PMID- 23770851
OWN - NLM
STAT- MEDLINE
DCOM- 20140724
LR  - 20220321
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 33
IP  - 21
DP  - 2014 May 22
TI  - MiR-221 promotes the development of androgen independence in prostate cancer 
      cells via downregulation of HECTD2 and RAB1A.
PG  - 2790-800
LID - 10.1038/onc.2013.230 [doi]
AB  - Hormone-sensitive prostate cancer typically progresses to castration resistant 
      prostate cancer (CRPC) after the androgen deprivation therapy. We investigated 
      the impact of microRNAs (miRs) in the transition of prostate cancer to CRPC. 
      MiR-221/-222 was highly expressed in bone metastatic CRPC tumor specimens. We 
      previously demonstrated that transient overexpression of miR-221/-222 in LNCaP 
      promoted the development of the CRPC phenotype. In current study, we show that 
      stably overexpressing miR-221 confers androgen independent (AI) cell growth in 
      LNCaP by rescuing LNCaP cells from growth arrest at G1 phase due to the lack of 
      androgen. Overexpressing of miR-221 in LNCaP reduced the transcription of a 
      subgroup of androgen-responsive genes without affecting the androgen receptor 
      (AR) or AR-androgen integrity. By performing systematic biochemical and 
      bioinformatical analyses, we identified two miR-221 targets, HECTD2 and RAB1A, 
      which could mediate the development of CRPC phenotype in multiple prostate cancer 
      cell lines. Downregulation of HECTD2 significantly affected the androgen-induced 
      and AR-mediated transcription, and downregulation of HECTD2 or RAB1A enhances AI 
      cell growth. As a result of the elevated expression of miR-221, expression of 
      many cell cycle genes was altered and pathways promoting epithelial to 
      mesenchymal transition/tumor metastasis were activated. We hypothesize that a 
      major biological consequence of upregulation of miR-221 is reprogramming of AR 
      signaling, which in turn may mediate the transition to the CRPC phenotype.
FAU - Sun, T
AU  - Sun T
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA, USA.
FAU - Wang, X
AU  - Wang X
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA, USA.
FAU - He, H H
AU  - He HH
AD  - 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA, USA [2] Department of Biostatistics and Computational 
      Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
FAU - Sweeney, C J
AU  - Sweeney CJ
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA, USA.
FAU - Liu, S X
AU  - Liu SX
AD  - Department of Biostatistics and Computational Biology, Dana-Farber Cancer 
      Institute, Harvard Medical School, Boston, MA, USA.
FAU - Brown, M
AU  - Brown M
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA, USA.
FAU - Balk, S
AU  - Balk S
AD  - Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical 
      Center, Harvard Medical School, Boston, MA, USA.
FAU - Lee, G-Sm
AU  - Lee GS
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA, USA.
FAU - Kantoff, P W
AU  - Kantoff PW
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA, USA.
LA  - eng
GR  - P01 CA163227/CA/NCI NIH HHS/United States
GR  - P50 CA090381/CA/NCI NIH HHS/United States
GR  - 2 P50 CA090381-06/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20130617
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Androgens)
RN  - 0 (MIRN221 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (Receptors, Androgen)
RN  - EC 2.3.2.26 (HECTD2 protein, human)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 3.6.5.2 (rab1 GTP-Binding Proteins)
SB  - IM
MH  - Androgens/pharmacology
MH  - Cell Cycle/genetics
MH  - Cell Line, Tumor
MH  - Epithelial-Mesenchymal Transition
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Male
MH  - MicroRNAs/*physiology
MH  - Phenotype
MH  - Prostatic Neoplasms, Castration-Resistant/genetics/*metabolism
MH  - RNA Interference
MH  - Receptors, Androgen/metabolism
MH  - Signal Transduction
MH  - Transcriptome
MH  - Ubiquitin-Protein Ligases/*genetics/metabolism
MH  - rab1 GTP-Binding Proteins/*genetics/metabolism
PMC - PMC3883998
MID - NIHMS509754
COIS- CONFLICT OF INTEREST The authors declare no conflict of interest.
EDAT- 2013/06/19 06:00
MHDA- 2014/07/25 06:00
PMCR- 2014/11/22
CRDT- 2013/06/18 06:00
PHST- 2012/08/02 00:00 [received]
PHST- 2013/04/15 00:00 [revised]
PHST- 2013/04/25 00:00 [accepted]
PHST- 2013/06/18 06:00 [entrez]
PHST- 2013/06/19 06:00 [pubmed]
PHST- 2014/07/25 06:00 [medline]
PHST- 2014/11/22 00:00 [pmc-release]
AID - onc2013230 [pii]
AID - 10.1038/onc.2013.230 [doi]
PST - ppublish
SO  - Oncogene. 2014 May 22;33(21):2790-800. doi: 10.1038/onc.2013.230. Epub 2013 Jun 
      17.