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 respo...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2008-04, Vol.68 (7), p.2479-2488 |
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| creator | Graham, Tisheeka R Zhau, Haiyen E Odero-Marah, Valerie A Osunkoya, Adeboye O Kimbro, K Sean Tighiouart, Mourad Liu, Tongrui Simons, Jonathan W O'Regan, Ruth M |
| description | 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. |
| doi_str_mv | 10.1158/0008-5472.CAN-07-2559 |
| format | Article |
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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. 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| source | MEDLINE; American Association for Cancer Research; Free E-Journal (出版社公開部分のみ） |
| subjects | Cadherins - metabolism Cell Line, Tumor Cell Movement - physiology DNA, Complementary - genetics Epithelial Cells - pathology Homeodomain Proteins - biosynthesis Homeodomain Proteins - genetics Homeodomain Proteins - metabolism Humans Immunohistochemistry Insulin-Like Growth Factor I - metabolism Male Mesoderm - pathology Mitogen-Activated Protein Kinases - metabolism Neoplasm Invasiveness Prostatic Neoplasms - genetics Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology RNA, Messenger - biosynthesis RNA, Messenger - genetics Signal Transduction Transcription Factors - biosynthesis Transcription Factors - genetics Transcription Factors - metabolism Transfection Up-Regulation Zinc Finger E-box-Binding Homeobox 1 |
| title | Insulin-like growth factor-I-dependent up-regulation of ZEB1 drives epithelial-to-mesenchymal transition in human prostate cancer cells |
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