Fibulin-3 suppresses Wnt/β-catenin signaling and lung cancer invasion.
The 5 year survival rate of lung cancer is <20%, with most patients dying from distant metastasis. However, the molecular mechanisms underlying lung cancer invasion and metastasis have not been fully characterized. In this study, we found that fibulin-3, a fibulin family extracellular matrix protein, functions as a suppressor of lung cancer invasion and metastasis. Fibulin-3 was downregulated in large fractions of lung tumors and cell lines, and inhibited lung cancer cell invasion and the expression of matrix metalloproteinase-7 (MMP-7), a promoter of lung cancer invasion. The expression levels of fibulin-3 and MMP-7 were inversely correlated in lung tumors. Fibulin-3 inhibited extracellular signal-regulated kinase (ERK) to activate glycogen synthase kinase 3β and suppress Wnt/β-catenin signaling, which induces MMP-7 expression in lung cancer cells. Furthermore, fibulin-3 expression impeded the growth and metastasis of lung tumors in mice. Collectively, these results suggest that downregulation of fibulin-3 contributes to lung cancer invasion and metastasis by activating Wnt/β-catenin signaling and MMP-7 expression.
Department 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 300070, China and Departments of Pharmacology and Chemical Biology and Pathology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Xiaojun
X
Chen
Department 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 300070, China and.
Jie
J
Meng
Departments of Pharmacology and Chemical Biology and Pathology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Wen
W
Yue
Departments of Pharmacology and Chemical Biology and Pathology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Jian
J
Yu
Department 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 300070, China and.
Jie
J
Yang
Department 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 300070, China and yaozhi@tmu.edu.cn.
Zhi
Z
Yao
Departments of Pharmacology and Chemical Biology and Pathology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Lin
L
Zhang
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D002465:Cell Movement; D049109:Cell Proliferation; D019175:DNA Methylation; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
C119630:EFEMP1 protein, human; D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger; D051153:Wnt Proteins; D051176:beta Catenin; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7