Post-transcriptional Gene Regulation by MicroRNA-194 Promotes Neuroendocrine Transdifferentiation in Prostate Cancer

被引：40

作者：

Fernandes, Rayzel C. ^{[1
,2
]}

Toubia, John ^{[3
,4
]}

Townley, Scott ^{[1
,2
]}

Hanson, Adrienne R. ^{[1
,2
]}

Dredge, B. Kate ^{[4
,5
]}

Pillman, Katherine A. ^{[4
,5
]}

Bert, Andrew G. ^{[4
,5
]}

Winter, Jean M. ^{[1
,2
]}

Iggo, Richard ^{[1
,2
,6
]}

Das, Rajdeep ^{[1
,2
,7
]}

Obinata, Daisuke ^{[8
,9
]}

Sandhu, Shahneen ^{[10
,11
]}

Risbridger, Gail P. ^{[9
,10
,11
]}

Taylor, Renea A. ^{[10
,12
]}

Lawrence, Mitchell G. ^{[9
,10
]}

Butler, Lisa M. ^{[13
,14
]}

Zoubeidi, Amina ^{[15
]}

Gregory, Philip A. ^{[4
,5
,14
]}

Tilley, Wayne D. ^{[1
,2
]}

Hickey, Theresa E. ^{[1
,2
]}

Goodall, Gregory J. ^{[4
,5
,16
]}

Selth, Luke A. ^{[1
,2
,17
]}

机构：

[1] Univ Adelaide, Dame Roma Mitchell Canc Res Labs, Adelaide Med Sch, Adelaide, SA 5005, Australia

[2] Univ Adelaide, Freemasons Fdn Ctr Mens Hlth, Adelaide Med Sch, Adelaide, SA 5005, Australia

[3] Ctr Canc Biol, Alliance SA Pathol, ACRF Canc Genom Facil, Frome Rd, Adelaide, SA 5005, Australia

[4] Univ South Australia, Frome Rd, Adelaide, SA 5005, Australia

[5] Ctr Canc Biol, Alliance SA Pathol, Adelaide, SA 5005, Australia

[6] Inst Bergonie Unicanc, INSERM U1218, Bordeaux, France

[7] Northwestern Univ, Transplant Immunol Lab, Comprehens Transplant Ctr, Feinberg Sch Med, Chicago, IL 60611 USA

[8] Nihon Univ, Dept Urol, Sch Med, Tokyo 1738610, Japan

[9] Monash Univ, Dept Anat & Dev Biol, Monash Partners Comprehens Canc Consortium, Monash Biomed Discovery Inst,Prostate Canc Res Gr, Clayton, Vic 3168, Australia

[10] Univ Melbourne, Peter MacCallum Canc Ctr, Canc Res Div, Canc Res Program, Melbourne, Vic 3000, Australia

[11] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3000, Australia

[12] Monash Univ, Monash Biomed Discovery Inst, Dept Physiol, Prostate Canc Res Grp,Monash Partners Comprehens, Clayton, Vic 3168, Australia

[13] South Australian Hlth & Med Res Inst, Adelaide, SA 5000, Australia

[14] Univ Adelaide, Fac Hlth & Med Sci, Adelaide, SA 5005, Australia

[15] Univ British Columbia, Vancouver Prostate Ctr, Vancouver, BC V6H 3Z6, Canada

[16] Univ Adelaide, Sch Biol Sci, Adelaide, SA 5005, Australia

[17] Flinders Univ S Australia, Flinders Hlth & Med Res Inst, Bedford Pk, SA 5042, Australia

来源：

CELL REPORTS | 2021年 / 34卷 / 01期

基金：

英国医学研究理事会;

关键词：

TRANSCRIPTION FACTORS; MAMMALIAN MICRORNAS; LINEAGE PLASTICITY; RECEPTOR; DIFFERENTIATION; ACTIVATION; REVEALS; BINDING; FOXA1; IDENTIFICATION;

D O I：

10.1016/j.celrep.2020.108585

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Potent therapeutic inhibition of the androgen receptor (AR) in prostate adenocarcinoma can lead to the emergence of neuroendocrine prostate cancer (NEPC), a phenomenon associated with enhanced cell plasticity. Here, we show that microRNA-194 (miR-194) is a regulator of epithelial-neuroendocrine transdifferentiation. In clinical prostate cancer samples, miR-194 expression and activity were elevated in NEPC and inversely correlated with AR signaling. miR-194 facilitated the emergence of neuroendocrine features in prostate cancer cells, a process mediated by its ability to directly target a suite of genes involved in cell plasticity. One such target was FOXA1, which encodes a transcription factor with a vital role in maintaining the prostate epithelial lineage. Importantly, a miR-194 inhibitor blocked epithelial-neuroendocrine transdifferentiation and inhibited the growth of cell lines and patient-derived organoids possessing neuroendocrine features. Overall, our study reveals a post-transcriptional mechanism regulating the plasticity of prostate cancer cells and provides a rationale for targeting miR-194 in NEPC.

引用

页数：23

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