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MYCN Amplification ...
MYCN Amplification Is Associated with Reduced Expression of Genes Encoding γ-Secretase Complex and NOTCH Signaling Components in Neuroblastoma
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- Agarwal, Prasoon (författare)
- Lund University,Lunds universitet,Avdelningen för arbets- och miljömedicin,Institutionen för laboratoriemedicin,Medicinska fakulteten,EPI@LUND,Forskargrupper vid Lunds universitet,Division of Occupational and Environmental Medicine, Lund University,Department of Laboratory Medicine,Faculty of Medicine,Lund University Research Groups
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- Glowacka, Aleksandra (författare)
- Karolinska Institute
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- Mahmoud, Loay (författare)
- Karolinska Institute
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- Bazzar, Wesam (författare)
- Uppsala University,Karolinska Institute
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- Larsson, Lars Gunnar (författare)
- Uppsala University,Karolinska Institute
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- Alzrigat, Mohammad (författare)
- Karolinska Institutet,Uppsala University,Karolinska Institute
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(creator_code:org_t)
- 2023
- 2023
- Engelska.
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Ingår i: International Journal of Molecular Sciences. - 1661-6596 .- 1422-0067. ; 24:9
- Relaterad länk:
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http://dx.doi.org/10... (free)
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https://lup.lub.lu.s...
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https://doi.org/10.3...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- Amplification of the MYCN oncogene is found in ~20% of neuroblastoma (NB) cases and correlates with high-risk disease and poor prognosis. Despite the plethora of studies describing the role of MYCN in NB, the exact molecular mechanisms underlying MYCN’s contribution to high-risk disease are not completely understood. Herein, we implemented an integrative approach combining publicly available RNA-Seq and MYCN ChIP-Seq datasets derived from human NB cell lines to define biological processes directly regulated by MYCN in NB. Our approach revealed that MYCN-amplified NB cell lines, when compared to non-MYCN-amplified cell lines, are characterized by reduced expression of genes involved in NOTCH receptor processing, axoneme assembly, and membrane protein proteolysis. More specifically, we found genes encoding members of the γ-secretase complex, which is known for its ability to liberate several intracellular signaling molecules from membrane-bound proteins such as NOTCH receptors, to be down-regulated in MYCN-amplified NB cell lines. Analysis of MYCN ChIP-Seq data revealed an enrichment of MYCN binding at the transcription start sites of genes encoding γ-secretase complex subunits. Notably, using publicly available gene expression data from NB primary tumors, we revealed that the expression of γ-secretase subunits encoding genes and other components of the NOTCH signaling pathway was also reduced in MYCN-amplified tumors and correlated with worse overall survival in NB patients. Genetic or pharmacological depletion of MYCN in NB cell lines induced the expression of γ-secretase genes and NOTCH-target genes. Chemical inhibition of γ-secretase activity dampened the expression of NOTCH-target genes upon MYCN depletion in NB cells. In conclusion, this study defines a set of MYCN-regulated pathways that are specific to MYCN-amplified NB tumors, and it suggests a novel role for MYCN in the suppression of genes of the γ-secretase complex, with an impact on the NOTCH-target gene expression in MYCN-amplified NB.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- MYCN
- MYCN amplification
- neuroblastoma
- NOTCH signaling
- γ-secretase
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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