Over-Expression of Platelet-Derived Growth Factor-D Promotes Tumor Growth and Invasion in Endometrial Cancer

Yuan Wang,Jinjin Yu,Shaoru Li,Weixu Hu,Haifeng Qiu

doi:10.3390/ijms15034780

Abstract

The platelet-derived growth factor-D (PDGF-D) was demonstrated to be able to promote tumor growth and invasion in human malignancies. However, little is known about its roles in endometrial cancer. In the present study, we investigated the expression and functions of PDGF-D in human endometrial cancer. Alterations of PDGF-D mRNA and protein were determined by real time PCR, western blot and immunohistochemical staining. Up-regulation of PDGF-D was achieved by stably transfecting the pcDNA3-PDGF-D plasmids into ECC-1 cells; and knockdown of PDGF-D was achieved by transient transfection with siRNA-PDGF-D into Ishikawa cells. The MTT assay, colony formation assay and Transwell assay were used to detect the effects of PDGF-D on cellular proliferation and invasion. The xenograft assay was used to investigate the functions of PDGF-D in vivo. Compared to normal endometrium, more than 50% cancer samples showed over-expression of PDGF-D (p < 0.001), and high level of PDGF-D was correlated with late stage (p = 0.003), deep myometrium invasion (p < 0.001) and lympha vascular space invasion (p = 0.006). In vitro, over-expressing PDGF-D in ECC-1 cells significantly accelerated tumor growth and promoted cellular invasion by increasing the level of MMP2 and MMP9; while silencing PDGF-D in Ishikawa cells impaired cell proliferation and inhibited the invasion, through suppressing the expression of MMP2 and MMP9. Moreover, we also demonstrated that over-expressed PDGF-D could induce EMT and knockdown of PDGF-D blocked the EMT transition. Consistently, in xenografts assay, PDGF-D over-expression significantly promoted tumor growth and tumor weights. We demonstrated that PDGF-D was commonly over-expressed in endometrial cancer, which was associated with late stage deep myometrium invasion and lympha vascular space invasion. Both in vitro and in vivo experiments showed PDGF-D could promote tumor growth and invasion through up-regulating MMP2/9 and inducing EMT. Thus, we propose targeting PDGF-D to be a potent strategy for endometrial cancer treatment.

Highlights

During recent decades, the incidence of endometrial cancer has been increasing in most regions of the world [1,2]
We demonstrated that platelet-derived growth factor-D (PDGF-D) was commonly over-expressed in endometrial cancer, which was associated with late stage deep myometrium invasion and lympha vascular space invasion
Frequent Over-Expression of PDGF-D in Human Endometrial Cancer. Compared to the their adjacent normal tissues, 32 of 58 (55.2%, Table 1) endometrial cancer samples presented the over-expression of PDGF-D (p < 0.001, Figures 1 and 2A); we found that high level of PDGF-D was related to late tumor stage (p = 0.003, Figure 2B), deep myometrium invasion (p < 0.001, Figure 2C) and lympha vascular space invasion (p = 0.0063, Figure 2D)

Summary

Introduction

The incidence of endometrial cancer has been increasing in most regions of the world [1,2]. There will be about 49,500 new cases and 8200 deaths in the United States in 2013 [3]. Despite the more than 70% cases were diagnosed at early stage, as much as 28% of patients’ occurred regional or distant metastasis. Their prognosis were usually pretty poor (a 5-year survival rate of

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Discussion

Conclusion