Oncotarget

Research Papers:

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

Xiaojun Chen _, Xiaomeng Song, Wen Yue, Dongshi Chen, Jian Yu, Zhi Yao and Lin Zhang

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Oncotarget. 2015; 6:15022-15034. https://doi.org/10.18632/oncotarget.3609

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Abstract

Xiaojun Chen1,2*, Xiaomeng Song1*, Wen Yue2, Dongshi Chen2, Jian Yu3, Zhi Yao1, Lin Zhang2

1Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Immuno Microenvironment and Disease of the Educational Ministry, Tianjin Medical University, Tianjin, P.R. China

2Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

3Department of Pathology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

*These authors have contributed equally to this work

Correspondence to:

Zhi Yao, e-mail: [email protected]

Lin Zhang, e-mail: [email protected]

Keywords: fibulin-5, lung cancer, invasion, MMP-7, β-catenin

Received: December 18, 2014     Accepted: March 14, 2015     Published: April 02, 2015

ABSTRACT

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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