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research
Hsa-miRNA-765 as a key mediator for inhibiting growth, migration and invasion in fulvestrant-treated prostate cancer
Authors
A Grimson
A Schaefer
+64 more
A Zou
B John
B Li
BP Lewis
Chi-Fai Ng
CJ Thompson
D Gaidatzis
DP Byar
Fanny Man-Ting Ma
Ho-Man Tse
I Leav
J Brennecke
J Kruger
JG Doench
Jindan Yu
JJ Wei
JL Ockrim
JM Gasent Blesa
Jodi Maranchie
JR Schultz
JS Lai
K Paech
Ka-Fai To
KE Lane
Kin-Mang Lau
KK Waltering
KM Lau
KM Lau
KM Lau
L He
M Hamilton
M Stein
MK Chadha
N Takaha
NN Tam
NN Tam
O Hassan
P Mak
Queeny Kwan-Yi Chan
RC Bergan
RE Langley
RL Shazer
RS Bhattacharyya
S Josson
S Saini
S Sevli
S Stein
SA Fernandes
SB von
Shuk-Mei Ho
SM Ho
SR Setlur
T Murata
V Coppola
WK Oh
X Zhu
XB Shi
XB Shi
Y Nakajima
Y Tamimi
Y Tamimi
YK Leung
YK Leung
Yuet-Kin Leung
Publication date
16 May 2014
Publisher
'Public Library of Science (PLoS)'
Doi
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on
PubMed
Abstract
Fulvestrant (ICI-182,780) has recently been shown to effectively suppress prostate cancer cell growth in vitro and in vivo. But it is unclear whether microRNAs play a role in regulating oncogene expression in fulvestrant-treated prostate cancer. Here, this study reports hsa-miR-765 as the first fulvestrant-driven, ERβ-regulated miRNA exhibiting significant tumor suppressor activities like fulvestrant, against prostate cancer cell growth via blockage of cell-cycle progression at the G2/M transition, and cell migration and invasion possibly via reduction of filopodia/intense stress-fiber formation. Fulvestrant was shown to upregulate hsa-miR-765 expression through recruitment of ERβ to the 5′-regulatory-region of hsa-miR-765. HMGA1, an oncogenic protein in prostate cancer, was identified as a downstream target of hsa-miR-765 and fulvestrant in cell-based experiments and a clinical study. Both the antiestrogen and the hsa-miR-765 mimic suppressed HMGA1 protein expression. In a neo-adjuvant study, levels of hsa-miR-765 were increased and HMGA1 expression was almost completely lost in prostate cancer specimens from patients treated with a single dose (250 mg) of fulvestrant 28 days before prostatectomy. These findings reveal a novel fulvestrant signaling cascade involving ERβ-mediated transcriptional upregulation of hsa-miR-765 that suppresses HMGA1 protein expression as part of the mechanism underlying the tumor suppressor action of fulvestrant in prostate cancer. © 2014 Leung et al
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