期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 181, 期 6, 页码 2188-2201出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2012.08.011
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资金
- Innsbruck Medical University for young scientists MUI-START [2010012007]
- Austrian Science Fund (FWF) [W1101]
- European Union grant PRO-NEST
Docetaxel is a standard chemotherapy for patients with metastatic prostate cancer. However, the response is rather limited and not all of the patients benefit from this treatment. To uncover key mechanisms of docetaxel insensitivity in prostate cancer, we have established docetaxel-resistant sublines. In this study, we report that docetaxel-resistant cells underwent an epithelial-to-mesenchymal transition during the selection process, leading to diminished E-cadherin levels and up-regulation of mesenchymal markers. Screening for key regulators of an epithelial phenotype revealed a significantly reduced expression of microRNA (miR)-200c and miR-205 in docetaxel-resistant cells. Transfection of either microRNA (miRNA) resulted in re-expression of E-cadherin. Functional assays confirmed reduced adhesive and increased invasive and migratory abilities. Furthermore, we detected an increased sub-population with stem cell-like properties in resistant cells. Tissue microarray analysis revealed a reduced E-cadherin expression in tumors after neoadjuvant chemotherapy. Low E-cadherin levels could be linked to tumor relapse. The present study uncovers epithelial-to-mesenchymal transition as a hallmark of docetaxel resistance. Therefore, we suggest that this mechanism is at least in part responsible for chemotherapy failure, with implications for the development of novel therapeutics. (Am J Pathol 2012, 181:2188-2201; http://dx.doi.org/10.1016/j.ajpath.2012.08.011)
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