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ZEB1 Promotes Invasiveness of Colorectal Carcinoma Cells Through the Opposing Regulation of Upa and PAI-1

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ZEB1 Promotes Invasiveness of Colorectal Carcinoma Cells Through the Opposing Regulation of Upa and PAI-1 Published OnlineFirst January 22, 2013; DOI: 10.1158/1078-0432.CCR-12-2675 Clinical Cancer Human Cancer Biology Research ZEB1 Promotes Invasiveness of Colorectal Carcinoma Cells through the Opposing Regulation of uPA and PAI-1 Ester Sanchez-Till o1,2, Oriol de Barrios1, Laura Siles1, Pier G. Amendola1, Douglas S. Darling6, Miriam Cuatrecasas3, Antoni Castells2,4, and Antonio Postigo1,2,5,7 Abstract Purpose: Carcinoma cells enhance their invasive capacity through dedifferentiation and dissolution of intercellular adhesions. A key activator of this process is the ZEB1 transcription factor, which is induced in invading cancer cells by canonical Wnt signaling (b-catenin/TCF4). Tumor invasiveness also entails proteolytic remodeling of the peritumoral stroma. This study aimed to investigate the potential regulation by ZEB1 of the plasminogen proteolytic system constituted by the urokinase plasminogen activator (uPA), and its inhibitor, plasminogen activator inhibitor-1 (PAI-1). Experimental Design: Through multiple experimental approaches, colorectal carcinoma (CRC) cell lines and samples from human primary CRC and ZEB1 (À/À) mice were used to examine ZEB1-mediated regulation of uPA and PAI-1 at the protein, mRNA, and transcriptional level. Results: ZEB1 regulates uPA and PAI-1 in opposite directions: induces uPA and inhibits PAI-1. In vivo expression of uPA depends on ZEB1 as it is severely reduced in the developing intestine of ZEB1 null (À/À) mice. Optimal induction of uPA by Wnt signaling requires ZEB1 expression. ZEB1 binds to the uPA promoter and activates its transcription through a mechanism implicating the histone acetyltransferase p300. In contrast, inhibition of PAI-1 by ZEB1 does not involve transcriptional repression but rather downregulation of mRNA stability. ZEB1-mediated tumor cell migration and invasion depend on its induction of uPA. ZEB1 coexpresses with uPA in cancer cells at the invasive front of CRCs. Conclusions: ZEB1 promotes tumor invasiveness not only via induction in cancer cells of a motile dedifferentiated phenotype but also by differential regulation of genes involved in stroma remodeling. Clin Cancer Res; 1–12. Ó2013 AACR. Introduction transcriptional level, E-cadherin is repressed by factors of During carcinoma progression, cancer cells enhance their the ZEB, Snail, and Twist families, with ZEB1 (also known as d migratory and invasive capacity through the downregula- EF1) as final downstream effector and having the most tion of epithelial markers involved in the maintenance of consistent inverse correlation with E-cadherin across carci- cell polarity and intercellular adhesion—chiefly the inhibi- nomas (1–5). In addition to repress epithelial polarity and tion of E-cadherin—and the acquisition of a motile ded- adhesion genes, ZEB1 activates mesenchymal and stemness ifferentiated phenotype as part of the epithelial-to-mesen- markers (2). Consequently, ZEB1 expression promotes chymal transition (EMT; reviewed in refs. 1–3). At the tumorigenesis and metastasis in mouse models and corre- lates with a poorer prognosis in human cancers, including colorectal carcinomas (CRC; refs. 2, 3, 6, 7). 1 Authors' Affiliations: Group of Transcriptional Regulation of Gene ZEB1 is induced by multiple signaling pathways includ- Expression, Department of Oncology and Hematology, IDIBAPS, Barce- lona, Spain; 2CIBERehd (Pancreatic and Gastrointestinal Oncology), IDI- ing TGF-b, Notch, and canonical Wnt (b-catenin/TCF4; BAPS, Barcelona, Spain; 3Department of Pathology (CDB) and Tumor reviewed in refs. 1–3, 8; 9–11). As a repressor of E-cadherin, Bank, IDIBAPS-Hospital Clinic, Barcelona, Spain; 4Institute of Digestive and Metabolic Diseases, Hospital Clinic, Barcelona, Spain; 5ICREA, Bar- ZEB1 is not expressed in normal epithelium or the tumor celona, Spain; 6Department of Oral Health and Center for Genetics and center of well-differentiated carcinomas (12). ZEB1 is Molecular Medicine, University of Louisville; and 7James Graham Brown rather upregulated at the invasive front of tumors in ded- Cancer Center, Louisville, Kentucky ifferentiated cancer cells that have translocated b-catenin to Note: Supplementary data for this article are available at Clinical Cancer the nucleus and therefore display active Wnt signaling Research Online (http://clincancerres.aacrjournals.org/). (7, 11–14). E. Sanchez-Till o and O. de Barrios contributed equally to this work. However, tumor invasiveness does not depend exclusive- Corresponding Author: Antonio Postigo, Group of Transcriptional Reg- ly on intrinsic cancer cell traits and often entails a deregu- ulation of Gene Expression, IDIBAPS, Villarroel 170, Barcelona 08036, lation of proteolytic systems operating in the stroma (15). Spain. E-mail: [email protected] Proteases produced at the tumor invasive front by cancer doi: 10.1158/1078-0432.CCR-12-2675 and stromal cells remodel the peritumoral matrix modify- Ó2013 American Association for Cancer Research. ing cancer cell adhesions and releasing active peptides that www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst January 22, 2013; DOI: 10.1158/1078-0432.CCR-12-2675 Sanchez-Till o et al. PAI-1 has proinvasive effects that are independent of its role Translational Relevance as enzymatic inhibitor of uPA but are rather related to its ZEB1 is expressed by invading carcinoma cells at the regulation of cell adhesion (21). Efficient tumor invasive- tumor front where it represses epithelial adhesion genes ness therefore requires a tight control of uPA and PAI-1 and induces a migratory and dedifferentiated pheno- expression in cancer cells. uPA is a downstream target of type. Consequently, ZEB1 promotes tumorigenesis and Wnt (b-catenin/TCF4) and Notch pathways (24, 25), and metastasis in mouse models and correlates with a poorer PAI-1 is transcriptionally activated or repressed by multiple clinical prognosis in human cancers. We identified here a signals (e.g. p53, TGF-b, hypoxia, insulin, KLF-2; reviewed novel mechanism for the promotion of tumor invasivi- in ref. 26). Expression of uPA by cancer cells at the invasive ness by ZEB1. Using cell lines and samples from primary tumor front of CRCs, where ZEB1 is also induced in human carcinomas and mice knocked out for ZEB1,we response to aberrant activation of Wnt signaling (11), show that ZEB1 regulates genes involved in proteolytic prompted us to investigate both the potential regulation remodeling of the peritumoral stroma: activating uro- of the uPA/PAI-1 system by ZEB1 and its contribution to kinase plasminogen activator (uPA) and inhibiting plas- ZEB1-mediated tumor invasiveness. minogen activator inhibitor-1 (PAI-1). In fact, our In this study, we show that ZEB1 controls both compo- data indicate that uPA is responsible for most of nents of the plasminogen activation system in CRC cells, ZEB1-mediated cancer cell migration and invasion and but in opposing ways; inducing uPA and inhibiting PAI-1. that both proteins are coexpressed in tumor cells at the ZEB1 upregulates uPA through direct binding to its pro- invasive front of primary carcinomas. Our results set moter and activation of transcription via a mechanism ZEB1 as a potential biomarker of prognosis and a poten- involving the histone acetyltransferase p300. Meanwhile, tial therapeutic target in colorectal carcinomas and prob- ZEB1 repressive effect on PAI-1 entails a downregulation of ably other carcinomas. PAI-1 mRNA stability. Importantly, the ability of ZEB1 to promote migration and invasion of CRC cells depends on its induction effect over uPA. In vivo relevance of these findings was confirmed through two approaches. In vivo promote tumor invasion. A key protease cascade involved in expression of uPA is critically dependent on ZEB1 as is tumor invasiveness is the plasminogen activation system virtually abrogated in the developing intestine of embryos formed by the urokinase plasminogen activator (uPA) and from ZEB1 null (À/À) mice. uPA also requires ZEB1 for its its inhibitor, the plasminogen activator inhibitor-1 (PAI-1; optimal induction by Wnt, which is hindered in ZEB1- ref. 16). uPA processes plasminogen into plasmin, which in deficient cells from these mice or CRC cells knocked down turn cleaves extracellular matrix components (16). uPA is for ZEB1. In addition, ZEB1 coexpresses with uPA in cancer upregulated in cancer and stromal cells at the invasive front cells at the invasive front of primary CRCs but inversely of colorectal and other carcinomas, where high expression correlates with PAI-1. by invading cancer cells correlates with metastasis and an adverse prognosis (17, 18). In turn, elimination of uPA in Materials and Methods either cancer or stromal cells reduces tumor growth and the Antibodies, plasmids, siRNAs, and shRNAs incidence of metastasis in mouse models (19, 20). Description and source of antibodies, plasmids, siRNAs PAI-1 plays distinct roles in tumor invasion depending on oligonucleotides, and short hairpin RNA (shRNA) lentivi- the cell type expressing it and the tumor model studied. At rus used in the study are detailed in Supplementary the invasive front of tumors, including CRCs, PAI-1 is Information. induced in cancer cells, but it is especially upregulated in stromal cells (17, 18). Paradoxically, considering its inhib- Cells itory function over uPA activity, PAI-1 expression at the SW480 and HCT116 cells originated as in ref. (14) and tumor front of colorectal and other carcinomas correlates
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