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HAND1 gene expression is negatively regulated by the High Mobility Group A1 proteins and is drastically reduced in human thyroid carcinomas

Oncogene volume 28, pages 876–885 (2009)Cite this article

A Corrigendum to this article was published on 27 June 2016

Abstract

HMGA1 proteins exert their major physiological function during embryonic development and play a critical role in neoplastic transformation. Here, we show that Hand1 gene, which codes for a transcription factor crucial for differentiation of trophoblast giant cells and heart development, is upregulated in hmga1 minus embryonic stem cells. We demonstrate that HMGA1 proteins bind directly to Hand1 promoter both in vitro and in vivo and inhibit Hand1 promoter activity. We have also investigated HAND1 expression in human thyroid carcinoma cell lines and tissues, in which HMGA proteins are overexpressed, with respect to normal thyroid; an inverse correlation between HMGA1 and HAND1 expression was found in all thyroid tumor histotypes. A correlation between HAND1 gene repression and promoter hypermethylation was found in anaplastic carcinomas but not in other thyroid tumor histotypes. Therefore, we can hypothesize that HMGA1 overexpression plays a key role on HAND1 silencing in differentiated thyroid carcinomas and that promoter hypermethylation occurs in later stages of thyroid tumor progression. Finally, the restoration of the HAND1 gene expression reduces the clonogenic ability of two human thyroid carcinoma-derived cell lines, suggesting that HAND1 downregulation may have a role in the process of thyroid carcinogenesis.

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References

  • Baldassarre G, Fedele M, Battista S . (2001). Onset of natural killer cell lymphomas in transgenic mice carrying a truncated HMGI-C gene by the chronic stimulation of the IL-2 and IL-15 pathway. Proc Natl Acad Sci USA 98: 7970–7975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Battista S, Pentimalli F, Baldassarre G, Fedele M, Fidanza V, Croce CM et al. (2003). Loss of Hmga1 gene function affects embryonic stem cell lympho-hematopoietic differentiation. FASEB J 17: 1496–1498.

    Article  CAS  PubMed  Google Scholar 

  • Berlingieri MT, Pierantoni GM, Giancotti V, Santoro M, Fusco A . (2002). Thyroid cell transformation requires the expression of the HMGA1 proteins. Oncogene 21: 2971–2980.

    Article  CAS  PubMed  Google Scholar 

  • Chiappetta G, Avantaggiato V, Visconti R, Fedele M, Battista S, Trapasso F et al. (1996). High level expression of the HMGI (Y) gene during embryonic development. Oncogene 5: 2439–2446.

    Google Scholar 

  • Cross JC, Flannery ML, Blanar MA, Steingrimsson E, Jenkins NA, Copeland NG et al. (1995). Hxt encodes a basic helix-loop-helix transcription factor that regulates trophoblast cell development. Development 121: 2513–2523.

    CAS  PubMed  Google Scholar 

  • Cserjesi P, Brown D, Lyons GE, Olson EN . (1995). Expression of the novel basic helix-loop-helix gene eHAND in neural crest derivatives and extraembryonic membranes during mouse development. Dev Biol 170: 664–678.

    Article  CAS  PubMed  Google Scholar 

  • Donato G, Martinez Hoyos J, Amorosi A, Maltese L, Lavano A, Volpentesta G et al. (2004). High mobility group A1 expression correlates with the histological grade of human glial tumors. Oncol Rep 6: 1209–1213.

    Google Scholar 

  • Fedele M, Battista S, Manfioletti G, Croce CM, Giancotti V, Fusco A . (2001). Role of the high mobility group A proteins in human lipomas. Carcinogenesis 22: 1583–1591.

    Article  CAS  PubMed  Google Scholar 

  • Fedele M, Fidanza V, Battista S, Pentimalli F, Klein-Szanto AJ, Visone R et al. (2006). Haploinsufficiency of the Hmga1 gene causes cardiac hypertrophy and myelo-lymphoproliferative disorders in mice. Cancer Res 66: 2536–2543.

    Article  CAS  PubMed  Google Scholar 

  • Fusco A, Fedele M . (2007). Roles of the HMGA proteins in cancer. Nat Rev Cancer 7: 899–910.

    Article  CAS  PubMed  Google Scholar 

  • Hagihara A, Miyamoto K, Furuta J, Hiraoka N, Wakazono K, Seki S et al. (2004). Identification of 27 5′ CpG islands aberrantly methylated and 13 genes silenced in human pancreatic cancers. Oncogene 23: 8705–8710.

    Article  CAS  PubMed  Google Scholar 

  • Kaneda A, Kaminishi M, Yanagihara K, Sugimura T, Ushijima T . (2002). Identification of silencing of nine genes in human gastric cancers. Cancer Res 62: 6645–6650.

    PubMed  Google Scholar 

  • Knofler M, Meinhardt G, Bauer S, Loregger T, Vasicek R, Bloor DJ et al. (2002). Human Hand1 basic helix-loop-helix (bHLH) protein: extra-embryonic expression pattern, interaction partners and identification of its transcriptional repressor domains. Biochem J 361: 641–651.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kondo T, Ezzat S, Asa S . (2006). Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nature Rev Cancer 6: 292–306.

    Article  CAS  Google Scholar 

  • Martinez Hoyos J, Fedele M, Battista S, Pentimalli F, Kruhoffer M, Arra C et al. (2004). Identification of the genes up- and down-regulated by the high mobility group A1 (HMGA1) proteins: tissue specificity of the HMGA1-dependent gene regulation. Cancer Res 64: 5728–5735.

    Article  PubMed  Google Scholar 

  • Pallante P, Berlingieri MT, Troncone G . (2005). UbcH10 overexpression may represent a marker of anaplastic thyroid carcinomas. Br J Cancer 93: 464–471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reeves R . (2001). Molecular biology of HMGA proteins: hubs of nuclear function. Gene 277: 63–81.

    Article  CAS  PubMed  Google Scholar 

  • Riley P, Anson-Cartwright L, Cross JC . (1998). The Hand1 bHLH transcription factor is essential for placentation and cardiac morphogenesis. Nat Genet 18: 271–275.

    Article  CAS  PubMed  Google Scholar 

  • Ritter O, Haase H, Schulte HD, Lange PE, Morano I . (1999). Remodeling of the hypertrophied human myocardium by cardiac bHLH transcription factors. J Cell Biochem 74: 551–561.

    Article  CAS  PubMed  Google Scholar 

  • Takada T, Yagi Y, Maekita T, Imura M, Nakagawa S, Tsao SW et al. (2004). Methylation-associated silencing of the Wnt antagonist SFRP1 gene in human ovarian cancers. Cancer Sci 95: 741–744.

    Article  CAS  PubMed  Google Scholar 

  • Thanos D, Maniatis T . (1995). Virus induction of human IFN β gene expression requires the assembly of an enhanceosome. Cell 83: 1091–1100.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from the Associazione Italiana Ricerca sul Cancro (AIRC), and the Ministero dell’Università e della Ricerca Scientifica e Tecnologica (MIUR). This work was supported from NOGEC-Naples Oncogenomic Center. We thank the Associazione Partenopea per le Ricerche Oncologiche (APRO) for its support. We thank Gabriella Sole, INN-CNR of Cagliari, for statistical analysis.

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Authors and Affiliations

  1. Dipartimento di Biologia e Patologia Cellulare e Molecolare e/o Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Facoltà di Medicina e Chirurgia di Napoli, Università degli Studi di Napoli ‘Federico II’, Naples, Italy

    J Martinez Hoyos, S Keller, I De Martino, M Fedele, F Esposito, L Chiariotti & A Fusco

  2. NOGEC (Naples Oncogenomic Center), CEINGE Biotecnologie Avanzate, Naples, Italy

    J Martinez Hoyos, A Ferraro, S Sacchetti, S Keller, I De Martino, E Borbone, P Pallante, D Montanaro, L Chiariotti & A Fusco

  3. Department of Cell and Molecular Biology, Tulane University, New Orleans, LA, USA

    P Cserjesi

  4. Dipartimento di Anatomia Patologica e Citopatologia, Facoltà di Medicina e Chirurgia, Università di Napoli ‘Federico II’, Naples, Italy

    G Troncone

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  1. J Martinez Hoyos
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  14. A Fusco
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Correspondence to A Fusco.

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Hoyos, J., Ferraro, A., Sacchetti, S. et al. HAND1 gene expression is negatively regulated by the High Mobility Group A1 proteins and is drastically reduced in human thyroid carcinomas. Oncogene 28, 876–885 (2009). https://doi.org/10.1038/onc.2008.438

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