TY - JOUR
T1 - Loss of p63 and its microRNA-205 target results in enhanced cell migration and metastasis in prostate cancer
AU - Tucci, Paola
AU - Agostini, Massimiliano
AU - Grespi, Francesca
AU - Markert, Elke K.
AU - Terrinoni, Alessandro
AU - Vousden, Karen H.
AU - Muller, Patricia A J
AU - Dötsch, Volker
AU - Kehrloesser, Sebastian
AU - Sayan, Berna S.
AU - Giaccone, Giuseppe
AU - Lowe, Scott W.
AU - Takahashi, Nozomi
AU - Vandenabeele, Peter
AU - Knight, Richard A.
AU - Levine, Arnold J.
AU - Melino, Gerry
N1 - P01CA87497, NCI NIH HHS, United States, Medical Research Council, United Kingdom
PY - 2012/9/18
Y1 - 2012/9/18
N2 - 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.
AB - 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.
KW - Apoptosis
KW - DU145 cell
KW - E-cadherin
KW - PC3 cell
KW - Tumorigenesis
U2 - 10.1073/pnas.1110977109
DO - 10.1073/pnas.1110977109
M3 - Article
C2 - 22949650
SN - 0027-8424
VL - 109
SP - 15312
EP - 15317
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 38
ER -
