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Onconeuronal cerebellar degeneration-related antigen, Cdr2, is strongly expressed in papillary renal cell carcinoma and leads to attenuated hypoxic response

Oncogene volume 28, pages 3274–3285 (2009)Cite this article

Abstract

The onconeuronal cerebellar degeneration-related antigen Cdr2 is associated with paraneoplastic syndromes. Neoplastic expression of Cdr2 in ovary and breast tumors triggers an autoimmune response that suppresses tumor growth by developing tumor immunity, but culminates in cerebellar degeneration when Cdr2-specific immune cells recognize neuronal Cdr2. We identified Cdr2 as a novel interactor of the hypoxia-inducible factor (HIF) prolyl-4-hydroxylase PHD1 and provide evidence that Cdr2 might represent a novel important tumor antigen in renal cancer. Strong Cdr2 protein expression was observed in 54.2% of papillary renal cell carcinoma (pRCC) compared with 7.8% of clear-cell RCC and no staining was observed in chromophobe RCC or oncocytoma. High Cdr2 protein levels correlated with attenuated HIF target gene expression in these solid tumors, and Cdr2 overexpression in tumor cell lines reduced HIF-dependent transcriptional regulation. This effect was because of both attenuation of hypoxic protein accumulation and suppression of the transactivation activity of HIF-1α. pRCC is known for its tendency to avascularity, usually associated with a lower pathological stage and higher survival rates. We provide evidence that Cdr2 protein strongly accumulates in pRCC, attenuates the HIF response to tumor hypoxia and may become of diagnostic importance as novel renal tumor marker.

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Acknowledgements

We would like to thank R Fischer and C Rüber (ETH Zürich, Switzerland) for the generation of monoclonal anti-Cdr2 antibodies, DM Katschinski (Georg August University Göttingen, Germany) for providing the custom-made mouse testis cDNA library, J Nesper (University of Konstanz, Germany) and MO Hottiger (University of Zürich, Switzerland) for help with the yeast two-hybrid screenings, DJ Peet (University of Adelaide, Australia) and N Sang (Thomas Jefferson University, PA, USA) for gifts of plasmids, P Carmeliet and M Schneider (Katholieke Universiteit Leuven and Flanders Institute for Biotechnology, Belgium) for Phd1−/− MEFs, I Flamme and F Oehme (Bayer HealthCare, Germany) for helpful discussions and P Spielmann, M Storz and S Behnke for excellent technical assistance. This work was supported by SNF 3100AO-116047/1 (RHW and GC), Sassella Stiftung (GC, KB and SB), Krebsliga des Kantons Zürich (GC), UZH University Research Priority Program ‘Integrative Human Physiology’ and the 6th Framework Programme of the European Commission EUROXY LSHCCT-2003-502932/SBF 03.0647-2 (RHW).

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  1. K Balamurugan

    Present address: 3Current address: Molecular Mechanisms in Development Group, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201, USA.,

  2. S Barth

    Present address: 4Current address: Ben May Department for Cancer Research, University of Chicago, Gordon Center for Integrative Sciences, Chicago, IL 60637, USA.,

Authors and Affiliations

  1. Institute of Physiology and Zürich Center for Integrative Human Physiology ZIHP, University of Zürich UZH, Zürich, Switzerland

    K Balamurugan, M R Kaufmann, V S Hofmann, S Barth, M R Bordoli, D P Stiehl, R H Wenger & G Camenisch

  2. Department of Pathology, Institute of Surgical Pathology, University Hospital Zürich, Zürich, Switzerland

    V-D Luu, G Boysen, H Moch & P Schraml

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Correspondence to G Camenisch.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Balamurugan, K., Luu, VD., Kaufmann, M. et al. Onconeuronal cerebellar degeneration-related antigen, Cdr2, is strongly expressed in papillary renal cell carcinoma and leads to attenuated hypoxic response. Oncogene 28, 3274–3285 (2009). https://doi.org/10.1038/onc.2009.186

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