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Fibulin-5 inhibits Wnt/β-catenin signaling in lung cancer

Metastatic lung cancer is incurable and a leading cause of cancer death in the United States. However, the molecular mechanism by which lung cancer cells invade other tissues has remained unclear. We previously identified fibulin-5, an extracellular matrix protein, as a frequently silenced gene in l...

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Autores principales: Chen, Xiaojun, Song, Xiaomeng, Yue, Wen, Chen, Dongshi, Yu, Jian, Yao, Zhi, Zhang, Lin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558133/
https://www.ncbi.nlm.nih.gov/pubmed/25909283
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author Chen, Xiaojun
Song, Xiaomeng
Yue, Wen
Chen, Dongshi
Yu, Jian
Yao, Zhi
Zhang, Lin
author_facet Chen, Xiaojun
Song, Xiaomeng
Yue, Wen
Chen, Dongshi
Yu, Jian
Yao, Zhi
Zhang, Lin
author_sort Chen, Xiaojun
collection PubMed
description Metastatic lung cancer is incurable and a leading cause of cancer death in the United States. However, the molecular mechanism by which lung cancer cells invade other tissues has remained unclear. We previously identified fibulin-5, an extracellular matrix protein, as a frequently silenced gene in lung cancer and a suppressor of cell invasion. In this study, we found fibulin-5 functions by inhibiting the Wnt/β-catenin pathway. The Cancer Genome Atlas (TCGA) datasets show a strong association between loss of fibulin-5 expression and poor outcomes of lung cancer patients, and also activation of the Wnt target genes MMP-7 and c-Myc. Fibulin-5 impedes Wnt/β-catenin signaling by inhibiting extracellular signal-regulated kinase (ERK) to activate glycogen synthase kinase-3 β (GSK3β), which downregulates β-catenin and prevents its nuclear accumulation, leading to suppression of MMP-7 and c-Myc expression. These effects of fibulin-5 are mediated by its amino-terminal integrin-binding RGD motif. Fibulin-5 also blocks Wnt/β-catenin signaling in vivo in H460 metastasis and H1299 tumor models. Furthermore, knockdown of β-catenin suppresses metastasis of H460 tumors, while knockdown of GSK3β promotes metastasis of fibulin-5-expressing H1752 tumors. Together, our results suggest that fibulin-5 functions as a metastasis suppressor in lung cancer by modulating tumor microenvironment to suppress Wnt/β-catenin signaling.
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spelling pubmed-45581332015-09-09 Fibulin-5 inhibits Wnt/β-catenin signaling in lung cancer Chen, Xiaojun Song, Xiaomeng Yue, Wen Chen, Dongshi Yu, Jian Yao, Zhi Zhang, Lin Oncotarget Research Paper Metastatic lung cancer is incurable and a leading cause of cancer death in the United States. However, the molecular mechanism by which lung cancer cells invade other tissues has remained unclear. We previously identified fibulin-5, an extracellular matrix protein, as a frequently silenced gene in lung cancer and a suppressor of cell invasion. In this study, we found fibulin-5 functions by inhibiting the Wnt/β-catenin pathway. The Cancer Genome Atlas (TCGA) datasets show a strong association between loss of fibulin-5 expression and poor outcomes of lung cancer patients, and also activation of the Wnt target genes MMP-7 and c-Myc. Fibulin-5 impedes Wnt/β-catenin signaling by inhibiting extracellular signal-regulated kinase (ERK) to activate glycogen synthase kinase-3 β (GSK3β), which downregulates β-catenin and prevents its nuclear accumulation, leading to suppression of MMP-7 and c-Myc expression. These effects of fibulin-5 are mediated by its amino-terminal integrin-binding RGD motif. Fibulin-5 also blocks Wnt/β-catenin signaling in vivo in H460 metastasis and H1299 tumor models. Furthermore, knockdown of β-catenin suppresses metastasis of H460 tumors, while knockdown of GSK3β promotes metastasis of fibulin-5-expressing H1752 tumors. Together, our results suggest that fibulin-5 functions as a metastasis suppressor in lung cancer by modulating tumor microenvironment to suppress Wnt/β-catenin signaling. Impact Journals LLC 2015-04-02 /pmc/articles/PMC4558133/ /pubmed/25909283 Text en Copyright: © 2015 Chen et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Chen, Xiaojun
Song, Xiaomeng
Yue, Wen
Chen, Dongshi
Yu, Jian
Yao, Zhi
Zhang, Lin
Fibulin-5 inhibits Wnt/β-catenin signaling in lung cancer
title Fibulin-5 inhibits Wnt/β-catenin signaling in lung cancer
title_full Fibulin-5 inhibits Wnt/β-catenin signaling in lung cancer
title_fullStr Fibulin-5 inhibits Wnt/β-catenin signaling in lung cancer
title_full_unstemmed Fibulin-5 inhibits Wnt/β-catenin signaling in lung cancer
title_short Fibulin-5 inhibits Wnt/β-catenin signaling in lung cancer
title_sort fibulin-5 inhibits wnt/β-catenin signaling in lung cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558133/
https://www.ncbi.nlm.nih.gov/pubmed/25909283
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