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CD97 amplifies LPA receptor signaling and promotes thyroid cancer progression in a mouse model

Oncogene volume 32, pages 2726–2738 (2013)Cite this article

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Abstract

CD97, a member of the adhesion family of G-protein-coupled receptors (GPCRs), complexes with and potentiates lysophosphatidic acid (LPA) receptor signaling to the downstream effector RHOA. We show here that CD97 was expressed in a majority of thyroid cancers but not normal thyroid epithelium and that the level of CD97 expression was further elevated with progression to poorly differentiated and undifferentiated carcinoma. Intratumoral progression also showed that CD97 expression correlates with invasiveness and dedifferentiation. To determine the functional role of CD97, we produced a transgenic model of thyroglobulin promoter-driven CD97 expression. Transgenic CD97 in combination with ThrbPV, an established mouse model of thyroid follicular cell carcinogenesis, significantly increased the occurrence of vascular invasion and lung metastasis. Expression of transgenic CD97 in thyroid epithelium led to elevated ERK phosphorylation and increased numbers of Ki67+ cells in developing tumors. In addition, tumor cell cultures derived from CD97 transgenic as compared with non-transgenic mice demonstrated enhanced, constitutive and LPA-stimulated ERK activation. In human thyroid cancer cell lines, CD97 depletion reduced RHO-GTP and decreased LPA-stimulated invasion but not EGF-stimulated invasion, further suggesting that CD97 influences an LPA-associated mechanism of progression. Consistent with the above, CD97 expression in human thyroid cancers correlated with LPA receptor and markers of aggressiveness including Ki67 and pAKT. This study shows an autonomous effect of CD97 on thyroid cancer progression and supports the investigation of this GPCR as a therapeutic target for these cancers.

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Acknowledgements

This work was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute and the Programa Ramón y Cajal—Ministerio de Ciencia e Innovación, Social EU Funds, Universidad de Valladolid, Spain. We acknowledge Barbara J Taylor, Subhadra Banerjee, William G Telford, and Veena Kapoor of the CCR FACS Core Facilities and Christopher D Heger of the CCR Antibody and Protein Purification Unit for their excellent technical support. We thank Drs Cameselle–Teijeiro, X Matías–Guiu, A Herrero and M Fresno–Forcelledo for providing human PDC and UC samples.

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  1. Y Ward and R Lake: These authors contributed equally to this work.

Authors and Affiliations

  1. Cell and Cancer Biology Branch, Center for Cancer Research, NCI, Bethesda, MD, USA

    Y Ward, R Lake, P L Martin & K Kelly

  2. Genetics Branch, Center for Cancer Research, NCI, Bethesda, MD, USA

    K Killian & P Meltzer

  3. Medical Oncology Branch, Center for Cancer Research, NCI, Bethesda, MD, USA

    P Salerno

  4. The Wistar Institute, Philadelphia, PA, USA

    T Wang

  5. Laboratory of Pathology, Center for Cancer Research, NCI, Bethesda, MD, USA

    M Merino

  6. Laboratory of Molecular Biology, Center for Cancer Research, NCI, Bethesda, MD, USA

    S-y Cheng

  7. Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita’ Federico II, Naples, Italy

    M Santoro

  8. Institute of Biology and Molecular Genetics, Valladolid University, Spanish Research Council, Valladolid, Spain

    G Garcia-Rostan

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  1. Y Ward
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Correspondence to K Kelly.

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Ward, Y., Lake, R., Martin, P. et al. CD97 amplifies LPA receptor signaling and promotes thyroid cancer progression in a mouse model. Oncogene 32, 2726–2738 (2013). https://doi.org/10.1038/onc.2012.301

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