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Alternative splicing of the ErbB-4 cytoplasmic domain and its regulation by hedgehog signaling identify distinct medulloblastoma subsets

Oncogene volume 25, pages 7267–7273 (2006)Cite this article

Abstract

Medulloblastoma (MB) results from aberrant development of cerebellar neurons in which altered hedgehog (Hh) signalling plays a major role. We investigated the possible influence of Hh signalling on ErbB-receptor expression in MB, in particular that of the ErbB-4 CYT-1 and CYT-2 isoforms generated by alternative splicing of the cytoplasmic domain. ErbB-4 expression was downregulated in Hh-induced MBs from Patched-1+/− mice. Hh signalling (reflected by enhanced expression of the Gli1 transcription factor) inhibited ErbB-4 expression in mouse cerebellar granule progenitors and human MB cells. Analysis of 26 human primary MBs revealed a subset of 11 tumors characterized by low Gli1 levels, upregulated ErbB-4 expression and increased CYT-1:CYT-2 ratios. Interestingly, CYT-1 and Gli1 levels were inversely correlated. ErbB-4 CYT-1 and CYT-2 had different phenotypic effects in cultured MB cells: in response to neuregulin treatment, CYT-2 overexpression inhibited proliferation whereas CYT-1, which includes a phosphatidylinositol 3-kinase (PI3K)-binding site that is missing in CYT-2, enhanced resistance to starvation- and etoposide-induced apoptosis by activating PI3K/Akt signalling. CYT-1:CYT-2 ratios displayed correlation with tumor histotype and ErbB-2 levels, which are established prognostic indices for MB. These findings demonstrate that low-level Hh signalling in human MB is associated with the selective maintenance of high ErbB-4 CYT-1 expression, an alteration that exerts tumor-promoting effects.

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Acknowledgements

This work was partially supported by Associazione Italiana per la Ricerca sul Cancro, Telethon Grant GGP04168, the National Research Council, the Ministry of University and Research, the Ministry of Health and Center of Excellence for Biology and Molecular Medicine (BEMM). E De Smaele was supported by a FIRC fellowship. We thank M Kent for editorial assistance and M Levrero for critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Experimental Medicine and Pathology, University La Sapienza, Roma, Italy

    E Ferretti, L Di Marcotullio, T Mattei, A Greco, A Po, E De Smaele, F Giangaspero, M Maroder, M Alimandi, I Screpanti & A Gulino

  2. Division of Neuropathology, National Neurological Institute ‘C. Besta’, Milano, Italy

    M Gessi

  3. Neuromed Institute, Pozzilli, Isernia, Italy

    F Giangaspero & A Gulino

  4. Department of Pediatrics, Catholic University, Rome, Italy

    R Riccardi

  5. Neurosurgery Institute, Catholic University, Rome, Italy

    C Di Rocco

  6. Biotechnology Unit, ENEA-CR Casaccia, Roma, Italy

    S Pazzaglia

  7. Pasteur Institute, Cenci Bolognetti Foundation, Roma, Italy

    I Screpanti

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  1. E Ferretti
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Correspondence to A Gulino.

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Ferretti, E., Di Marcotullio, L., Gessi, M. et al. Alternative splicing of the ErbB-4 cytoplasmic domain and its regulation by hedgehog signaling identify distinct medulloblastoma subsets. Oncogene 25, 7267–7273 (2006). https://doi.org/10.1038/sj.onc.1209716

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