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Lymphoma

GAPDH enhances the aggressiveness and the vascularization of non-Hodgkin’s B lymphomas via NF-κB-dependent induction of HIF-1α

Leukemia volume 29, pages 1163–1176 (2015)Cite this article

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Abstract

Deregulated expression of glycolytic enzymes contributes not only to the increased energy demands of transformed cells but also has non-glycolytic roles in tumors. However, the contribution of these non-glycolytic functions in tumor progression remains poorly defined. Here, we show that elevated expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), but not of other glycolytic enzymes tested, increased aggressiveness and vascularization of non-Hodgkin’s lymphoma. Elevated GAPDH expression was found to promote nuclear factor-κB (NF-κB) activation via binding to tumor necrosis factor receptor-associated factor-2 (TRAF2), enhancing the transcription and the activity of hypoxia-inducing factor-1α (HIF-1α). Consistent with this, inactive mutants of GAPDH failed to bind TRAF2, enhance HIF-1 activity or promote lymphomagenesis. Furthermore, elevated expression of gapdh mRNA in biopsies from diffuse large B-cell non-Hodgkin’s lymphoma patients correlated with high levels of hif-1α, vegf-a, nfkbia mRNA and CD31 staining. Collectively, these data indicate that deregulated GAPDH expression promotes NF-κB-dependent induction of HIF-1α and has a key role in lymphoma vascularization and aggressiveness.

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Acknowledgements

We gratefully acknowledge the Centre Méditerranéen de Médecine Moléculaire animal and microscopy facilities. We thank Drs Tanti JF, Cormont M and Giorgetti-Peraldi S for the hypoxic chamber, Larbret F for cell sorting, Dr Pouysségur J for HIF-1α antibody, Escoubas C, Paquet A and Barbry P for their help. Acknowledgement to the Tumorothèque of Hopital Saint-Louis for the preparation of the tumoral samples of the patients. This work was supported by the Fondation ARC (Association pour la Recherche sur le Cancer), the Agence Nationale de la Recherche (ANR-09-JCJC-0003, LABEX SIGNALIFE ANR-11-LABX-0028-01), by la Fondation de France, the Centre Scientifique de Monaco and the Cancéropole PACA. JC was supported by the Fondation ARC and by la Fondation de France. LM was supported by Fondation pour la Recherche Medicale (FRM) and la Ville de Nice.

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Authors and Affiliations

  1. Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe ‘contrôle métabolique des morts cellulaires’, équipe 3, Nice, France

    J Chiche, S Pommier, M Beneteau, L Mondragón, O Meynet, B Zunino, A Mouchotte, E Verhoeyen, M Carles & J-E Ricci

  2. Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France

    J Chiche, S Pommier, M Beneteau, L Mondragón, O Meynet, B Zunino, A Mouchotte, E Verhoeyen, M Guyot, G Pagès, V Imbert, P Colosetti, D Goncalvès, S Marchetti, M Carles & J-E Ricci

  3. Département d’Anesthésie Réanimation, Centre Hospitalier Universitaire de Nice, Nice, France

    S Pommier, M Carles & J-E Ricci

  4. Institute for Research on Cancer and Aging, CNRS UMR 7284/U INSERM 1081, Centre A. Lacassagne, Nice, France

    M Guyot & G Pagès

  5. Département d’Onco-Hématologie, Centre Hospitalier Universitaire de Nice, Nice, France

    N Mounier

  6. Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe ‘inflammation, cancer et cellules souches cancéreuses’, Nice, France

    V Imbert

  7. Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe ‘mort cellulaire, différenciation, inflammation et cancer’, Nice, France

    P Colosetti, D Goncalvès & S Marchetti

  8. AP-HP-Hôpital Saint-Louis, Service d’hémato-Oncologie, Université Paris Diderot, Sorbonne Paris Cité, F-75010, Paris, France

    J Brière & C Thieblemont

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Correspondence to J-E Ricci.

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Chiche, J., Pommier, S., Beneteau, M. et al. GAPDH enhances the aggressiveness and the vascularization of non-Hodgkin’s B lymphomas via NF-κB-dependent induction of HIF-1α. Leukemia 29, 1163–1176 (2015). https://doi.org/10.1038/leu.2014.324

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