Loss of p63 and its microRNA-205 target results in enhanced cell migration and metastasis in prostate cancer Journal Article
| Authors: | Tucci, P.; Agostini, M.; Grespi, F.; Markert, E. K.; Terrinoni, A.; Vousden, K. H.; Muller, P. A. J.; Dötsch, V.; Kehrloesser, S.; Sayan, B. S.; Giaccone, G.; Lowe, S. W.; Takahashi, N.; Vandenabeele, P.; Knight, R. A.; Levine, A. J.; Melino, G. |
| Article Title: | Loss of p63 and its microRNA-205 target results in enhanced cell migration and metastasis in prostate cancer |
| Abstract: | 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. |
| Keywords: | controlled study; protein expression; human cell; major clinical study; mutation; nonhuman; lymph node metastasis; mutant protein; cell proliferation; mouse; animals; mice; gene targeting; metastasis; apoptosis; gene expression profiling; protein targeting; tumor markers, biological; animal experiment; animal model; in vitro study; cell line, tumor; protein p53; mice, inbred balb c; transcription factors; tumorigenesis; prostate cancer; gleason score; prostatic neoplasms; gene expression regulation; cancer inhibition; lung metastasis; gene expression regulation, neoplastic; cancer cell; cancer infiltration; tumor suppressor proteins; neoplasm metastasis; cell migration; cell movement; phosphoproteins; predictor variable; protein p63; trans-activators; gene silencing; neoplasm transplantation; cell marker; micrornas; protein isoforms; e-cadherin; vimentin; epithelial-mesenchymal transition; epithelial mesenchymal transition; cancer prognosis; du145 cell; pc3 cell; microrna 205 |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 109 |
| Issue: | 38 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2012-01-01 |
| Start Page: | 15312 |
| End Page: | 15317 |
| Language: | English |
| DOI: | 10.1073/pnas.1110977109 |
| PROVIDER: | scopus |
| PUBMED: | 22949650 |
| PMCID: | PMC3458363 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 2 November 2012" - "CODEN: PNASA" - "Source: Scopus" |
