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

Ludwig Institute for Cancer Research, Box 595 Biomedical Center, Uppsala University, SE-751 24 Uppsala, Sweden.
Journal of Biological Chemistry (Impact Factor: 4.6). 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: HMGA2, the High Mobility Group A2 gene, plays a very important role in fetal development and carcinogenesis. As an oncofetal gene, it is upregulated in tumors of both epithelial and mesenchymal tissue origin. Chromosomal translocations of HMGA2 are common in mesenchymal tumors, whereas the regulatory mechanisms of HMGA2 in malignant epithelial tumors are much more complex. As an architectural transcription factor, it is involved in multiple biological pathways by targeting different downstream genes in different cancers. HMGA2 is upregulated in both the early and late stages of high-grade serous ovarian carcinoma (HGSOC) and, according to The Cancer Genomic Atlas, is among a signature of genes overexpressed in ovarian cancer. Recent identification of miR-182 as a mediator of BRCA1 and HMGA2 deregulation in ovarian cancer cells may guide us toward a better understanding of the roles of HMGA2 in ovarian carcinogenesis. In this article, we will review recent developments and findings related to HMGA2, including its regulation, oncogenic properties, major functional pathways associated with the tumorigenesis of HGSOC, and its potential role as a biomarker for clinical application.
    Journal of Molecular Medicine 05/2013; 91(10). DOI:10.1007/s00109-013-1055-8 · 4.74 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Transforming growth factor-β (TGFβ) suppresses tumor formation since it inhibits cell growth and promotes apoptosis. However, in advanced cancers TGFβ elicits tumor promoting effects through its ability to induce epithelial-mesenchymal transition (EMT) which enhances invasiveness and metastasis; in addition, TGFβ exerts tumor promoting effects on non-malignant cells of the tumor, including suppression of immune surveillance and stimulation of angiogenesis. TGFβ promotes EMT by transcriptional and posttranscriptional regulation of a group of transcription factors that suppresses epithelial features, such as expression of components of cell junctions and polarity complexes, and enhances mesenchymal features, such as production of matrix molecules and several cytokines and growth factors that stimulate cell migration. The EMT program has certain similarities with the stem cell program. Inducers and effectors of EMT are interesting targets for the development of improved diagnosis, prognosis and therapy of cancer.
    FEBS letters 02/2012; 586(14):1959-70. DOI:10.1016/j.febslet.2012.02.037 · 3.34 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Parathyroid hormone-related protein (PTHrP) acts on the mammary mesenchyme and is required for proper embryonic mammary development. In order to understand PTHrP's effects on mesenchymal cells, we profiled gene expression in WT and PTHrP(-/-) mammary buds, and in WT and K14-PTHrP ventral skin at E15.5. By cross-referencing the differences in gene expression between these groups, we identified 35 genes potentially regulated by PTHrP in the mammary mesenchyme, including 6 genes known to be involved in BMP signaling. One of these genes was MMP2. We demonstrated that PTHrP and BMP4 regulate MMP2 gene expression and MMP2 activity in mesenchymal cells. Using mammary bud cultures, we demonstrated that MMP2 acts downstream of PTHrP to stimulate ductal outgrowth. Future studies on the functional role of other genes on this list should expand our knowledge of how PTHrP signaling triggers the onset of ductal outgrowth from the embryonic mammary buds.
    Developmental Dynamics 11/2009; 238(11):2713-24. DOI:10.1002/dvdy.22097 · 2.67 Impact Factor

E-Jean Tan