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

Arf tumor suppressor and miR-205 regulate cell adhesion and formation of extraembryonic endoderm from pluripotent stem cells

“…Notably, some of the outcomes observed during ExEn formation in EBs were inconsistent with the reported role of miR-205 in maintaining epithelial fates and E-cadherin expression and in forestalling the epithelial to mesenchymal transition (EMT) during tumor progression (29,33,34). The few reported targets of miR-205 in tumor cells include Although these experiments were not designed to identify genes directly targeted by miR-205, we selected the most probable miR-205 mouse target genes in each of three public databases (miRDB.org, TargetScan.org, and microRNA.org) and chose 26 genes for further analysis that were concordantly ranked in the "top 60."…”

“…Down-regulation of miR-205 in tumor cells promotes the EMT and metastasis in several forms of cancer (29,33,34,40,41). A parsimonious hypothesis is that a role for Arf as a tumor suppressor in somatic cells is mediated, at least in part, by its regulation of EMT in response to oncogene activation.…”

“…Analysis of EBs in which Arf expression could be conditionally up-or down-regulated provided direct evidence for positively correlated Arf and miR-205 expression. In turn, miR-205 expression is induced by p53, and its promoter is directly regulated by other p53 family members (27)(28)(29).…”

“…In unrelated studies, we determined that the levels of a single microRNA, miR-205, were selectively decreased by >15-fold in the Arf-null testes of postnatal day-18 mice, a time when p19 Arf levels in spermatogonia are maximal and are synchronously expressed throughout the developing seminiferous tubules. miR-205 is up-regulated by p53 (27), and its promoter is directly bound and induced by other p53-related family members, p63 and p73 (28,29).…”

Regulation of HMGB3 by antitumor miR-205-5p inhibits cancer cell aggressiveness and is involved in prostate cancer pathogenesis

“…There is accumulating evidence that downregulation of miR-205-5p occurs in several cancers, e.g., breast, lung, esophageal and prostate cancers, and that it acts as an antitumor miRNA [33]. Downregulation of miR-205-5p in PCa tissues and its antitumor roles in PCa cells have been observed in past studies, including data from our laboratory [22,34]. Androgen signaling through AR is an essential pathway in PCa progression and aggressiveness [35].…”