miR-200 regulates PDGF-D-mediated epithelial-mesenchymal transition, adhesion, and invasion of prostate cancer cells.
MicroRNAs have been implicated in tumor progression. Recent studies have shown that the miR-200 family regulates epithelial-mesenchymal transition (EMT) by targeting zinc-finger E-box binding homeobox 1 (ZEB1) and ZEB2. Emerging evidence from our laboratory and others suggests that the processes of EMT can be triggered by various growth factors, such as transforming growth factor beta and platelet-derived growth factor-D (PDGF-D). Moreover, we recently reported that overexpression of PDGF-D in prostate cancer cells (PC3 PDGF-D cells) leads to the acquisition of the EMT phenotype, and this model offers an opportunity for investigating the molecular interplay between PDGF-D signaling and EMT. Here, we report, for the first time, significant downregulation of the miR-200 family in PC3 PDGF-D cells as well as in PC3 cells exposed to purified active PDGF-D protein, resulting in the upregulation of ZEB1, ZEB2, and Snail2 expression. Interestingly, re-expression of miR-200b in PC3 PDGF-D cells led to reversal of the EMT phenotype, which was associated with the downregulation of ZEB1, ZEB2, and Snail2 expression, and these results were consistent with greater expression levels of epithelial markers. Moreover, transfection of PC3 PDGF-D cells with miR-200b inhibited cell migration and invasion, with concomitant repression of cell adhesion to the culture surface and cell detachment. From these results, we conclude that PDGF-D-induced acquisition of the EMT phenotype in PC3 cells is, in part, a result of repression of miR-200 and that any novel strategy by which miR-200 could be upregulated would become a promising approach for the treatment of invasive prostate cancer.
Kong
Dejuan
D
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Li
Yiwei
Y
Wang
Zhiwei
Z
Banerjee
Sanjeev
S
Ahmad
Aamir
A
Kim
Hyeong-Reh Choi
HR
Sarkar
Fazlul H
FH
D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics*; D008297:Male; D008648:Mesoderm / Q000473:pathology; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics*; D009361:Neoplasm Invasiveness; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis* / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
D018398:Homeodomain Proteins; D008222:Lymphokines; D035683:MicroRNAs; C427493:PDGFD protein, human; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C486307:ZEB1 protein, human; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1