microRNA 17/20 inhibits cellular invasion and tumor metastasis in breast cancer by heterotypic signaling.
microRNAs are thought to regulate tumor progression and invasion via direct interaction with target genes within cells. Here the microRNA17/20 cluster is shown to govern cellular migration and invasion of nearby cells via heterotypic secreted signals. microRNA17/20 abundance is reduced in highly invasive breast cancer cell lines and node-positive breast cancer specimens. Cell-conditioned medium from microRNA17/20-overexpressing noninvasive breast cancer cell MCF7 was sufficient to inhibit MDA-MB-231 cell migration and invasion through inhibiting secretion of a subset of cytokines, and suppressing plasminogen activation via inhibition of the secreted plasminogen activators (cytokeratin 8 and alpha-enolase). microRNA17/20 directly repressed IL-8 by targeting its 3' UTR, and inhibited cytokeratin 8 via the cell cycle control protein cyclin D1. At variance with prior studies, these results demonstrated a unique mechanism of how the altered microRNA17/20 expression regulates cellular secretion and tumor microenvironment to control migration and invasion of neighboring cells in breast cancer. These findings not only reveal an antiinvasive function of miR-17/20 in breast cancer, but also identify a heterotypic secreted signal that mediates the microRNA regulation of tumor metastasis.
Yu
Zuoren
Z
Department of Cancer Biology, Thomas Jefferson University and Hospital, Kimmel Cancer Center, Philadelphia, PA 19107, USA.
Willmarth
Nicole E
NE
Zhou
Jie
J
Katiyar
Sanjay
S
Wang
Min
M
Liu
Yang
Y
McCue
Peter A
PA
Quong
Andrew A
AA
Lisanti
Michael P
MP
Pestell
Richard G
RG
D020413:3' Untranslated Regions; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010958:Plasminogen / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction
D020413:3' Untranslated Regions; D016209:Interleukin-8; C524941:MIRN17 microRNA, human; C534451:MIRN20a microRNA, human; D035683:MicroRNAs; D010958:Plasminogen
Nature. 2007 Oct 11;449(7163):682-8
17898713
Oncogene. 2005 Mar 31;24(14):2375-85
15674322
Cancer Res. 2007 Dec 1;67(23):11099-101
18056431
J Clin Invest. 2000 Dec;106(12):1441-3
11120750
Biochem J. 1996 Aug 1;317 ( Pt 3):763-9
8760360
Ann Clin Biochem. 2008 May;45(Pt 3):299-306
18482919
Blood. 2009 May 28;113(22):5588-98
19182206
N Engl J Med. 2005 Oct 27;353(17):1793-801
16251535
Nature. 2005 Jun 9;435(7043):839-43
15944709
Nature. 2008 Jan 10;451(7175):147-52
18185580
Biochim Biophys Acta. 1997 Jan 4;1337(1):27-39
9003434
J Cell Biol. 2008 Aug 11;182(3):509-17
18695042
Nat Rev Cancer. 2006 Nov;6(11):857-66
17060945
Mol Cell Biol. 2006 Jun;26(11):4240-56
16705174
Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2999-3004
14973191
Cancer Treat Rev. 2008 Apr;34(2):122-36
18162327
Science. 2005 Sep 2;309(5740):1519-24
16141061
Int J Radiat Biol. 2001 Oct;77(10):1033-42
11682008
J Cell Sci. 1995 Mar;108 ( Pt 3):1071-82
7542667
Nat Cell Biol. 2009 Aug;11(8):1031-8
19633662
Mol Cell Biol. 2007 Feb;27(4):1356-69
17145782
Cancer Res. 2006 Oct 15;66(20):9986-94
17047061
Mol Cell Biol. 2003 Sep;23(17):6159-73
12917338
Cancer Cell. 2003 Jul;4(1):67-79
12892714