A molecular role for lysyl oxidase-like 2 enzyme in Snail regulation and tumor progression

Peinado, Héctor; Cruz, Maria del Carmen Iglesias-de la; Olmeda, David; Csiszár, Katalin; Fong, Keith S. K.; Vega, Sonia; Nieto, M. Ángela; Cano, Amparo; Portillo, Francisco

doi:10.1038/sj.emboj.7600781

Cited by 406 publications

(469 citation statements)

References 33 publications

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“…Experiments using siRNA also demonstrated that TGF-␤ efficiently induced EMT markers in NMuMG cells transfected with Snail siRNA (Supplementary Figure 1, A-C). Snail has recently been reported to be activated during EMT through various mechanisms, including up-regulation by HMGA2, phosphorylation by GSK3␤, activation by lysyl oxidase-like 2, and induction of nuclear localization by zinc transporter LIV1 (Yamashita et al, 2004;Zhou et al, 2004;Peinado et al, 2005;Thuault et al, 2006). The present findings, however, suggest that Snail is not the primary mediator of TGF-␤-mediated EMT in NMuMG cells and that it may require other molecules to induce EMT in these cells.…”

Section: Snail Is Not Involved In the Repression Of E-cadherin Exprescontrasting

confidence: 52%

Differential Regulation of Epithelial and Mesenchymal Markers by δEF1 Proteins in Epithelial–Mesenchymal Transition Induced by TGF-β

Shirakihara

Saitoh

Miyazono

2007

MBoC

286

298

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Epithelial-mesenchymal transition (EMT), a crucial event in cancer progression and embryonic development, is induced by transforming growth factor (TGF)-␤ in mouse mammary NMuMG epithelial cells. Id proteins have previously been reported to inhibit major features of TGF-␤-induced EMT.In this study, we show that expression of the ␦EF1 family proteins, ␦EF1 (ZEB1) and SIP1, is gradually increased by TGF-␤ with expression profiles reciprocal to that of E-cadherin. SIP1 and ␦EF1 each dramatically down-regulated the transcription of E-cadherin in NMuMG cells through direct binding to the E-cadherin promoter. Silencing of the expression of both SIP1 and ␦EF1, but not either alone, completely abolished TGF-␤-induced E-cadherin repression. However, expression of mesenchymal markers, including fibronectin, N-cadherin, and vimentin, was not affected by knockdown of SIP1 and ␦EF1. TGF-␤-induced the expression of Ets1, which in turn activated ␦EF1 promoter activity. Moreover, up-regulation of SIP1 and ␦EF1 expression by TGF-␤ was suppressed by knockdown of Ets1 expression. In addition, Id2 suppressed the TGF-␤-and Ets1-induced up-regulation of ␦EF1. Taken together, these findings suggest that the ␦EF1 family proteins, SIP1 and ␦EF1, are necessary, but not sufficient, for TGF-␤-induced EMT and that Ets1 induced by TGF-␤ may function as an upstream transcriptional regulator of SIP1 and ␦EF1. INTRODUCTIONTransforming growth factor (TGF)-␤, a prototypical member of the TGF-␤ family, regulates a broad range of cellular responses, including cell proliferation, differentiation, adhesion, migration, and apoptosis (Bierie and Moses, 2006). TGF-␤ and related factors exhibit their pleiotropic effects through binding to transmembrane serine-threonine kinase receptors type I (T␤R-I) and type II (T␤R-II). On ligand-induced heteromeric complex formation between T␤R-I and T␤R-II, T␤R-I is phosphorylated and activated by T␤R-II kinase and mediates specific intracellular signaling through phosphorylation of receptor-regulated Smads (R-Smads). Phosphorylated R-Smads interact with coSmad (Smad4) and translocate into the nucleus, where they regulate transcription of target genes in cooperation with various transcription factors and transcriptional coactivators or corepressors (Miyazawa et al., 2002;Miyazono et al., 2003;Shi and Massague, 2003).TGF-␤ has potent antiproliferative effects on a wide variety of cells, including epithelial cells, endothelial cells, and hematopoietic cells, although under certain conditions it promotes the proliferation of mesenchymal cells, including fibroblasts, chondrocytes, and osteoblasts. TGF-␤ also induces the deposition of extracellular matrix proteins. In early stages of tumorigenesis, TGF-␤ inhibits the growth of epithelial cells, and insensitivity to this growth-inhibitory effect is associated with progression of tumors Derynck et al., 2001). Transgenic mice expressing a dominant-negative T␤R-II in epidermis exhibit malignant conversion of epithelial cells and promotion of tumor formation (Gorska et al., 20...

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Section: Snail Is Not Involved In the Repression Of E-cadherin Exprescontrasting

confidence: 52%

Differential Regulation of Epithelial and Mesenchymal Markers by δEF1 Proteins in Epithelial–Mesenchymal Transition Induced by TGF-β

Shirakihara

Saitoh

Miyazono

2007

MBoC

286

298

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“…Among all these genes, apoptosis was found to be the category, which composed of the highest number of differentially expressed genes (Figure 6a). The expression levels of four representative apoptosis-related genes, including mitogen-activated protein kinase kinase kinase 7 interacting protein (MAP3K7IP2), 24 lysyl oxidase-like 2 (LOXL2), 25 immunoglobulin heavy constant gamma 1 (IGHG1) 26 and Qk1, 27 were further validated by semiquantitative RT-PCR (Figure 6b and c). 28,29 Using this model, we showed that intratumoral injection of rAAV-hTERTC27 dramatically reduces the growth and tumorigenicity of the human glioblastoma U87-MG cells.…”

Section: Raav-htertc27 Treatment Induces Differential Expression Of Gmentioning

confidence: 99%

A novel glioblastoma cancer gene therapy using AAV-mediated long-term expression of human TERT C-terminal polypeptide

Gao

Chau

et al. 2007

Cancer Gene Ther

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Glioblastoma multiforme is the most aggressive form of human brain tumor, which has no effective cure. Previously, we have demonstrated that overexpression of the C-terminal fragment of the human telomerase reverse transcriptase (hTERTC27) inhibits the growth and tumorigenicity of human cervical cancer HeLa cells. In this study, the therapeutic effect and molecular mechanisms of hTERTC27-mediated cancer gene therapy were further explored in vivo in established human glioblastoma xenografts in nude mice. We showed that intratumoral injection of adeno-associated virus carrying hTERTC27 (rAAV-hTERTC27) is highly effective in reducing the growth of the subcutaneously transplanted glioblastoma tumors. Histological analyses showed that rAAV-hTERTC27 treatment leads to profound necrosis, apoptosis, infiltration of polymorphonuclear neutrophils and reduced microvessel density in the tumor samples. To study the molecular mechanism of rAAV-hTERTC27-mediated antitumor effects, we analyzed the global gene expression profiles of the rAAV-hTERTC27-treated tumor tissues and cell line as compared with that of the control rAAV-green fluorescent protein-treated samples by DNA microarray. Our results suggest that hTERTC27 exerts its effect through complex mechanisms, which involve genes regulating apoptosis, cell adhesion, cell cycle, immune responses, metabolism, signal transduction, transport, transcription and telomere maintenance.

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“…Generation of pcDNA3-Snail, Slug and Snail-EGFP expression vectors have been previously described (Cano et al, 2000;Bolos et al, 2003;Peinado et al, 2005). The generation of shRNA, containing specific oligonucleotide sequences against EGFP (22nt) (Caplen et al, 2001) or against mouse/human Snail (19nt: 5 0 -GATGCACATCCGAAGCCAC-3 0 ), cloned into the pSuperior-Puro vector (Oligoengine) has been recently described (Jorda et al, 2005).…”

Section: Generation Of Expression Vectors and Stable Cell Linesmentioning

confidence: 99%

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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A molecular role for lysyl oxidase-like 2 enzyme in Snail regulation and tumor progression

Cited by 406 publications

References 33 publications

Differential Regulation of Epithelial and Mesenchymal Markers by δEF1 Proteins in Epithelial–Mesenchymal Transition Induced by TGF-β

Differential Regulation of Epithelial and Mesenchymal Markers by δEF1 Proteins in Epithelial–Mesenchymal Transition Induced by TGF-β

A novel glioblastoma cancer gene therapy using AAV-mediated long-term expression of human TERT C-terminal polypeptide

Snail silencing effectively suppresses tumour growth and invasiveness

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