Insulin-like Growth Factor-I–Dependent Up-regulation of ZEB1 Drives Epithelial-to-Mesenchymal Transition in Human Prostate Cancer Cells

Abstract

The epithelial-to-mesenchymal transition (EMT) is crucial for the migration and invasion of many epithelial tumors, including prostate cancer. Although it is known that ZEB1 overexpression promotes EMT primarily through down-regulation of E-cadherin in a variety of cancers, the soluble ligands responsible for the activation of ZEB1 have yet to be identified. In the present study, we investigated the role of insulin-like growth factor-I (IGF-I) in the regulation of ZEB1 during EMT associated with prostate tumor cell migration. We found that ZEB1 is expressed in highly aggressive prostate cancer cells and that its expression correlates directly with Gleason grade in human prostate tumors (P < 0.001). IGF-I upregulates ZEB1 expression in prostate cancer cells exhibiting an epithelial phenotype. In prostate cancer cells displaying a mesenchymal phenotype, ZEB1 inhibition reverses the suppression of E-cadherin protein and down-regulates the expression of the mesenchymal markers N-cadherin and fibronectin. Furthermore, ZEB1 blockade decreases migratory and invasive potential in ARCaP M compared with the control. These results identify ZEB1 as a key transcriptional regulator of EMT in prostate cancer and suggest that the aberrant expression of ZEB1 in prostate cancer cells occurs in part in response to IGF-I stimulation. [Cancer Res 2008;68(7):2479-88]

Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis

“…showed that PI(3) kinase contributes to TrkB signaling as well (including anoikis resistance; Douma et al, 2004), in aggregate these data suggest a model in which TrkB activates multiple pathways, some of which critically depend on Zeb1 (Figure 7). Several reports have shown a correlation between Zeb1 expression and the aggressiveness of tumors, including those of endometrial (Spoelstra et al, 2006;Singh et al, 2008), colon (Pena et al, 2005;Aigner et al, 2007b), breast (Aigner et al, 2007a), lung (Dohadwala et al, 2006), gallbladder (Adachi et al, 2009), ovarian (Bendoraite et al, 2010) and prostate origin (Graham et al, 2008). In colon cancer, Zeb1 expression is linked to loss of the basement membrane, which correlates with increased metastasis (Spaderna et al, 2006).…”

Mechanism of the Mesenchymal–Epithelial Transition and Its Relationship with Metastatic Tumor Formation

“…ZEB1 and ZEB2 are able to initiate EMT by binding to E-boxes within the E-cadherin promoter and repressing its transcription, and silencing of ZEB1 was shown to increase the expression of E-cadherin (69,70). Downregulation of ZEB2 mRNA via ZEB2 siRNA in 4TO7 cells increased E-cadherin mRNA, and the cells that had stably silenced ZEB2 expression also adopted an epithelial-like morphology (25).…”

Anoikis: an emerging hallmark in health and diseases

“…Actually, ZEB factors and miR200 reciprocally control their expression in a strict feedback loop [133]. Of note, ZEB1 is a key EMT regulator in many human cancers including prostate, colon, breast and pancreatic [132,[134][135][136], while miR200 family members are often down-regulated in cancer cells [131]. Actually, the regulation of EMT by miRNAs is a very general phenomenon not limited to TrkB signalling [137].…”