IGFBP-2 acts as a tumour suppressor and plays a role in determining chemosensitivity in bladder cancer cells
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Zhen Tang1, David Gillatt2, Edward Rowe3, Anthony Koupparis3, Jeff M.P. Holly1,* and Claire M. Perks1
1 IGFs & Metabolic Endocrinology Group, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS10 5N, England
2 Department of Surgery, Macquarie University Hospital, Macquarie University, Sydney, NSW 2109, Australia
3 Department of Urology, Southmead Hospital and Bristol Urological Institute, Bristol, BS10 5NB, England
* Co-senior authors
|Claire M. Perks,||email:||[email protected]|
Keywords: IGFBP-2; methylation; chemosensitivity; invasion; bladder cancer
Received: July 15, 2019 Accepted: October 21, 2019 Published: December 17, 2019
There are mixed reports on the role that IGFBP-2 plays in cancer progression, with some indicating a tumour suppressive role and others showing that IGFBP-2 may act as an oncogene. These apparent contradictions may be context and tissue specific. In this study we determined the role that IGFBP-2 played on the phenotype and chemosensitivity of a selection of bladder cancer cell lines and investigated how the abundance of IGFBP-2 was regulated. We found that IGFBP-2 was more abundant in the epithelial bladder cancer cells, RT4 and UMUC3 and absent in the more mesenchymal T24 and TCCSUP cells. Silencing IGFBP-2 using siRNA in epithelial RT4 cells promoted cell proliferation, invasion, colony formation, resulted in a reduction in epithelial (E-cadherin) and an increase in mesenchymal (N-cadherin) markers and increased sensitivity to cisplatin-induced cell death. Conversely, we observed the opposite effects when adding exogenous IGFBP-2 to the mesenchymal T24 cells. We determined that IGFBP-2 was epigenetically silenced via DNA methylation as the cells adopted a mesenchymal phenotype. Collectively these data suggest that IGFBP-2 acts as a tumour suppressor and marker of chemosensitivity in epithelial bladder cancer cells and that IGFBP-2 is epigenetically silenced by methylation to promote bladder cancer progression.
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