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Prohibitin promotes dedifferentiation and is a potential therapeutic target in neuroblastoma
Ian C. MacArthur, … , Alex Kentsis, Anton G. Henssen
Ian C. MacArthur, … , Alex Kentsis, Anton G. Henssen
Published April 18, 2019
Citation Information: JCI Insight. 2019;4(10):e127130. https://doi.org/10.1172/jci.insight.127130.
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Research Article Genetics Oncology

Prohibitin promotes dedifferentiation and is a potential therapeutic target in neuroblastoma

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Abstract

Gain of the long arm of chromosome 17 (17q) is a cytogenetic hallmark of high-risk neuroblastoma, yet its contribution to neuroblastoma pathogenesis remains incompletely understood. Combining whole-genome and RNA sequencing of neuroblastomas, we identified the prohibitin (PHB) gene as highly expressed in tumors with 17q gain. High PHB expression correlated with poor prognosis and was associated with loss of gene expression programs promoting neuronal development and differentiation. PHB depletion induced differentiation and apoptosis and slowed cell cycle progression of neuroblastoma cells, at least in part through impaired ERK1/2 activation. Conversely, ectopic expression of PHB was sufficient to increase proliferation of neuroblastoma cells and was associated with suppression of markers associated with neuronal differentiation and favorable neuroblastoma outcome. Thus, PHB is a 17q oncogene in neuroblastoma that promotes tumor cell proliferation and dedifferentiation.

Authors

Ian C. MacArthur, Yi Bei, Heathcliff Dorado Garcia, Michael V. Ortiz, Joern Toedling, Filippos Klironomos, Jana Rolff, Angelika Eggert, Johannes H. Schulte, Alex Kentsis, Anton G. Henssen

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Figure 7

RocA treatment impairs ERK activation in an ALK-mutant, patient-derived xenograft in vivo.

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RocA treatment impairs ERK activation in an ALK-mutant, patient-derived ...
(A) Heatmaps showing excess over Bliss synergy scores for combination treatment with RocA and trametinib in neuroblastoma cells. Values greater than 1 (shown in red) denote synergistic combinations while values less than 1 (shown in green) denote antagonistic combinations. Data represent 3 technical triplicates. (B) Dosing schedule of RocA, trametinib, and vehicle controls for patient-derived xenograft treatment. (C) Western blot analysis of patient-derived xenografts of mice treated with RocA, trametinib, or RocA and trametinib combination treatment compared with vehicle control–treated mice.

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