 1 National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.|2 Graduate Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.|3 Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Chang
authors.affiliation: 1 National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
authors.forename: Ching-Feng
authors.initials: CF
authors.lastname: Chiu
authors.affiliation: 4 Department of Internal Medicine, School of Medicine, College of Medicine, and.|5 Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Kang-Yun
authors.initials: KY
authors.lastname: Lee
authors.affiliation: 1 National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
authors.forename: Chih-Chen
authors.initials: CC
authors.lastname: Hong
authors.affiliation: 1 National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
authors.forename: Yi-Yun
authors.initials: YY
authors.lastname: Wang
authors.affiliation: 1 National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
authors.forename: Ching-Chia
authors.initials: CC
authors.lastname: Cheng
authors.affiliation: 3 Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Yi-Hua
authors.initials: YH
authors.lastname: Jan
authors.affiliation: 6 Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ming-Shyan
authors.initials: MS
authors.lastname: Huang
authors.affiliation: 3 Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.affiliation: 1 National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
authors.forename: Jui-Ti
authors.initials: JT
authors.lastname: Ma
authors.affiliation: 1 National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.|7 Graduate Institute of Cancer Biology, College of Medicine, China Medical University, Taichung, Taiwan.|8 Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan; and.|9 Department of Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Jen-Liang
authors.initials: JL
authors.lastname: Su
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D035683:MicroRNAs / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D054778:NM23 Nucleoside Diphosphate Kinases / Q000378:metabolism*; D009362:Neoplasm Metastasis; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D053468:CARD Signaling Adaptor Proteins; C430880:CARD10 protein, human; D035683:MicroRNAs; C538984:Mirn182 microRNA, human; D016328:NF-kappa B; D054778:NM23 Nucleoside Diphosphate Kinases; C517940:NME2 protein, human
keywords: CARMA3; NME2; cancer metastasis; miR-182; nuclear factor-κB