Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/118254
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Type: | Journal article |
Title: | Transcriptome profiling of caspase-2 deficient EµMyc and Th-MYCN mouse tumors identifies distinct putative roles for caspase-2 in neuronal differentiation and immune signaling |
Other Titles: | Transcriptome profiling of caspase-2 deficient EmuMyc and Th-MYCN mouse tumors identifies distinct putative roles for caspase-2 in neuronal differentiation and immune signaling |
Author: | Dorstyn, L. Hackett-Jones, E. Nikolic, A. Norris, M.D. Lim, Y. Toubia, J. Haber, M. Kumar, S. |
Citation: | Cell Death and Disease, 2019; 10(2):56-1-56-16 |
Publisher: | Springer Nature |
Issue Date: | 2019 |
ISSN: | 2041-4889 2041-4889 |
Statement of Responsibility: | Loretta Dorstyn, Emily Hackett-Jones, Andrej Nikolic, Murray D. Norris, Yoon Lim, John Toubia, Michelle Haber, and Sharad Kumar |
Abstract: | Caspase-2 is a highly conserved cysteine protease with roles in apoptosis and tumor suppression. Our recent findings have also demonstrated that the tumor suppression function of caspase-2 is context specific. In particular, while caspase-2 deficiency augments lymphoma development in the EμMyc mouse model, it leads to delayed neuroblastoma development in Th-MYCN mice. However, it is unclear how caspase-2 mediates these differential outcomes. Here we utilized RNA sequencing to define the transcriptomic changes caused by caspase-2 (Casp2-/-) deficiency in tumors from EμMyc and Th-MYCN mice. We describe key changes in both lymphoma and neuroblastoma-associated genes and identified differential expression of the EGF-like domain-containing gene, Megf6, in the two tumor types that may contribute to tumor outcome following loss of Casp2. We identified a panel of genes with altered expression in Th-MYCN/Casp2-/- tumors that are strongly associated with neuroblastoma outcome, with roles in melanogenesis, Wnt and Hippo pathway signaling, that also contribute to neuronal differentiation. In contrast, we found that key changes in gene expression in the EμMyc/Casp2-/- tumors, are associated with increased immune signaling and T-cell infiltration previously associated with more aggressive lymphoma progression. In addition, Rap1 signaling pathway was uniquely enriched in Casp2 deficient EμMyc tumors. Our findings suggest that Casp2 deficiency augments immune signaling pathways that may be in turn, enhance lymphomagenesis. Overall, our study has identified new genes and pathways that contribute to the caspase-2 tumor suppressor function and highlight distinct roles for caspase-2 in different tissues. |
Keywords: | Neurons B-Lymphocytes Animals Mice Lymphoma Neuroblastoma Thoracic Neoplasms Disease Models, Animal Survival Analysis Gene Expression Profiling Signal Transduction Cell Differentiation Tumor Suppressor Protein p53 Caspase 2 N-Myc Proto-Oncogene Protein |
Rights: | © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
DOI: | 10.1038/s41419-018-1296-0 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1021456 http://purl.org/au-research/grants/nhmrc/1043057 http://purl.org/au-research/grants/nhmrc/1103006 |
Published version: | http://dx.doi.org/10.1038/s41419-018-1296-0 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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hdl_118254.pdf | Published version | 3.16 MB | Adobe PDF | View/Open |
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