Abstract
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 (β-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). Through multiple experimental approaches, colorectal carcinoma (CRC) cell lines and samples from human primary CRC and ZEB1 (-/-) mice were used to examine ZEB1-mediated regulation of uPA and PAI-1 at the protein, mRNA, and transcriptional level. 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 (-/-) 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. 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.
Highlights
During carcinoma progression, cancer cells enhance their migratory and invasive capacity through the downregulation of epithelial markers involved in the maintenance of cell polarity and intercellular adhesion— the inhibition of E-cadherin—and the acquisition of a motile dedifferentiated phenotype as part of the epithelial-to-mesenchymal transition (EMT; reviewed in refs. 1–3)
ZEB1 promotes tumor invasiveness via induction in cancer cells of a motile dedifferentiated phenotype and by differential regulation of genes involved in stroma remodeling
Using cell lines and samples from primary human carcinomas and mice knocked out for ZEB1, we show that ZEB1 regulates genes involved in proteolytic remodeling of the peritumoral stroma: activating urokinase plasminogen activator and inhibiting plasminogen activator inhibitor-1 (PAI-1)
Summary
Cancer cells enhance their migratory and invasive capacity through the downregulation of epithelial markers involved in the maintenance of cell polarity and intercellular adhesion— the inhibition of E-cadherin—and the acquisition of a motile dedifferentiated phenotype as part of the epithelial-to-mesenchymal transition (EMT; reviewed in refs. 1–3). Cancer cells enhance their migratory and invasive capacity through the downregulation of epithelial markers involved in the maintenance of cell polarity and intercellular adhesion— the inhibition of E-cadherin—and the acquisition of a motile dedifferentiated phenotype as part of the epithelial-to-mesenchymal transition Transcriptional level, E-cadherin is repressed by factors of the ZEB, Snail, and Twist families, with ZEB1 ( known as dEF1) as final downstream effector and having the most consistent inverse correlation with E-cadherin across carcinomas [1,2,3,4,5]. In addition to repress epithelial polarity and adhesion genes, ZEB1 activates mesenchymal and stemness markers [2]. ZEB1 expression promotes tumorigenesis and metastasis in mouse models and correlates with a poorer prognosis in human cancers, including colorectal carcinomas ZEB1 expression promotes tumorigenesis and metastasis in mouse models and correlates with a poorer prognosis in human cancers, including colorectal carcinomas (CRC; refs. 2, 3, 6, 7)
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