The role of microRNAs 371 and 34a in androgen receptor control influencing prostate cancer behavior.
BACKGROUND
The molecular mechanisms involved in androgen receptor (AR) signaling pathways are not completely understood, and deregulation of microRNAs (miRNAs) expression may play a role in prostate cancer (PC) development and progression.


METHODS
The expression levels of miRNA and AR were evaluated with quantitative real-time polymerase chain reaction using frozen tissue from the surgical specimens of 83 patients submitted to radical prostatectomy. The expression level of miRNAs was correlated with prognostic factors and biochemical recurrence during a follow-up period of 45 months. In vitro and in vivo experiments were performed to understand the effect of miRNAs over AR in the context of that seen in a PC model.


RESULTS
MiR-371 underexpression correlated with non-organ-confined (pT3) disease (P = 0.009). In vitro transfection of miR-371 reduced the levels of AR by 22% and 28% in LNCaP and PC3 cell lines, respectively, and in kallikrein 3, it was reduced by 51%. PC was induced in Balb/c mice using PC-3M-luc-C6 cells, and animals were treated with 3 local doses of miR-371. Tumor growth evaluated by in vivo imaging after luciferase injection was slower in animals treated with miR-371. To explore further the possible role of miRNAs in the AR pathway, LNCaP cell line was treated with 5α-dihydrotestosterone and flutamide showing alteration in miRNAs expression, especially miR-34a, which was significantly underexpressed after treatment with high doses of 5α-dihydrotestosterone.


CONCLUSIONS
Our data support a role for miRNAs, especially miR-371 and miR-34a, in the complex disarrangement of AR signaling pathway and in the behavior of PC.
Laboratory of Medical Research, Department of Urology, LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil. Electronic address: katiaramos@uol.com.br.
Katia R M
KR
Leite
Laboratory of Medical Research, Department of Urology, LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil.
Denis Reis
DR
Morais
Laboratory of Medical Research, Department of Urology, LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil.
Manuel Garcia
MG
Florez
Laboratory of Medical Research, Department of Urology, LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil.
Sabrina T
ST
Reis
Laboratory of Medical Research, Department of Urology, LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil.
Alexandre
A
Iscaife
Laboratory of Medical Research, Department of Urology, LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil.
Nayara
N
Viana
Laboratory of Medical Research, Department of Urology, LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil.
Caio M
CM
Moura
Laboratory of Medical Research, Department of Urology, LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil.
Iran A
IA
Silva
Laboratory of Medical Research, Department of Urology, LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil.
Betina S
BS
Katz
Laboratory of Medical Research, Department of Urology, LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil.
Jose
J
Pontes
Laboratory of Medical Research, Department of Urology, LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil.
Adriano
A
Nesrallah
Laboratory of Medical Research, Department of Urology, LIM55, University of Sao Paulo Medical School, Sao Paulo, Brazil.
Miguel
M
Srougi
D000368:Aged; D059002:Androgen Receptor Antagonists / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D018450:Disease Progression; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics*; D015398:Signal Transduction
D059002:Androgen Receptor Antagonists; D035683:MicroRNAs; D011944:Receptors, Androgen
Androgen receptor; Cell lines; In vitro; In vivo; MicroRNAs; Prognosis; Prostate cancer