title: MCPIP1 Selectively Destabilizes Transcripts Associated with an Antiapoptotic Gene Expression Program in Breast Cancer Cells That Can Elicit Complete Tumor Regression.
abstract: The ability of cancer cells to evade apoptosis is dictated by a shift in the balance between proapoptotic and antiapoptotic gene expression programs. Monocyte chemotactic protein-induced protein 1 (MCPIP1) is a zinc-finger RNA binding protein with important roles in mediating inflammatory responses. Overexpression of MCPIP1 in different cancer cell types has been implicated in eliciting an antitumor response, but a direct role of MCPIP1 in apoptosis has not been established. In this study, we demonstrate that MCPIP1 functions as a potent tumor suppressor that induces apoptosis of breast tumor cells by selectively enhancing mRNA decay of antiapoptotic gene transcripts, including Bcl2L1, Bcl2A1, RelB, Birc3, and Bcl3. Mechanistically, MCPIP1 physically interacted with a stem-loop structure in the 3' untranslated region of these transcripts through its PIN domain, causing mRNA destabilization. Furthermore, we found that MCPIP1 expression was repressed in breast tumor cells, and overexpression of MCPIP1 induced apoptosis, whereas its depletion enhanced cancer cell proliferation. Moreover, MCPIP1 induction in vivo resulted in complete regression of established tumors and a significant reduction in metastatic disease. Notably, low MCPIP1 expression in tumor samples from breast cancer patients was strongly associated with poor survival over 13 years of follow-up. Collectively, our results highlight that MCPIP1 is a new tumor suppressor in breast cancer that induces cell death by tipping the balance in favor of proapoptotic gene expression.
authors.affiliation: Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis University, St. Louis, Missouri.
authors.forename: Wenbao
authors.initials: W
authors.lastname: Lu
authors.affiliation: Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis University, St. Louis, Missouri.
authors.forename: Huan
authors.initials: H
authors.lastname: Ning
authors.affiliation: Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis University, St. Louis, Missouri.
authors.forename: Ling
authors.initials: L
authors.lastname: Gu
authors.affiliation: Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis University, St. Louis, Missouri.
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.affiliation: Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis University, St. Louis, Missouri.
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis University, St. Louis, Missouri.
authors.forename: Rong
authors.initials: R
authors.lastname: Hou
authors.affiliation: Shock/Trauma Research Center and Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri.
authors.forename: Mingui
authors.initials: M
authors.lastname: Fu
authors.affiliation: Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis University, St. Louis, Missouri.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hoft
authors.affiliation: Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis University, St. Louis, Missouri. jliu9@slu.edu.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Liu
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D020871:RNA Stability / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics; D012260:Ribonucleases / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D016601:RNA-Binding Proteins; D012260:Ribonucleases; C541320:Zc3h12a protein, mouse
references.citation: Carcinogenesis. 2000 Mar;21(3):485-95
references.pmid: 10688869
references.citation: Nucleic Acids Res. 2012 Aug;40(14):6957-65
references.pmid: 22561375
references.citation: Oncogene. 2001 Nov 15;20(52):7645-57
references.pmid: 11753642
references.citation: Nat Rev Cancer. 2002 Apr;2(4):277-88
references.pmid: 12001989
references.citation: Nucleic Acids Res. 2003 Jul 1;31(13):3429-31
references.pmid: 12824340
references.citation: Science. 1995 Mar 10;267(5203):1445-9
references.pmid: 7878463
references.citation: Science. 1995 Mar 10;267(5203):1456-62
references.pmid: 7878464
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13550-5
references.pmid: 16141321
references.citation: Circ Res. 2006 May 12;98(9):1177-85
references.pmid: 16574901
references.citation: Nat Protoc. 2006;1(1):302-7
references.pmid: 17406249
references.citation: Ageing Res Rev. 2012 Sep;11(4):473-84
references.pmid: 22387927
references.citation: PLoS One. 2012;7(11):e49841
references.pmid: 23185455
references.citation: Cancer Cell. 2012 Dec 11;22(6):812-24
references.pmid: 23238016
references.citation: Nucleic Acids Res. 2013 Mar 1;41(5):3314-26
references.pmid: 23355615
references.citation: Immunol Rev. 2013 May;253(1):253-72
references.pmid: 23550651
references.citation: Cell Signal. 2013 May;25(5):1228-34
references.pmid: 23422584
references.citation: Cell. 2013 May 9;153(4):869-81
references.pmid: 23663784
references.citation: Arterioscler Thromb Vasc Biol. 2013 Jun;33(6):1384-91
references.pmid: 23580143
references.citation: J Immunol. 2013 Jun 1;190(11):5894-902
references.pmid: 23645882
references.citation: FEBS J. 2013 Jun;280(11):2665-74
references.pmid: 23551903
references.citation: Cell. 2013 May 23;153(5):1036-49
references.pmid: 23706741
references.citation: Cell Death Dis. 2013;4:e834
references.pmid: 24091677
references.citation: Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):19083-8
references.pmid: 24191027
references.citation: J Interferon Cytokine Res. 2014 Apr;34(4):233-41
references.pmid: 24697201
references.citation: Oncol Rep. 2014 May;31(5):2385-92
references.pmid: 24626857
references.citation: J Immunol. 2014 Oct 15;193(8):4159-68
references.pmid: 25225661
references.citation: J Cell Biochem. 2015 Feb;116(2):260-7
references.pmid: 25187114
references.citation: J Biol Chem. 2011 Dec 2;286(48):41692-700
references.pmid: 21971051
references.citation: J Biol Chem. 2008 Mar 7;283(10):6337-46
references.pmid: 18178554
references.citation: Oncogene. 2008 Oct 27;27(50):6398-406
references.pmid: 18955968
references.citation: Nat Immunol. 2008 Dec;9(12):1371-8
references.pmid: 18997794
references.citation: Clin Cancer Res. 2009 Feb 15;15(4):1126-32
references.pmid: 19228717
references.citation: Nature. 2009 Apr 30;458(7242):1185-90
references.pmid: 19322177
references.citation: J Biol Chem. 2010 Mar 26;285(13):9317-21
references.pmid: 20139083
references.citation: FEBS Lett. 2010 Jul 16;584(14):3065-72
references.pmid: 20561987
references.citation: J Biol Chem. 2010 Jul 16;285(29):21951-60
references.pmid: 20460684
references.citation: J Exp Med. 2010 Dec 20;207(13):2959-73
references.pmid: 21115689
references.citation: Cell Death Dis. 2010;1:e40
references.pmid: 21364647
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: J Immunol. 2011 Jun 1;186(11):6454-64
references.pmid: 21515794
references.citation: Nucleic Acids Res. 2011 May;39(10):4373-86
references.pmid: 21278420
references.citation: Mol Cell. 2011 Nov 4;44(3):424-36
references.pmid: 22055188
references.citation: Nat Immunol. 2011 Dec;12(12):1167-75
references.pmid: 22037600
references.citation: Front Biosci (Landmark Ed). 2012;17:174-88
references.pmid: 22201737
references.citation: Mol Cancer. 2011;10:152
references.pmid: 22195643
references.citation: Blood. 2012 Jun 21;119(25):6032-42
references.pmid: 22581448
references.citation: Endocr Relat Cancer. 2000 Dec;7(4):257-69
references.pmid: 11174847