Snail Induction of Epithelial to Mesenchymal Transition in Tumor Cells Is Accompanied by MUC1 Repression andZEB1 Expression

Guaita, Sandra; Puig, Isabel; Francı́, Clara; Garrido, Marta; Domı́nguez, David; Batlle, Eduard; Sancho, Elena; Dedhar, Shoukat; Herreros, Antonio Garcı́a de; Baulida, Josep

doi:10.1074/jbc.m206400200

Cited by 429 publications

(415 citation statements)

References 29 publications

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“…Snail induces a full EMT when overexpressed in epithelial Madin Darby canine kidney (MDCK) cells leading to the acquisition of a motile/invasive phenotype (Cano et al, 2000;Peinado et al, 2004b). In agreement with this role, Snail (also known as Snail1) has also been found to downregulate the expression of additional epithelial genes, such as occluding, claudins or muc1 (Guaita et al, 2002;Ikenouchi et al, 2003;Ohkubo and Ozawa, 2004;Martinez-Estrada et al, 2005), or to induce the expression of mesenchymal and invasive genes, like fibronectin and metalloproteinase (MMP)-9 (Cano et al, 2000;Guaita et al, 2002;Jorda et al, 2005). Snail expression has been detected in increasing number of different human carcinoma and melanoma cell lines (reviewed in Peinado et al, 2004a).…”

Section: Introductionmentioning

confidence: 84%

Snail silencing effectively suppresses tumour growth and invasiveness

et al. 2006

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The transcription factor Snail has been recently proposed as an important mediator of tumour invasion because of its role in downregulation of E-cadherin and induction of epithelial-mesenchymal transitions (EMT). This behaviour has led to the consideration of Snail as a potential therapeutic target to block tumour progression. In this report, we provide evidence for this hypothesis. We show that silencing of Snail by stable RNA interference in MDCK-Snail cells induces a complete mesenchymal to epithelial transition (MET), associated to the upregulation of E-cadherin, downregulation of mesenchymal markers and inhibition of invasion. More importantly, stable interference of endogenous Snail in two independent carcinoma cell lines leads to a dramatic reduction of in vivo tumour growth, accompanied by increased tumour differentiation and a significant decrease in the expression of MMP-9 and angiogenic markers and invasiveness. These results indicate that use of RNA interference can be an effective tool for blocking Snail function, opening the way for its application in new antiinvasive therapies.

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Section: Introductionmentioning

confidence: 84%

Snail silencing effectively suppresses tumour growth and invasiveness

et al. 2006

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“…Similar results were obtained in two other cellular models of EMT (EpRas cells and FosER cells). At first sight, this is surprising since in several other models of tumor progression based on established carcinoma cell lines, E-cadherin repression occurred mainly at the transcriptional level (Cano et al, 2000;Guaita et al, 2002). Similarly, repression of E-cadherin mRNA occurs during EMT-like processes in development, such as differentiation of the dorsal ectoderm into the neural tube (Nose and Takeichi, 1986).…”

Section: Discussionmentioning

confidence: 99%

Raf plus TGFβ-dependent EMT is initiated by endocytosis and lysosomal degradation of E-cadherin

Janda

Nevolo

Lehmann³

et al. 2006

Oncogene

145

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Oncogenic Ras interferes with adhesive functions of epithelial cells, but requires tumor growth factor b (TGFb) signaling to cause epithelial-mesenchymal transition (EMT) and tumor progression in model systems. To investigate the mechanisms by which Ras and TGFb pathways cooperate in EMT induction, we introduced a tamoxifen-inducible version of Raf-1 (RafER) into fully polarized, mammary epithelial cells (EpH4). EMT characterized by loss of E-cadherin expression and upregulation of invasiveness-promoting genes was induced by TGFb plus 4-hydroxytamoxifen (4HT) activation of RafER. Downregulation of E-cadherin by RafER plus TGFb was detectable in total cell lysates after 48 h and much earlier in detergent-insoluble fractions of E-cadherin. Both pathways cooperated to strongly enhance endocytosis of E-cadherin, mainly via the clathrin-dependent route. Pulse-chase experiments showed decreased E-cadherin protein stability in cells stimulated with TGFb and 4HT and increased E-cadherin half-life in the presence of monensin. Monensin and chloroquine prevented E-cadherin degradation to different extent, but only monensin effectively blocked the loss of E-cadherin from the junctional complexes. Both lysosome inhibitors caused accumulation of E-cadherin vesicles, some of which were positive for Cathepsin D and lysosome-associated membrane protein 1 (LAMP-1). In addition, TGFb and mitogen-activated protein kinase hyperactivation synergistically induced E-cadherin ubiquitination, suggesting that the cooperation of Raf and TGFb favors lysosomal degradation of E-cadherin instead of its recycling. Our data indicate that early stages of EMT involve cooperative, post-translational downregulation of E-cadherin, whereas loss of E-cadherin via transcriptional repression is a late event in EMT.

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“…This hypothesis is supported by the fact that SNAI1 was detected in five normal tissues adjacent to tumor in our series. Alternatively, as SNAI1-expressing tumors are more invasive (Cano et al, 2000;Guaita et al, 2002), they are more prone to disrupt the boundaries established with neighboring tissues. Otherwise, although the mechanism remains unknown, the experiments with tumor cell lines showed that Snai1-expressing cells could paracrinally downregulate the expression of CDH1 and VDR in neighboring cells without changing the endogenous level of SNAI1.…”

Section: Adh-gfp Adh-sn Row Column Cytokine Cytokinefull Name Median mentioning

confidence: 99%

“…SNAI1 expression in epithelial cells promotes the acquisition of a fibroblastoid morphotype with invasive and migratory properties and characteristic changes in gene expression (Cano et al, 2000;Guaita et al, 2002). Importantly, SNAI1 represses the CDH1 gene (Batlle et al, 2000), which encodes E-cadherin, the main component of adherent junctions responsible for the maintenance of the adhesive and polarized phenotype of epithelial cells (Perez-Moreno et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…CDH1 downregulation is one of the hallmarks of EMT. The transcription factor ZEB1 also downregulates CDH1 in cultured cells and cooperates with SNAI1 in inducing EMT (Grooteclaes and Frisch, 2000;Guaita et al, 2002;Peinado et al, 2007). In contrast, vitamin D (1a,25-dihydroxyvitamin D 3 ) induces the expression of CDH1 and an epithelial phenotype in human colon cells expressing vitamin D receptor (VDR) (Palmer et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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SNAI1 expression in colon cancer related with CDH1 and VDR downregulation in normal adjacent tissue

et al. 2009

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SNAI1, ZEB1, E-cadherin (CDH1), and vitamin D receptor (VDR) genes regulate the epithelial-mesenchymal transition (EMT) that initiates the invasion process of many tumor cells. We hypothesized that this process could also affect the behavior of normal cells adjacent to the tumor. To verify this hypothesis, the expression level of these genes was determined by quantitative RT-PCR in tumor, normal adjacent, and normal distant tissues from 32 colorectal cancer (CC) patients. In addition, we extended the study to human HaCaT normal keratinocytes and SW480-ADH colon cancer cells co-cultured with SW480-ADH cells overexpressing the mouse Snai1 gene. Of 18 CC cases with SNAI1 expression in tumor tissue, five also had SNAI1 in normal adjacent tissue (NAT). Expression of SNAI1 in tumor tissue correlated with downregulation of CDH1 and VDR genes in both tumor (P ¼ 0.047 and P ¼ 0.014, respectively) and NAT lacking SNAI1 expression (P ¼ 0.054 and P ¼ 0.003). ZEB1 expression was directly related to VDR expression in tumor tissue (r ¼ 0.39; P ¼ 0.027) and inversely to CDH1 in NAT (r ¼ À0.46; P ¼ 0.010). CDH1 and VDR were also downregulated in SW480-ADH and MaCaT cells, respectively, when they were co-cultured with Snai1-expressing cells. Furthermore, cytokine analysis showed differences in the conditioned media obtained from the two cell types. These results indicate that histologically normal tissue adjacent to tumor tissue expressing the EMT-inducing gene SNAI1 shows alterations in the expression of epithelial differentiation genes such as CDH1 and VDR.

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Snail Induction of Epithelial to Mesenchymal Transition in Tumor Cells Is Accompanied by MUC1 Repression andZEB1 Expression

Cited by 429 publications

References 29 publications

Snail silencing effectively suppresses tumour growth and invasiveness

Snail silencing effectively suppresses tumour growth and invasiveness

Raf plus TGFβ-dependent EMT is initiated by endocytosis and lysosomal degradation of E-cadherin

SNAI1 expression in colon cancer related with CDH1 and VDR downregulation in normal adjacent tissue

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