MicroRNA let-7a inhibits proliferation of human prostate cancer cells in vitro and in vivo by targeting E2F2 and CCND2.
BACKGROUND
Previous work has shown reduced expression levels of let-7 in lung tumors. But little is known about the expression or mechanisms of let-7a in prostate cancer. In this study, we used in vitro and in vivo approaches to investigate whether E2F2 and CCND2 are direct targets of let-7a, and if let-7a acts as a tumor suppressor in prostate cancer by down-regulating E2F2 and CCND2.


RESULTS
Findings Real-time RT-PCR demonstrated that decreased levels of let-7a are present in resected prostate cancer samples and prostate cancer cell lines. Cellular proliferation was inhibited in PC3 cells and LNCaP cells after transfection with let-7a. Cell cycle analysis showed that let-7a induced cell cycle arrest at the G1/S phase. A dual-luciferase reporter assay demonstrated that the 3'UTR of E2F2 and CCND2 were directly bound to let-7a and western blotting analysis further indicated that let-7a down-regulated the expression of E2F2 and CCND2. Our xenograft models of prostate cancer confirmed the capability of let-7a to inhibit prostate tumor development in vivo.


CONCLUSIONS
These findings help to unravel the anti-proliferative mechanisms of let-7a in prostate cancer. Let-7a may also be novel therapeutic candidate for prostate cancer given its ability to induce cell-cycle arrest and inhibit cell growth, especially in hormone-refractory prostate cancer.
Dong
Qingchuan
Q
Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. dongqc168@yahoo.com.cn
Meng
Ping
P
Wang
Tao
T
Qin
Weiwei
W
Qin
Weijun
W
Wang
Fuli
F
Yuan
Jianlin
J
Chen
Zhinan
Z
Yang
Angang
A
Wang
He
H
D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D056742:Cyclin D2 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D050703:E2F2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D014162:Transfection
C080336:CCND2 protein, human; D056742:Cyclin D2; D050703:E2F2 Transcription Factor; C493761:E2F2 protein, human; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human