title: Krüppel-like factor 8 promotes tumorigenic mammary stem cell induction by targeting miR-146a.
abstract: The properties of stem cells can be induced during the epithelial to mesenchymal transition (EMT). The responsible molecular mechanisms, however, remain largely undefined. Here we report the identification of the microRNA-146a (miR-146a) as a common target of Krüppel-like factor 8 (KLF8) and TGF-β, both of which are known EMT-inducers. Upon KLF8 overexpression or TGF-β treatment, a significant portion of the MCF-10A cells gained stem cell traits as demonstrated by an increased expression of CD44(high)/CD24low, activity of aldehyde dehydrogenase (ALDH), mammosphere formation and chemoresistance. Along with this change, the expression of miR-146a was highly upregulated in the cells. Importantly, we found that miR-146a was aberrantly co-overexpressed with KLF8 in a panel of invasive human breast cancer cell lines. Ectopic expression of KLF8 failed to induce the stem cell traits in the MCF-10A cells if the cells were pre-treated with miR-146a inhibitor, whereas overexpression of miR-146a in the MCF-10A cells alone was sufficient to induce the stem cell traits. Co-staining and luciferase reporter analyses indicated that miR-146a targets the 3'-UTR of the Notch signaling inhibitor NUMB for translational inhibition. Overexpression of KLF8 dramatically potentiated the tumorigenecity of MCF-10A cells expressing the H-Ras oncogene, which was accompanied by a loss of NUMB expression in the tumors. Taken together, this study identifies a novel role and mechanism for KLF8 in inducing pro-tumorigenic mammary stem cells via miR-146a potentially by activating Notch signaling. This mechanism could be exploited as a therapeutic target against drug resistance of breast cancer.
authors: Burnett School of Biomedical Sciences, University of Central Florida, College of Medicine Orlando, FL.
authors: Xianhui
authors: X
authors: Wang
authors: Heng
authors: H
authors: Lu
authors: Tianshu
authors: T
authors: Li
authors: Lin
authors: L
authors: Yu
authors: Gang
authors: G
authors: Liu
authors: Xu
authors: X
authors: Peng
authors: Jihe
authors: J
authors: Zhao
keywords: EMT; KLF8; mammary stem cells; miR-146a; tumorigenesis
references: Cell. 2008 May 16;133(4):704-15
references: 18485877
references: Cancer Metastasis Rev. 2009 Jun;28(1-2):35-49
references: 19169797
references: Biochem Biophys Res Commun. 2009 Feb 27;380(1):177-82
references: 19167348
references: Science. 2004 Apr 23;304(5670):594-6
references: 15105502
references: Cancer Res. 2009 Aug 15;69(16):6704-12
references: 19654291
references: Carcinogenesis. 2010 Feb;31(2):167-74
references: 19897602
references: Cancer Res. 2007 Aug 1;67(15):7184-93
references: 17671186
references: Cell Mol Life Sci. 2012 Nov;69(21):3529-31
references: 22926413
references: Nat Med. 2011 Aug 07;17(9):1101-8
references: 21822286
references: Tumour Biol. 2012 Feb;33(1):53-61
references: 22081373
references: Cell Cycle. 2010 Feb 1;9(3):601-11
references: 20107328
references: Cancer Lett. 2009 Jun 28;279(1):8-12
references: 19022563
references: Gastroenterology. 2012 Sep;143(3):799-810.e2
references: 22677193
references: J Cell Biochem. 2006 Sep 1;99(1):35-52
references: 16823799
references: Oncogene. 2007 Jan 18;26(3):456-61
references: 16832343
references: Breast Cancer Res. 2011 Jun 10;13(3):211
references: 21672282
references: J Biol Chem. 2008 Oct 3;283(40):26937-47
references: 18687676
references: Int J Hematol. 2010 Jul;92(1):129-35
references: 20577838
references: Cancer Res. 2009 Feb 15;69(4):1279-83
references: 19190326
references: J Mammary Gland Biol Neoplasia. 2010 Jun;15(2):213-23
references: 20499142
references: Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9623-8
references: 22623533
references: Genes Dev. 2009 Sep 15;23(18):2140-51
references: 19759262
references: J Biol Chem. 2008 May 16;283(20):13934-42
references: 18353772
references: EMBO Mol Med. 2011 May;3(5):279-90
references: 21472990
references: J Mammary Gland Biol Neoplasia. 2012 Mar;17(1):15-21
references: 22331423
references: Histochem Cell Biol. 2009 Jul;132(1):47-58
references: 19365637
references: J Biol Chem. 2011 Jun 10;286(23):20335-44
references: 21518760
references: Am J Transl Res. 2011 Feb;3(2):121-32
references: 21416054
references: Clin Cancer Res. 2009 Aug 15;15(16):5060-72
references: 19671845
references: Front Biosci (Schol Ed). 2012 Jan 01;4:810-8
references: 22202092
references: RNA Biol. 2008 Jul-Sep;5(3):115-9
references: 19182522
references: Oncogene. 2008 Sep 18;27(42):5643-7
references: 18504431
references: Oncogene. 2014 Jan 2;33(1):10-8
references: 23222713
references: Blood Cells Mol Dis. 2005 Sep-Oct;35(2):227-35
references: 16023392
references: Cancer Res. 2008 Oct 1;68(19):7846-54
references: 18829540
references: J Cancer Res Clin Oncol. 2010 Aug;136(8):1255-65
references: 20182889
references: Int J Cancer. 2010 Oct 15;127(8):1785-94
references: 20099276
references: J Biol Chem. 2012 Dec 21;287(52):43720-9
references: 23105099
references: Clin Cancer Res. 2012 Feb 15;18(4):981-92
references: 22114139
references: Biochem Biophys Res Commun. 2011 Nov 4;414(4):675-80
references: 21982769
references: Retrovirology. 2008 Nov 12;5:100
references: 19014482
references: EMBO Rep. 2008 Jun;9(6):582-9
references: 18483486
references: Genes Dev. 2008 Apr 1;22(7):894-907
references: 18381893
references: Nat Cell Biol. 2009 Dec;11(12):1487-95
references: 19935649
references: J Mammary Gland Biol Neoplasia. 2012 Mar;17(1):79-87
references: 22350993
references: Oncogene. 2011 Apr 21;30(16):1901-11
references: 21151179
references: J Biol Chem. 2006 Jun 16;281(24):16664-71
references: 16617055
references: Nucleic Acids Res. 2000 May 1;28(9):1955-62
references: 10756197
references: Gastroenterology. 2010 Dec;139(6):2146-2157.e12
references: 20728449
references: Mol Cell. 2003 Jun;11(6):1503-15
references: 12820964
references: PLoS One. 2008 Aug 06;3(8):e2888
references: 18682804
references: Cell. 2009 Nov 25;139(5):871-90
references: 19945376
references: RNA Biol. 2007 Nov;4(3):131-7
references: 18347435
references: Mol Cancer. 2010 Jun 28;9:169
references: 20579395
references: PLoS One. 2012;7(1):e30429
references: 22276196
references: Nat Cell Biol. 2008 May;10(5):593-601
references: 18376396
references: Am J Transl Res. 2012;4(3):357-63
references: 22937212
references: Cell Prolif. 2003 Oct;36 Suppl 1:59-72
references: 14521516
references: Cancer Res. 2010 Feb 15;70(4):1486-95
references: 20124483
references: J Biol Chem. 2008 May 30;283(22):14910-4
references: 18411277
references: Cell Stem Cell. 2012 Jun 14;10(6):717-728
references: 22704512
references: J Clin Endocrinol Metab. 2010 Mar;95(3):1421-30
references: 20061417
references: J Virol. 2008 Feb;82(4):1946-58
references: 18057241
references: Cancer Res. 2011 Sep 15;71(18):5950-4
references: 21917736
references: Mol Cancer Ther. 2009 May;8(5):1055-66
references: 19435871
references: Genes Dev. 2003 May 15;17(10):1253-70
references: 12756227
references: Cell Res. 2009 Sep;19(9):1098-109
references: 19488069
references: PLoS One. 2012;7(6):e39668
references: 22761862
references: Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12481-6
references: 16885212
references: Oncol Rep. 2012 Feb;27(2):559-66
references: 22020746
references: Histol Histopathol. 2009 Oct;24(10):1343-55
references: 19688699
references: Cancer Lett. 2011 Jan 1;300(1):10-9
references: 20965651
references: Mol Med Rep. 2012 Feb;5(2):347-50
references: 22076119