The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44.
Cancer stem cells (CSCs), or tumor-initiating cells, are involved in tumor progression and metastasis. MicroRNAs (miRNAs) regulate both normal stem cells and CSCs, and dysregulation of miRNAs has been implicated in tumorigenesis. CSCs in many tumors--including cancers of the breast, pancreas, head and neck, colon, small intestine, liver, stomach, bladder and ovary--have been identified using the adhesion molecule CD44, either individually or in combination with other marker(s). Prostate CSCs with enhanced clonogenic and tumor-initiating and metastatic capacities are enriched in the CD44(+) cell population, but whether miRNAs regulate CD44(+) prostate cancer cells and prostate cancer metastasis remains unclear. Here we show, through expression analysis, that miR-34a, a p53 target, was underexpressed in CD44(+) prostate cancer cells purified from xenograft and primary tumors. Enforced expression of miR-34a in bulk or purified CD44(+) prostate cancer cells inhibited clonogenic expansion, tumor regeneration, and metastasis. In contrast, expression of miR-34a antagomirs in CD44(-) prostate cancer cells promoted tumor development and metastasis. Systemically delivered miR-34a inhibited prostate cancer metastasis and extended survival of tumor-bearing mice. We identified and validated CD44 as a direct and functional target of miR-34a and found that CD44 knockdown phenocopied miR-34a overexpression in inhibiting prostate cancer regeneration and metastasis. Our study shows that miR-34a is a key negative regulator of CD44(+) prostate cancer cells and establishes a strong rationale for developing miR-34a as a novel therapeutic agent against prostate CSCs.
Department of Molecular Carcinogenesis, the University of Texas M.D. Anderson Cancer Center, Science Park, Smithville, Texas, USA.
Can
C
Liu
Kevin
K
Kelnar
Bigang
B
Liu
Xin
X
Chen
Tammy
T
Calhoun-Davis
Hangwen
H
Li
Lubna
L
Patrawala
Hong
H
Yan
Collene
C
Jeter
Sofia
S
Honorio
Jason F
JF
Wiggins
Andreas G
AG
Bader
Randy
R
Fagin
David
D
Brown
Dean G
DG
Tang
D000818:Animals; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018960:Hyaluronan Receptors / Q000187:drug effects*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000627:therapeutic use*; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs
Cancer Res. 2008 May 15;68(10):3655-61
18483247
Stem Cells. 2009 May;27(5):1006-20
19415765
Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10158-63
17548814
Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8
12629218
Cancer Res. 2008 Jun 1;68(11):4311-20
18519691
Cell. 2009 Aug 7;138(3):592-603
19665978
Cell. 2005 Jul 15;122(1):6-7
16009126
Curr Biol. 2007 Aug 7;17(15):1298-307
17656095
Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14016-21
19666525
Cancer Cell. 2008 Feb;13(2):153-66
18242515
Nat Med. 2006 Oct;12(10):1167-74
16998484
Cell Death Differ. 2010 Feb;17(2):193-9
19461653
Cell. 2007 Dec 14;131(6):1109-23
18083101
Cancer Res. 2009 Oct 1;69(19):7569-76
19773441
Stem Cells. 2009 May;27(5):993-1005
19415763
Nat Rev Cancer. 2006 Apr;6(4):259-69
16557279
Cancer Res. 2005 Jul 15;65(14):6207-19
16024622
Mol Cell. 2007 Jun 8;26(5):745-52
17540599
J Biol Chem. 2008 Oct 10;283(41):27957-27972
18662989
Methods Mol Biol. 2009;568:85-138
19582423
Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13421-6
18755897
Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):973-8
17210912
Cell Cycle. 2007 Jul 1;6(13):1586-93
17554199
Cancer Res. 2005 Dec 1;65(23):10946-51
16322242
Nature. 2010 Feb 4;463(7281):621-6
20054295
Clin Cancer Res. 2008 Nov 1;14(21):6751-60
18980968
Nat Rev Cancer. 2008 Oct;8(10):755-68
18784658
Cancer Res. 2007 Aug 15;67(16):7713-22
17699775
Mol Cell. 2007 Jun 8;26(5):731-43
17540598
Nature. 2007 Jun 28;447(7148):1130-4
17554337
Oncogene. 2006 Mar 16;25(12):1696-708
16449977
Cancer Res. 2007 Jul 15;67(14):6796-805
17638891
Cancer Res. 2008 Mar 15;68(6):1820-5
18339862
Genes Dev. 2003 May 15;17(10):1253-70
12756227
PLoS One. 2009 Aug 28;4(8):e6816
19714243
Cancer Res. 2007 Feb 1;67(3):1030-7
17283135
Cell. 2008 Jul 11;134(1):62-73
18614011
Cell. 2006 Sep 22;126(6):1203-17
16990141
Cancer Res. 2010 Jul 15;70(14):5923-30
20570894