Abstract
Metastasis is the major cause of cancer deaths, and the epithelial-mesenchymal transition (EMT) has been considered to be a fundamental event in cancer metastasis. However, the role of growth differentiation factor 15 (GDF15) in colorectal cancer (CRC) metastasis and EMT remains poorly understood. Here, we showed that GDF15 promoted CRC cell metastasis both in vitro and in vivo. In addition, the EMT process was enhanced by GDF15 through binding to TGF-β receptor to activate Smad2 and Smad3 pathways. Clinical data showed GDF15 level in tumor tissues, and the serum was significantly increased, in which high GDF15 level correlated with a reduced overall survival in CRC. Thus, GDF15 may promote colorectal cancer metastasis through activating EMT. Promisingly, GDF15 could be considered as a novel prognostic marker for CRC in the clinic.
Highlights
growth differentiation factor 15 (GDF15) is a divergent member of the BMPsubfamily of the TGF-β superfamily, which is designated as macrophage inhibitory cytokine-1 (MIC-1), prostate-derived factor (PDF), placental bone morphogenetic protein (PLAB), placental transforming growth factor (PTGF) and nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) [1,2,3,4,5]
GDF15-Flag vector led to a significant reduction in E-cadherin as well as increases in the MMP9 and Twist expression levels in HT29 cells, and significant increases in Vimentin in SW480 cells (Fig. 2a); Immunofluorescence assay validated www.impactjournals.com/oncotarget that GDF15 caused the changes in the expression of these epithelial–mesenchymal transition (EMT) markers in SW480 cells (Fig. 2b)
Since it is well known that GDF15 is a secreted protein, we used recombinant GDF15 protein to test whether GDF15 promoted EMT and metastasis through paracrine signal in colorectal cancer cells
Summary
GDF15 is a divergent member of the BMPsubfamily of the TGF-β superfamily, which is designated as macrophage inhibitory cytokine-1 (MIC-1), prostate-derived factor (PDF), placental bone morphogenetic protein (PLAB), placental transforming growth factor (PTGF) and nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) [1,2,3,4,5]. GDF15 is widely distributed in mammalian tissues and has multiple functions in various pathologies, including inflammation, cancer, cardiovascular diseases and obesity [6]. In endometrial [7], prostate [8], pancreatic [9], and colorectal [10] cancers, the circulating levels of GDF15 were elevated, which may correlate with poor clinical outcomes. GDF15 serves as a negative prognostic marker in CRC, and high level GDF15 both in tumor tissues and plasma correlate with an increased risk of recurrence and reduced overall survival [10, 13, 14]. GDF15 has been considered as the target for CRC therapy in some studies [15, 16], the biological function is not clear so far
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