Insulin-like growth factor-I-dependent up-regulation of ZEB1 drives epithelial-to-mesenchymal transition in human prostate cancer cells.
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 up-regulates 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.
Graham
Tisheeka R
TR
Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
Zhau
Haiyen E
HE
Odero-Marah
Valerie A
VA
Osunkoya
Adeboye O
AO
Kimbro
K Sean
KS
Tighiouart
Mourad
M
Liu
Tongrui
T
Simons
Jonathan W
JW
O'Regan
Ruth M
RM
D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D018076:DNA, Complementary / Q000235:genetics; D004847:Epithelial Cells / Q000473:pathology; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D008648:Mesoderm / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation; D000071799:Zinc Finger E-box-Binding Homeobox 1
D015820:Cadherins; D018076:DNA, Complementary; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D007334:Insulin-Like Growth Factor I; D020928:Mitogen-Activated Protein Kinases