Loss of p63 and its microRNA-205 target results in enhanced cell migration and metastasis in prostate cancer

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-09, Vol.109 (38), p.15312-15317
• Main Authors: Tucci, Paola, Agostini, Massimiliano, Grespi, Francesca, Markert, Elke K, Terrinoni, Alessandro, Vousden, Karen H, Muller, Patricia A. J, Dötsch, Volker, Kehrloesser, Sebastian, Sayan, Berna S, Giaccone, Giuseppe, Lowe, Scott W, Takahashi, Nozomi, Vandenabeele, Peter, Knight, Richard A, Levine, Arnold J, Melino, Gerry
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Biomarkers, Tumor - metabolism; Cadherins; Cancer; caudal vein; Cell adhesion & migration; Cell cycle; Cell Line, Tumor; Cell lines; Cell Movement; Cell Proliferation; data collection; Epithelial-Mesenchymal Transition; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; lymph nodes; Male; Metastasis; Mice; Mice, Inbred BALB C; MicroRNAs - genetics; mutants; Mutation; Neoplasm Metastasis; Neoplasm Transplantation; patients; Phosphoproteins - genetics; prognosis; Prostate cancer; prostatic neoplasms; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Protein Isoforms; Ribonucleic acid; RNA; Rodents; Signatures; Trans-Activators - genetics; Transcription Factors - genetics; Transfection; Tumor Suppressor Proteins - genetics; Tumors; Vimentin
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1110977109

p63 inhibits metastasis. Here, we show that p63 (both TAp63 and ΔNp63 isoforms) regulates expression of miR-205 in prostate cancer (PCa) cells, and miR-205 is essential for the inhibitory effects of p63 on markers of epithelial–mesenchymal transition (EMT), such as ZEB1 and vimentin. Correspondingly, the inhibitory effect of p63 on EMT markers and cell migration is reverted by anti–miR-205. p53 mutants inhibit expression of both p63 and miR-205, and the cell migration, in a cell line expressing endogenous mutated p53, can be abrogated by pre–miR-205 or silencing of mutated p53. In accordance with this in vitro data, ΔNp63 or miR-205 significantly inhibits the incidence of lung metastasis in vivo in a mouse tail vein model. Similarly, one or both components of the p63/miR-205 axis were absent in metastases or colonized lymph nodes in a set of 218 human prostate cancer samples. This was confirmed in an independent clinical data set of 281 patients. Loss of this axis was associated with higher Gleason scores, an increased likelihood of metastatic and infiltration events, and worse prognosis. These data suggest that p63/miR-205 may be a useful clinical predictor of metastatic behavior in prostate cancer.