MicroRNA expression signature of castration-resistant prostate cancer: the microRNA-221/222 cluster functions as a tumour suppressor and disease progression marker.
BACKGROUND
Our present study of the microRNA (miRNA) expression signature in castration-resistant prostate cancer (CRPC) revealed that the clustered miRNAs microRNA-221 (miR-221) and microRNA-222 (miR-222) are significantly downregulated in cancer tissues. The aim of this study was to investigate the functional roles of miR-221 and miR-222 in prostate cancer (PCa) cells.


METHODS
A CRPC miRNA signature was constructed by PCR-based array methods. Functional studies of differentially expressed miRNAs were analysed using PCa cells. The association between miRNA expression and overall survival was estimated by the Kaplan-Meier method. In silico database and genome-wide gene expression analyses were performed to identify molecular targets regulated by the miR-221/222 cluster.


RESULTS
miR-221 and miR-222 were significantly downregulated in PCa and CRPC specimens. Kaplan-Meier survival curves showed that low expression of miR-222 predicted a short duration of progression to CRPC. Restoration of miR-221 or miR-222 in cancer cells revealed that both miRNAs significantly inhibited cancer cell migration and invasion. Ecm29 was directly regulated by the miR-221/222 cluster in PCa cells.


CONCLUSIONS
Loss of the tumour-suppressive miR-221/222 cluster enhanced migration and invasion in PCa cells. Our data describing targets regulated by the tumour-suppressive miR-221/222 cluster provide insights into the mechanisms of PCa and CRPC progression.
Department of Functional Genomics, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Japan.|Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan.
Yusuke
Y
Goto
Department of Urology, Teikyo University Chiba Medical Centre, Chiba, Japan.
Satoko
S
Kojima
Department of Functional Genomics, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Japan.|Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan.
Rika
R
Nishikawa
Department of Functional Genomics, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Japan.|Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan.
Akira
A
Kurozumi
Department of Functional Genomics, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Japan.|Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan.
Mayuko
M
Kato
Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Hideki
H
Enokida
Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Ryosuke
R
Matsushita
Department of Pathology, Teikyo University Chiba Medical Centre, Chiba, Japan.
Kazuto
K
Yamazaki
Department of Pathology, Teikyo University Chiba Medical Centre, Chiba, Japan.
Yasuo
Y
Ishida
Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Masayuki
M
Nakagawa
Department of Urology, Teikyo University Chiba Medical Centre, Chiba, Japan.
Yukio
Y
Naya
Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan.
Tomohiko
T
Ichikawa
Department of Functional Genomics, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Japan.
Naohiko
N
Seki
D014408:Biomarkers, Tumor / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family; D011379:Prognosis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D016019:Survival Analysis
D014408:Biomarkers, Tumor; D035683:MicroRNAs; C525709:MIR221, human; C525710:MIR222, human