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Systematic Analysis of MicroRNAs Targeting the Androgen Receptor in Prostate Cancer Cells.

Ostling, Päivi; Leivonen, Suvi-Katri; Aakula, Anna; Kohonen, Pekka; Mäkelä, Rami; Hagman, Zandra LU ; Edsjö, Anders LU ; Kangaspeska, Sara; Edgren, Henrik and Nicorici, Daniel, et al. (2011) In Cancer Research 71. p.1956-1967
Abstract
Androgen receptor (AR) is expressed in all stages of prostate cancer progression, including in castration-resistant tumors. Eliminating AR function continues to represent a focus of therapeutic investigation, but AR regulatory mechanisms remain poorly understood. To systematically characterize mechanisms involving microRNAs (miRNAs), we conducted a gain-of function screen of 1129 miRNA molecules in a panel of human prostate cancer cell lines and quantified changes in AR protein content using protein lysate microarrays. In this way, we defined 71 unique miRNAs that influenced the level of AR in human prostate cancer cells. RNA sequencing data revealed that the 3'UTR of AR (and other genes) is much longer than currently used in miRNA target... (More)
Androgen receptor (AR) is expressed in all stages of prostate cancer progression, including in castration-resistant tumors. Eliminating AR function continues to represent a focus of therapeutic investigation, but AR regulatory mechanisms remain poorly understood. To systematically characterize mechanisms involving microRNAs (miRNAs), we conducted a gain-of function screen of 1129 miRNA molecules in a panel of human prostate cancer cell lines and quantified changes in AR protein content using protein lysate microarrays. In this way, we defined 71 unique miRNAs that influenced the level of AR in human prostate cancer cells. RNA sequencing data revealed that the 3'UTR of AR (and other genes) is much longer than currently used in miRNA target prediction programs. Our own analyses predicted that most of the miRNA regulation of AR would target an extended 6 kb 3'UTR. 3'UTR-binding assays validated 13 miRNAs that are able to regulate this long AR 3'UTR (miR-135b, miR-185, miR-297, miR-299-3p, miR-34a, miR-34c, miR-371-3p, miR-421, miR-449a, miR-449b, miR-634, miR-654-5p, and miR-9). Fifteen AR downregulating miRNAs decreased androgen-induced proliferation of prostate cancer cells. In particular, analysis of clinical prostate cancers confirmed a negative correlation of miR-34a and miR-34c expression with AR levels. Our findings establish that miRNAs interacting with the long 3'UTR of the AR gene are important regulators of AR protein levels, with implications for developing new therapeutic strategies to inhibit AR function and androgen-dependent cell growth. Cancer Res; 71(5); 1-12. ©2011 AACR. (Less)
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Contribution to journal
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published
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Cancer Research
volume
71
pages
1956 - 1967
publisher
American Association for Cancer Research
external identifiers
  • wos:000287845300045
  • pmid:21343391
  • scopus:79952205258
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-10-2421
language
English
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yes
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d3c1d67f-f7f4-4af5-9028-f4fdadebea06 (old id 1831553)
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http://www.ncbi.nlm.nih.gov/pubmed/21343391?dopt=Abstract
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2011-03-01 17:33:43
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2017-05-21 04:36:14
@article{d3c1d67f-f7f4-4af5-9028-f4fdadebea06,
  abstract     = {Androgen receptor (AR) is expressed in all stages of prostate cancer progression, including in castration-resistant tumors. Eliminating AR function continues to represent a focus of therapeutic investigation, but AR regulatory mechanisms remain poorly understood. To systematically characterize mechanisms involving microRNAs (miRNAs), we conducted a gain-of function screen of 1129 miRNA molecules in a panel of human prostate cancer cell lines and quantified changes in AR protein content using protein lysate microarrays. In this way, we defined 71 unique miRNAs that influenced the level of AR in human prostate cancer cells. RNA sequencing data revealed that the 3'UTR of AR (and other genes) is much longer than currently used in miRNA target prediction programs. Our own analyses predicted that most of the miRNA regulation of AR would target an extended 6 kb 3'UTR. 3'UTR-binding assays validated 13 miRNAs that are able to regulate this long AR 3'UTR (miR-135b, miR-185, miR-297, miR-299-3p, miR-34a, miR-34c, miR-371-3p, miR-421, miR-449a, miR-449b, miR-634, miR-654-5p, and miR-9). Fifteen AR downregulating miRNAs decreased androgen-induced proliferation of prostate cancer cells. In particular, analysis of clinical prostate cancers confirmed a negative correlation of miR-34a and miR-34c expression with AR levels. Our findings establish that miRNAs interacting with the long 3'UTR of the AR gene are important regulators of AR protein levels, with implications for developing new therapeutic strategies to inhibit AR function and androgen-dependent cell growth. Cancer Res; 71(5); 1-12. ©2011 AACR.},
  author       = {Ostling, Päivi and Leivonen, Suvi-Katri and Aakula, Anna and Kohonen, Pekka and Mäkelä, Rami and Hagman, Zandra and Edsjö, Anders and Kangaspeska, Sara and Edgren, Henrik and Nicorici, Daniel and Bjartell, Anders and Ceder, Yvonne and Perälä, Merja and Kallioniemi, Olli},
  issn         = {1538-7445},
  language     = {eng},
  pages        = {1956--1967},
  publisher    = {American Association for Cancer Research},
  series       = {Cancer Research},
  title        = {Systematic Analysis of MicroRNAs Targeting the Androgen Receptor in Prostate Cancer Cells.},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-10-2421},
  volume       = {71},
  year         = {2011},
}