The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs

Abstract

Invasion and metastasis of carcinomas is promoted by the activation of the embryonic 'epithelial to mesenchymal transition' (EMT) program, which triggers cellular mobility and subsequent dissemination of tumour cells. We recently showed that the EMT-activator ZEB1 (zinc finger E-box binding homeobox 1) is a crucial promoter of metastasis and demonstrated that ZEB1 inhibits expression of the microRNA-200 (miR-200) family, whose members are strong inducers of epithelial differentiation. Here, we report that ZEB1 not only promotes tumour cell dissemination, but is also necessary for the tumour-initiating capacity of pancreatic and colorectal cancer cells. We show that ZEB1 represses expression of stemness-inhibiting miR-203 and that candidate targets of miR-200 family members are also stem cell factors, such as Sox2 and Klf4. Moreover, miR-200c, miR-203 and miR-183 cooperate to suppress expression of stem cell factors in cancer cells and mouse embryonic stem (ES) cells, as demonstrated for the polycomb repressor Bmi1. We propose that ZEB1 links EMT-activation and stemness-maintenance by suppressing stemness-inhibiting microRNAs (miRNAs) and thereby is a promoter of mobile, migrating cancer stem cells. Thus, targeting the ZEB1-miR-200 feedback loop might form the basis of a promising treatment for fatal tumours, such as pancreatic cancer.

Anoikis: an emerging hallmark in health and diseases

“…Snail is able to induce also ZEB1, another transcription factor which suppresses E-cadherin [130]. An intriguing feedback loop between ZEB transcription factors and members of the miR200 family [131] in controlling EMT, anoikis resistance and metastasis has been recently elucidated [132]. The expression of ZEB1 is strictly correlated to the miR200 family [131], although they control opposite phenomena, ZEB1 being a crucial EMT activator, whereas miR200 members induce the reverse process, ie epithelial differentiation.…”

“…Actually, ZEB factors and miR200 reciprocally control their expression in a strict feedback loop [133]. Of note, ZEB1 is a key EMT regulator in many human cancers including prostate, colon, breast and pancreatic [132,[134][135][136], while miR200 family members are often down-regulated in cancer cells [131]. Actually, the regulation of EMT by miRNAs is a very general phenomenon not limited to TrkB signalling [137].…”

Epithelial-Mesenchymal Transition (EMT) in Tumor-Initiating Cells and Its Clinical Implications in Breast Cancer

“…A double negative feedback pathway involving TGFß, Zeb1, and Zeb2, as well as the miR-200 family members, has been shown to regulate EMT. Furthermore, disruption of this inhibitory pathway, perhaps regulated by local paracrine TGFß signaling from the microenvironment, may be responsible for the reciprocal MET [34,35]. Also of interest is the recent observation that the Akt pathway and specifically Akt2 also may negatively regulate miR-200 family expression, and that Akt1 may antagonize the inhibitory effect of Akt2 [36].…”

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

“…A body of literature now substantiates regulation of EMT and stemness by miRNA. In one of the earliest studies of pancreatic and colon cancers, Wellner et al discovered that Zeb1 promotes tumorigenicity by repressing stemness-inhibiting miRNAs [156]. In follow up investigations, they determined that the miR-200 family targets Notch pathway components, such as Jagged1, to mediate enhanced Notch activation of Zeb1 in two aggressive types of human solid tumors [157].…”