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

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.

• Authors: Xiaojun Chen, Xiaomeng Song, Wen Yue, Dongshi Chen, Jian Yu, Zhi Yao, Lin Zhang
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 17 Pg. 15022-34 (Jun 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25909283 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Extracellular Matrix Proteins
• FBLN5 protein, human
• Proto-Oncogene Proteins c-myc
• beta Catenin
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Glycogen Synthase Kinase 3
• MMP7 protein, human
• Matrix Metalloproteinase 7

Topics

• Adult
• Aged
• Animals
• Blotting, Western
• Carcinoma, Non-Small-Cell Lung (genetics, metabolism, pathology)
• Cell Line, Tumor
• Extracellular Matrix Proteins (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Glycogen Synthase Kinase 3 (genetics, metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Kaplan-Meier Estimate
• Lung Neoplasms (genetics, metabolism, pathology)
• Male
• Matrix Metalloproteinase 7 (genetics, metabolism)
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Neoplasm Metastasis
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Transplantation, Heterologous
• Wnt Signaling Pathway (genetics)
• beta Catenin (genetics, metabolism)