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HMGA2 and Smads co-regulate SNAIL1 expression during induction of epithelial-to-mesenchymal transition. J Biol Chem

Ludwig Institute for Cancer Research, Box 595 Biomedical Center, Uppsala University, SE-751 24 Uppsala, Sweden.
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2008; 283(48):33437-46. DOI: 10.1074/jbc.M802016200
Source: PubMed

ABSTRACT Epithelial-mesenchymal transition (EMT) is important during embryonic cell layer movement and tumor cell invasiveness. EMT converts adherent epithelial cells to motile mesenchymal cells, favoring metastasis in the context of cancer progression. Transforming growth factor-beta (TGF-beta) triggers EMT via intracellular Smad transducers and other signaling proteins. We previously reported that the high mobility group A2 (HMGA2) gene is required for TGF-beta to elicit EMT in mammary epithelial cells. In the present study we investigated the molecular mechanisms by which HMGA2 induces EMT. We found that HMGA2 regulates expression of many important repressors of E-cadherin. Among these, we analyzed in detail the zinc-finger transcription factor SNAIL1, which plays key roles in tumor progression and EMT. We demonstrate that HMGA2 directly binds to the SNAIL1 promoter and acts as a transcriptional regulator of SNAIL1 expression. Furthermore, we observed that HMGA2 cooperates with the TGF-beta/Smad pathway in regulating SNAIL1 gene expression. The mechanism behind this cooperation involves physical interaction between these factors, leading to an increased binding of Smads to the SNAIL1 promoter. SNAIL1 seems to play the role of a master effector downstream of HMGA2 for induction of EMT, as SNAIL1 knock-down partially reverts HMGA2-induced loss of epithelial differentiation. The data propose that HMGA2 acts in a gene-specific manner to orchestrate the transcriptional network necessary for the EMT program.

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    • "The so-called EMT transcription factors (EMT-TFs) are zinc finger proteins, such as the transcriptional repressors Snail (SNAI1) [25] [26] and Slug (SNAI2) [27] [28]; zinc finger and homeobox domain proteins, such as δEF1/ZEB1 [29] and SIP1/ZEB2 [30]; basic helix–loop–helix (bHLH) proteins such as E47 [31] and Twist1 [32] transcription factors. In addition, the chromatin protein high-mobility group A2 (HMGA2) integrates EMT signals downstream of TGFβ in breast cancer cell lines, and coordinates the transcriptional induction of Snail, Slug, Twist1 and the repression of the inhibitor of differentiation ID2 [33] [34] [35]. The molecular networks that coordinate the expression and function of the EMT-TFs in breast cancer are being understood at increasingly deeper levels [36], and specific examples will be listed below under the action of TGFβ. "
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    ABSTRACT: Background The progression of cancer through stages that guide a benign hyperplastic epithelial tissue towards a fully malignant and metastatic carcinoma, is driven by genetic and microenvironmental factors that remodel the tissue architecture. The concept of epithelial-mesenchymal transition (EMT) has evolved to emphasize the importance of plastic changes in tissue architecture, and the cross-communication of tumor cells with various cells in the stroma and with specific molecules in the extracellular matrix (ECM). Scope of the review Among the multitude of ECM-embedded cytokines and the regulatory potential of ECM molecules, this article focuses on the cytokine transforming growth factor β (TGFβ) and the glycosaminoglycan hyaluronan, and their roles in cancer biology and EMT. For brevity, we concentrate our effort on breast cancer. Major conclusions Both normal and abnormal TGFβ signaling can be detected in carcinoma and stromal cells, and TGFβ-induced EMT requires the expression of hyaluronan synthase 2 (HAS2). Correspondingly, hyaluronan is a major constituent of tumor ECM and aberrant levels of both hyaluronan and TGFβ are thought to promote a wounding reaction to the local tissue homeostasis. The link between EMT and metastasis also involves the mesenchymal-epithelial transition (MET). ECM components, signaling networks, regulatory non-coding RNAs and epigenetic mechanisms form the network of regulation during EMT-MET. General significance Understanding the mechanism that control epithelial plasticity in the mammary gland promises the development of valuable biomarkers for the prognosis of breast cancer progression and even provides new ideas for a more integrative therapeutic approach against disease. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.
    Biochimica et Biophysica Acta (BBA) - General Subjects 08/2014; 1840(8). DOI:10.1016/j.bbagen.2014.02.004 · 3.83 Impact Factor
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    • "Grivennikov et al. (2009) have confirmed that IL-6 can augment the malignant transformation of colon epithelial cells through intracellular TGF-β signaling pathway, and IL-10 could lead to the same transformation through the same signaling pathway after the activation of STAT3 (Hoentjen et al., 2005). Except that, TGF-β also can induce the expression of transcriptional factors and transcriptional regulators in EMT such as δEF1, SIP1, Snail, thus Thuault and his colleagues concluded that TGF-β could contribute to the occurrence of EMT in colonic epithelium (Thuault et al., 2008). It is known that TNF-α is one of the most important inflammatory factors in the pathogenesis of IBD, and also plays critical role in colitis-associated colorectal cancer (CAC). "
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    ABSTRACT: Epithelial-to-mesenchymal transition (EMT) is a collection of events that allows the conversion of adherent epithelial cells, tightly bound to each other within an organized tissue, into independent fibroblastic cells possessing migratory properties and the ability to invade the extracellular matrix. EMT contributes to the complex architecture of the embryo by permitting the progression of embryogenesis from a simple single-cell layer epithelium to a complex three-dimensional organism composed of both epithelial and mesenchymal cells. However, in most tissues EMT is a developmentally restricted process and fully differentiated epithelia typically maintain their epithelial phenotype. Recently, elements of EMT, specially the loss of epithelial markers and the gain of mesenchymal markers, have been observed in pathological states, including epithelial cancers. Increasing evidence has confirmed its presence in human colon during colorectal carcinogenesis. In general, chronic inflammation is considered to be one of the causes of many human cancers including colorectal cancer(CRC). Accordingly, epidemiologic and clinical studies indicate that patients affected by ulcerative colitis and Crohn's disease, the two major forms of inflammatory bowel disease, have an increased risk of developing CRC. A large body of evidence supports roles for the SMAD/STAT3 signaling pathway, the NF-kB pathway, the Ras-mitogen- activated protein kinase/Snail/Slug and microRNAs in the development of colorectal cancers via epithelial-to- mesenchymal transition. Thus, EMT appears to be closely involved in the pathogenesis of colorectal cancer, and analysis refered to it can yield novel targets for therapy.
    Asian Pacific journal of cancer prevention: APJCP 05/2013; 14(5):2689-2698. DOI:10.7314/APJCP.2013.14.5.2689 · 2.51 Impact Factor
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    • "Function Target gene Expression References Promoting EMT Twist Upregulation Tan et al. 2012 Twist, HDAC6, CD44 Upregulation Zha et al. 2012 SOX7, AXIN1 Downregulation Zha et al. 2012 LUM, POSTN, ID1 Downregulation Wu et al., 2011 STC2 Upregulation Wu et al., 2011 Snail Upregulation Thuault et al. 2008 Watanabe et al. 2009 Promoting proliferation PIT1 Upregulation Palmieri et al. 2012 CCNB2 Upregulation De Martino et al. 2009 Mia/Cd-rap Downregulation De Martino et al. 2007 E2F1 Upregulation Fedele et al. 2006 cyclin A Upregulation Tessari et al. 2003 "
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    Journal of Molecular Medicine 05/2013; 91(10). DOI:10.1007/s00109-013-1055-8 · 4.74 Impact Factor
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E-Jean Tan