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

作者：Chen, Xiaojun; Song, Xiaomeng; Yue, Wen; Chen, Dongshi; Yu, Jian; Yao, Zhi^*; Zhang, Lin

来源：Oncotarget, 2015, 6(17): 15022-15034.

DOI：10.18632/oncotarget.3609

• fibulin-5
• lung cancer
• invasion
• MMP-7
• beta-catenin

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/beta-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/beta-catenin signaling by inhibiting extracellular signal-regulated kinase (ERK) to activate glycogen synthase kinase-3 beta (GSK3 beta), which downregulates beta-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/beta-catenin signaling in vivo in H460 metastasis and H1299 tumor models. Furthermore, knockdown of beta-catenin suppresses metastasis of H460 tumors, while knockdown of GSK3 beta 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/beta-catenin signaling.

• 出版日期2015-6-20
• 单位天津医科大学