AIMS: Tumor microenvironment is a strong determinant for the acquisition of metastatic potential of cancer cells. We have recently demonstrated that cancer-associated fibroblasts (CAFs) elicit a redox-dependent epithelial-mesenchymal transition (EMT) in prostate cancer (PCa) cells, driven by cycloxygenase-2/hypoxia-inducible factor-1 (HIF-1)/nuclear factor-κB pathway and enhancing tumor aggressiveness. Here, we investigated the involvement of microRNAs (miRNAs) in tumor-stroma interplay to identify possible tools to counteract oxidative stress and metastasis dissemination. RESULTS: We found that miR-205 is the most downmodulated miRNA in PCa cells upon CAF stimulation, due to direct transcriptional repression by HIF-1, a known redox-sensitive transcription factor. Rescue experiments demonstrated that ectopic miR-205 overexpression in PCa cells counteracts CAF-induced EMT, thus impairing enhancement of cell invasion, acquisition of stem cell traits, tumorigenicity, and metastatic dissemination. In addition, miR-205 blocks tumor-driven activation of surrounding fibroblasts by reducing pro-inflammatory cytokine secretion. INNOVATION: Overall, such findings suggest miR-205 as a brake against PCa metastasis by blocking both the afferent and efferent arms of the circuit between tumor cells and associated fibroblasts, thus interrupting the pro-oxidant and pro-inflammatory circuitries engaged by reactive stroma. CONCLUSION: The evidence that miR-205 replacement in PCa cells is able not only to prevent but also to revert the oxidative/pro-inflammatory axis leading to EMT induced by CAFs sets the rationale for developing miRNA-based approaches to prevent and treat metastatic disease.
AIMS: Tumor microenvironment is a strong determinant for the acquisition of metastatic potential of cancer cells. We have recently demonstrated that cancer-associated fibroblasts (CAFs) elicit a redox-dependent epithelial-mesenchymal transition (EMT) in prostate cancer (PCa) cells, driven by cycloxygenase-2/hypoxia-inducible factor-1 (HIF-1)/nuclear factor-κB pathway and enhancing tumor aggressiveness. Here, we investigated the involvement of microRNAs (miRNAs) in tumor-stroma interplay to identify possible tools to counteract oxidative stress and metastasis dissemination. RESULTS: We found that miR-205 is the most downmodulated miRNA in PCa cells upon CAF stimulation, due to direct transcriptional repression by HIF-1, a known redox-sensitive transcription factor. Rescue experiments demonstrated that ectopic miR-205 overexpression in PCa cells counteracts CAF-induced EMT, thus impairing enhancement of cell invasion, acquisition of stem cell traits, tumorigenicity, and metastatic dissemination. In addition, miR-205 blocks tumor-driven activation of surrounding fibroblasts by reducing pro-inflammatory cytokine secretion. INNOVATION: Overall, such findings suggest miR-205 as a brake against PCa metastasis by blocking both the afferent and efferent arms of the circuit between tumor cells and associated fibroblasts, thus interrupting the pro-oxidant and pro-inflammatory circuitries engaged by reactive stroma. CONCLUSION: The evidence that miR-205 replacement in PCa cells is able not only to prevent but also to revert the oxidative/pro-inflammatory axis leading to EMT induced by CAFs sets the rationale for developing miRNA-based approaches to prevent and treat metastatic disease.
Authors: Erez Feige; Satoru Yokoyama; Carmit Levy; Mehdi Khaled; Vivien Igras; Richard J Lin; Stephen Lee; Hans R Widlund; Scott R Granter; Andrew L Kung; David E Fisher Journal: Proc Natl Acad Sci U S A Date: 2011-09-26 Impact factor: 11.205
Authors: Barbara Chiavarina; Diana Whitaker-Menezes; Gemma Migneco; Ubaldo E Martinez-Outschoorn; Stephanos Pavlides; Anthony Howell; Herbert B Tanowitz; Mathew C Casimiro; Chenguang Wang; Richard G Pestell; Philip Grieshaber; Jaime Caro; Federica Sotgia; Michael P Lisanti Journal: Cell Cycle Date: 2010-09-04 Impact factor: 4.534
Authors: Manav Korpal; Brian J Ell; Francesca M Buffa; Toni Ibrahim; Mario A Blanco; Toni Celià-Terrassa; Laura Mercatali; Zia Khan; Hani Goodarzi; Yuling Hua; Yong Wei; Guohong Hu; Benjamin A Garcia; Jiannis Ragoussis; Dino Amadori; Adrian L Harris; Yibin Kang Journal: Nat Med Date: 2011-08-07 Impact factor: 53.440
Authors: Yoshiaki Mizuguchi; Susan Specht; John G Lunz; Kumiko Isse; Natasha Corbitt; Toshihiro Takizawa; Anthony J Demetris Journal: PLoS One Date: 2012-02-22 Impact factor: 3.240
Authors: Holger K Eltzschig; Parween Abdulla; Edgar Hoffman; Kathryn E Hamilton; Dionne Daniels; Caroline Schönfeld; Michaela Löffler; German Reyes; Michael Duszenko; Jorn Karhausen; Andreas Robinson; Karen A Westerman; Imogen R Coe; Sean P Colgan Journal: J Exp Med Date: 2005-12-05 Impact factor: 14.307
Authors: Paola Tucci; Massimiliano Agostini; Francesca Grespi; Elke K Markert; Alessandro Terrinoni; Karen H Vousden; Patricia A J Muller; Volker Dötsch; Sebastian Kehrloesser; Berna S Sayan; Giuseppe Giaccone; Scott W Lowe; Nozomi Takahashi; Peter Vandenabeele; Richard A Knight; Arnold J Levine; Gerry Melino Journal: Proc Natl Acad Sci U S A Date: 2012-09-04 Impact factor: 11.205