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Human KIT ligand promoter is positively regulated by HMGA1 in breast and ovarian cancer cells

Oncogene volume 23, pages 8557–8562 (2004)Cite this article

Abstract

KIT ligand (KL) and its receptor, c-kit, are coexpressed in many types of cancer cells and have been implicated in tumor growth and angiogenesis. While Sertoli cell-specific regulation of the KL promoter has been well characterized, regulation in cancer cells remains to be elucidated. We recently reported microarray results demonstrating that increased high-mobility group (HMG) A1a protein expression correlates with increased KL transcription in MCF-7 human breast cancer cells. Sequence analysis indicates a potential for multiple HMGA1 binding sites within the human KL promoter. In order to better define the underlying molecular mechanisms that HMGA1 uses to facilitate malignant transformation of cancer cells, we have used a variety of methods to determine whether HMGA1a directly regulates the human KL promoter in breast and ovarian cancer cells. Our results indicate that: (i) KL promoter activity is significantly higher in MCF-7 cells overexpressing HMGA1a; (ii) HMGA1a protein binds to AT-rich regions of the KL promoter DNA both in vitro and in vivo; (iii) mutation of the AT-rich regions inhibits HMGA1a binding in vitro; and (iv) HMGA1a-specific inhibition significantly decreases transcription of KL in OCC1 human ovarian cancer cells. In addition, MCF-7 cells with transgenic HMGA1 overexpression stained positive for the KL protein by immunocytochemistry and immunohistochemistry, and were growth-inhibited by KL neutralization. The cumulative evidence indicates that HMGA1 positively regulates the human KL promoter in breast and ovarian cancer cells and implicates serum KL as a diagnostic marker for HMGA1-positive carcinomas.

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Acknowledgements

This work was supported, in part, by NIH Grant GM-46352 and WSU Cancer Research Development Fund Grant 17A-0165 (both to RR), by NIH Grant T-32 GM008336 for predoctoral training in biotechnology (to NRT), and by the WSU Laboratory for Biotechnology and Bioanalysis I. We thank Derek Pouchnik, Dale Edberg, Jaideep Chaudhary, and Tera Muir.

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  1. Nathan R Treff

    Present address: Department of Surgery, University of Wisconsin-Madison School of Medicine, 600 Highland Ave., Madison, WI, 53792, USA

Authors and Affiliations

  1. School of Molecular Biosciences, Washington State University, PO Box 644660, Pullman, 99164-4660, WA, USA

    Nathan R Treff, Gregory A Dement, Jennifer E Adair, Rachel L Britt, Rong Nie, James E Shima & Raymond Reeves

  2. Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R Drew University of Medicine and Science, Los Angeles, 90059, CA, USA

    Wayne E Taylor

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Correspondence to Raymond Reeves.

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Treff, N., Dement, G., Adair, J. et al. Human KIT ligand promoter is positively regulated by HMGA1 in breast and ovarian cancer cells. Oncogene 23, 8557–8562 (2004). https://doi.org/10.1038/sj.onc.1207926

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