PDGF-D promotes cell growth, aggressiveness, angiogenesis and EMT transformation of colorectal cancer by activation of Notch1/Twist1 pathway.

Jinhuang Chen,Liang Wu,Xiaogang Shu,Zili Zhou,Wenzheng Yuan,Qiang Tang,Jintong Ji,Zhijun Ma,Qinghua Xia,Yifeng Cheng,Zhengyi Liu

doi:10.18632/oncotarget.14283

Jinhuang Chen, Liang Wu + Show 9 more

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https://doi.org/10.18632/oncotarget.14283

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Journal: Oncotarget	Publication Date: Dec 27, 2016
Citations: 60	License type: cc-by

Affiliation: Huazhong University of Science and Technology

Abstract

Platelet-derived growth factor-D (PDGF-D) plays a crucial role in the progression of several cancers. However, its role in colorectal cancer (CRC) remains unclear. Our study showed that PDGF-D was highly expressed in CRC tissues and was positively associated with the clinicopathological features. Down-regulation of PDGF-D inhibited the tumor growth, migration and angiogenesis of SW480 cells in vitro and in vivo. Whereas up-regulation of PDGF-D promoted the malignant behaviors of HCT116 cells. Moreover, PDGF-D up-regulated the expression of Notch1 and Twist1 in CRC cells. In addition, PDGF-D expression promoted Epithelial to mesenchymal transition (EMT), which was accompanied with decreased E-cadherin and increased Vimentin expression. Consistently, PDGF-D, Notch1, and Twist1 are obviously up-regulated in transforming growth factor-beta 1 (TGF-β1) treated HCT116 cells. Since Notch1 and Twist1 play an important role in EMT and tumor progression, we examined whether there is a correlation between Notch1 and Twist1 in EMT status. Our results showed that up-regulation of Notch1 was able to rescue the effects of PDGF-D down-regulation on Twist1 expression in SW480 cells, whereas down-regulation of Notch1 reduced Twist1 expression in HCT116 cells. Furthermore, we found that Twist1 promoted EMT and aggressiveness of CRC cells. These results suggest that PDGF-D promotes tumor growth and aggressiveness of CRC, moreover, down-regulation of PDGF-D inactivates Notch1/Twist1 axis, which could reverse EMT and prevent CRC progression.

Highlights

Growth factors and their receptors are important in tumor growth, metastasis and angiogenesis in several cancers [1, 2]
Our study showed that Platelet-derived growth factor-D (PDGF-D) was highly expressed in colorectal cancer (CRC) tissues and was positively associated with the clinicopathological features
PDGF-D expression was examined in 54 primary CRC tissues, their corresponding normal adjacent mucosa, and cultured FHC, SW620, SW480, HCT116, HT29, DLD1 cell lines

Summary

Introduction

Growth factors and their receptors are important in tumor growth, metastasis and angiogenesis in several cancers [1, 2]. Previous studies revealed that PDGF-D is over-expressed in human breast, pancreatic and gastric cancer and involved in cell growth, aggressiveness, and angiogenesis [3,4,5]. It has been reported that PDGF-D increases tumor growth and aggressiveness by activating Notch and NFκB in human pancreatic and breast cancer [3, 4]. PDGF-D enhances tumor metastasis and angiogenesis of renal cancer through increasing the expression of matrix metalloproteinase-9 (MMP9) and vascular endothelial growth factor (VEGF) [7]. PDGF-D plays an important role in EMT transformation [8] These findings indicate that PDGF-D promotes the development of the human cancers, and it www.impactjournals.com/oncotarget is important to investigate the potential role of PDGF-D in CRC

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