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The PAX8/PPARγ fusion oncoprotein transforms immortalized human thyrocytes through a mechanism probably involving wild-type PPARγ inhibition

Oncogene volume 23, pages 3634–3641 (2004)Cite this article

Abstract

Follicular thyroid carcinoma (FTC) frequently harbors the PAX8/PPARγ fusion gene (PPFP); however, its oncogenic role and mechanism(s) of action remain undefined. We investigated PPFP's effects on cell growth, apoptosis, cell–cell, and cell–matrix interactions in immortalized human thyroid cells (Nthy-ori 3-1) and NIH 3T3 cells. PPFP expression increased the growth of transient and stable Nthy-ori transfectants (∼threefold by 72 h). There was an 8.4% increase of cells in the S+G2/M phase, a 7.8% decrease in cells in the G0+G1 phase and a 66% decline in apoptosis at 72 h. Stable Nthy-ori PPFP transfectants grew in soft agar, and PPFP-transfected NIH 3T3 cells exhibited efficient focus formation, suggesting loss of anchorage-dependent growth and contact inhibition, respectively. Overexpression of PPARγ in Nthy-ori cells did not recapitulate PPFP's growth effects. Treatment of Nthy-ori cells with an irreversible PPARγ inhibitor mimicked the growth-promoting effects of PPFP and co-expression of PPFP and PPARγ blocked PPARγ transactivation activity. Our data provide functional evidence that PPFP acts as an oncoprotein, whose transforming properties depend in part on inhibition of PPARγ. Our data suggest that PPFP contributes to malignant transformation during FTC oncogenesis by acting on several cellular pathways, at least some of which are normally regulated by PPARγ.

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Acknowledgements

We thank Drs Nita Maihle and Raul Urrutia for assistance with the soft agar colony assays and NIH 3T3 cell focus assays, respectively. This work was supported by NIH grant CA80117 (NLE), the Mayo Foundation, and the Endocrine Society 2002 Abbott Thyroid Research Clinical Mentor Award (BM) and the Abbott Thyroid Research Clinical Fellowship Award (JGP).

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Authors and Affiliations

  1. Department of Medicine, Division of Endocrinology, Mayo Clinic, Rochester, 55906, MN, USA

    J Gregory Powell, Brandon L Allard, Ian D Hay, Henry J Hiddinga, Stefan KG Grebe, Norman L Eberhardt & Bryan McIver

  2. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, 55906, MN, USA

    Xiying Wang & Stefan KG Grebe

  3. Endocrinology Department, Ankara University Medical School, Ankara, Turkey

    Mustafa Sahin

  4. Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, 55906, MN, USA

    Xiao-Li Wang

  5. Departments of Pathology and Laboratory Medicine and Hematology and Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, 30322, GA, USA

    Seema S Deshpande & Todd G Kroll

  6. Department of Biochemistry & Molecular Biology, Mayo Clinic, Rochester, 55906, MN, USA

    Norman L Eberhardt

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  1. J Gregory Powell
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Correspondence to Norman L Eberhardt.

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Gregory Powell, J., Wang, X., Allard, B. et al. The PAX8/PPARγ fusion oncoprotein transforms immortalized human thyrocytes through a mechanism probably involving wild-type PPARγ inhibition. Oncogene 23, 3634–3641 (2004). https://doi.org/10.1038/sj.onc.1207399

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