CARMA3 represses metastasis suppressor NME2 to promote lung cancer stemness and metastasis

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, Jen Liang Su

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Rationale: 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. 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 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 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.

Original languageEnglish
Pages (from-to)64-75
Number of pages12
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume192
Issue number1
DOIs
Publication statusPublished - Jul 1 2015

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Membrane Proteins
Neoplasm Metastasis
Lung
MicroRNAs
Nuclear Matrix-Associated Proteins
Survival
Chromatin Immunoprecipitation
Kaplan-Meier Estimate
Survival Analysis
Luciferases
Disease-Free Survival
Cell Movement
Stem Cells
Immunohistochemistry
Staining and Labeling
Neoplasms

Keywords

  • Cancer metastasis
  • CARMA3
  • miR-182
  • NME2
  • Nuclear factor-κB

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine
  • Medicine(all)

Cite this

CARMA3 represses metastasis suppressor NME2 to promote lung cancer stemness and metastasis. / Chang, Yi Wen; Chiu, Ching Feng; Lee, Kang Yun; Hong, Chih Chen; Wang, Yi Yun; Cheng, Ching Chia; Jan, Yi Hua; Huang, Ming Shyan; Hsiao, Michael; Ma, Jui Ti; Su, Jen Liang.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 192, No. 1, 01.07.2015, p. 64-75.

Research output: Contribution to journalArticle

Chang, Yi Wen ; Chiu, Ching Feng ; Lee, Kang Yun ; Hong, Chih Chen ; Wang, Yi Yun ; Cheng, Ching Chia ; Jan, Yi Hua ; Huang, Ming Shyan ; Hsiao, Michael ; Ma, Jui Ti ; Su, Jen Liang. / CARMA3 represses metastasis suppressor NME2 to promote lung cancer stemness and metastasis. In: American Journal of Respiratory and Critical Care Medicine. 2015 ; Vol. 192, No. 1. pp. 64-75.
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abstract = "Rationale: 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. 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 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 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.",
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AU - Chang, Yi Wen

AU - Chiu, Ching Feng

AU - Lee, Kang Yun

AU - Hong, Chih Chen

AU - Wang, Yi Yun

AU - Cheng, Ching Chia

AU - Jan, Yi Hua

AU - Huang, Ming Shyan

AU - Hsiao, Michael

AU - Ma, Jui Ti

AU - Su, Jen Liang

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AB - Rationale: 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. 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 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 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.

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KW - miR-182

KW - NME2

KW - Nuclear factor-κB

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