miR-205 hinders the malignant interplay between prostate cancer cells and associated fibroblasts.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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.
1 Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori , Milan, Italy .
Paolo
P
Gandellini
Elisa
E
Giannoni
Anna
A
Casamichele
Maria Letizia
ML
Taddei
Maurizio
M
Callari
Claudia
C
Piovan
Riccardo
R
Valdagni
Marco Alessandro
MA
Pierotti
Nadia
N
Zaffaroni
Paola
P
Chiarugi
D002460:Cell Line; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005347:Fibroblasts / Q000473:pathology*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*
D016207:Cytokines; D051793:Hypoxia-Inducible Factor 1; D035683:MicroRNAs; C534425:MIR205, human