ZEB1 is neither sufficient nor required for epithelial-mesenchymal transition in LS174T colorectal cancer cells

Jägle, Sabine; Dertmann, Annika; Schrempp, Monika; Hecht, Andreas

doi:10.1016/j.bbrc.2016.12.017

Cited by 19 publications

(19 citation statements)

References 24 publications

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“…Because EpCAM is also used as a marker of biliary hyperplasia, the activation of EpCAM by H19 likely contributes to the ductular reaction. A recent study reported that ZEB1 is neither required nor sufficient for EMT in LS174T colorectal cancer cells lacking endogenous EMT‐inducing transcription factors . In our studies, H19 markedly diminishes ZEB1 in MSCs that express high levels of EpCAM but has no effect on down‐regulating ZEB1 in MLCs that contain low levels of EpCAM.…”

Section: Discussioncontrasting

confidence: 66%

H19 promotes cholestatic liver fibrosis by preventing ZEB1‐mediated inhibition of epithelial cell adhesion molecule

et al. 2017

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Based on our recent finding that disruption of bile acid (BA) homeostasis in mice results in the induction of hepatic lncRNA H19 expression, we sought to elucidate the role of H19 in cholestatic liver fibrosis. Hepatic overexpression of H19RNA augmented bile duct ligation (BDL)-induced liver fibrosis, which was accompanied by the elevation of serum ALT, AST, bilirubin, and BA levels. Multiple genes related to liver fibrosis, inflammation, and biliary hyperplasia were increased in H19-BDL vs Null-BDL mice, whereas genes in BA synthesis were decreased. Livers and spleens of H19-BDL mice showed significant enrichment of CD3+γδ+, IL-4, and IL-17 producing CD4+ and CD8+ immune cell populations. H19 downregulated hepatic zinc finger E-box-binding homeobox 1 (ZEB1) but upregulated epithelial cell adhesion molecule (EpCAM) and SRY (sex determining region Y)-box 9 (SOX9) expression. Mechanistically, ZEB1 repressed EpCAM promoter activity and gene transcription. H19RNA impeded ZEB1’s inhibitory action by interacting with ZEB1 protein to prevent its binding to the EpCAM promoter. Hepatic overexpression of ZEB1 or knockdown of EpCAM diminished H19-induced fibrosis; the latter was also prevented in H19−/− mice. H19RNA was markedly induced by bile acids in mouse small cholangiocytes (MSC) and to a lesser extent in mouse large cholangiocytes (MLC). The upregulation of H19RNA and EpCAM correlated positively with the downregulation of ZEB1 in primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) liver specimens. Conclusions: The activation of hepatic H19RNA promoted cholestatic liver fibrosis in mice through the ZEB1/EpCAM signaling pathway.

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Section: Discussioncontrasting

confidence: 66%

H19 promotes cholestatic liver fibrosis by preventing ZEB1‐mediated inhibition of epithelial cell adhesion molecule

et al. 2017

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“…Interestingly, ZEB1 expression was increased in #7 P6 OR1, but not #7 P6 OR2, whereas vimentin expression was increased in both #7 P6 OR1 and #7 P6 OR2, compared with #7. ZEB1 expression is not always increased in mesenchymal cells as suggested in the literature . Collectively, we concluded that both #7 P6 OR1 and #7 OR2 have mesenchymal phenotype rather than epithelial phenotype (Figure ).…”

Section: Discussionsupporting

confidence: 72%

“…ZEB1 expression is not always increased in mesenchymal cells as suggested in the literature. 35 Collectively, we concluded that both #7 P6 OR1 and #7 OR2 have mesenchymal phenotype rather than epithelial phenotype ( Figure S5). Our PDX model with osimertinib resistance may be useful to clarify the precise resistance mechanisms and develop novel therapies to overcome resistance as a result of EMT.…”

Section: Discussionmentioning

confidence: 79%

Patient‐derived xenograft models of non‐small cell lung cancer for evaluating targeted drug sensitivity and resistance

et al. 2019

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Patient‐derived xenograft (PDX) models are a useful tool in cancer biology research. However, the number of lung cancer PDX is limited. In the present study, we successfully established 10 PDX, including three adenocarcinoma (AD), six squamous cell carcinoma (SQ) and one large cell carcinoma (LA), from 30 patients with non‐small cell lung cancer (NSCLC) (18 AD, 10 SQ, and 2 LA), mainly in SCID hairless outbred (SHO) mice (Crlj:SHO‐PrkdcscidHrhr). Histology of SQ, advanced clinical stage (III‐IV), status of lymph node metastasis (N2‐3), and maximum standardized uptake value ≥10 when evaluated using a delayed 18F‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography (FDG‐PET) scan was associated with successful PDX establishment. Histological analyses showed that PDX had histology similar to that of patients’ surgically resected tumors (SRT), whereas components of the microenvironment were replaced with murine cells after several passages. Next‐generation sequencing analyses showed that after two to six passages, PDX preserved the majority of the somatic mutations and mRNA expressions of the corresponding SRT. Two out of three PDX with AD histology had epidermal growth factor receptor (EGFR) mutations (L858R or exon 19 deletion) and were sensitive to EGFR tyrosine kinase inhibitors (EGFR‐TKI), such as gefitinib and osimertinib. Furthermore, in one of the two PDX with an EGFR mutation, osimertinib resistance was induced that was associated with epithelial‐to‐mesenchymal transition. This study presented 10 serially transplantable PDX of NSCLC in SHO mice and showed the use of PDX with an EGFR mutation for analyses of EGFR‐TKI resistance.

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“…This raised questions regarding the roles of SNAI1 and ZEB1 in the signaling network regulating mesenchymal transition. Previous reports have shown that SNAI1 can activate expression of ZEB1 during mesenchymal transition (30)(31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

“…The current model suggests that SNAI1 and ZEB1 are key components in regulation of mesenchymal transition, although there is some discrepancy regarding their exact roles. There are reports that suggest that they act in a parallel manner (27)(28)(29), while other reports suggest that ZEB1 acts downstream of SNAI1 (30)(31)(32)(33) in the regulatory network.…”

mentioning

confidence: 99%

Fibroblast growth factor 2 induces proliferation and fibrosis via SNAI1-mediated activation of CDK2 and ZEB1 in corneal endothelium

Lee

Jung

Heur

2018

Journal of Biological Chemistry

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Investigating stimulation of endogenous wound healing in corneal endothelial cells (CECs) may help address the global shortage of donor corneas by decreasing the number of transplants performed for blindness due to endothelial dysfunction. We previously reported that IL-1β stimulation leads to fibroblast growth factor (FGF2) expression, enhancing migration and proliferation of mammalian CECs. However, FGF2 also promotes the endothelial-mesenchymal transition, which can lead to retrocorneal membrane formation and blindness. This prompted us to investigate downstream FGF2 signaling targets that could be manipulated to prevent retrocorneal membrane formation. FGF2 stimulation altered cell morphology and induced expression of mesenchymal transition marker genes such as snail family transcriptional repressor 1 (SNAI1), SNAI2, zinc finger E-boxbinding homeobox 1 (ZEB1), and ZEB2. This, in turn, induced expression of fibronectin, vimentin and, type I collagen and suppressed E-cadherin in CECs in vitro and ex vivo. siRNA-mediated SNAI1 knockdown revealed that SNAI1 induces ZEB1 expression, in turn inducing expression of type I collagen, the major component of retrocorneal membranes, and of cyclin-dependent kinase 2 (CDK2) and cyclin E1, promoting cell proliferation. siRNA-mediated knockdown of SNAI1 or ZEB1, but not of CDK2, inhibited FGF2-dependent expression of fibronectin, vimentin, and type I collagen and of suppression of E-cadherin expression. We conclude that SNAI1 is a key regulator of FGF2-dependent mesenchymal transition in human ex vivo corneal endothelium, with ZEB1 regulating type I collagen expression and CDK2 regulating cell proliferation. These results suggest that SNAI1 promotes fibrosis and cell proliferation in human corneal endothelium through ZEB1 and CDK2.The cornea is the anterior, transparent tissue of the human eye and consists of epithelium, stroma and endothelium. The corneal endothelium is composed of a monolayer of cells and plays a critical role in maintaining corneal transparency that is critical for sharp vision through its pump function (1,2). Adult human corneal endothelial cells (CEC) are usually mitotically inactive and arrested at the G 1 phase of the cell cycle (3,4). Because of the cell cycle arrest, there is a progressive decline in CEC density that can be further accelerated by injury, such as intraocular surgery or infection. When the density decreases below a critical threshold, corneal edema ensues, leading to loss of transparency and vision. Vision loss secondary to endothelial dysfunction is a common indication for corneal transplantation in developed nations.There have been many attempts to overcome the cell cycle arrest using various approaches including the use of growth factors such as FGF, EGF, and TGF-β, the use of endothelial cell growth supplements (5-9), and disruption of contact inhibition using EDTA (10). Moreover, severely injured CEC can undergo mesenchymal transition through which they lose their polarity and assume a fibroblastic phenotype. These CEC a...

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ZEB1 is neither sufficient nor required for epithelial-mesenchymal transition in LS174T colorectal cancer cells

Cited by 19 publications

References 24 publications

H19 promotes cholestatic liver fibrosis by preventing ZEB1‐mediated inhibition of epithelial cell adhesion molecule

H19 promotes cholestatic liver fibrosis by preventing ZEB1‐mediated inhibition of epithelial cell adhesion molecule

Patient‐derived xenograft models of non‐small cell lung cancer for evaluating targeted drug sensitivity and resistance

Fibroblast growth factor 2 induces proliferation and fibrosis via SNAI1-mediated activation of CDK2 and ZEB1 in corneal endothelium

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