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Low DLG2 gene expression, a link between 11q-deleted and MYCN-amplified neuroblastoma, causes forced cell cycle progression, and predicts poor patient survival
University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). (Translationell medicin (TRIM), Translational Medicine)
University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). (Translationell medicin (TRIM), Translational Medicine)
University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. (Translationell bioinformatik, Translational bioinformatics)ORCID iD: 0000-0003-1837-429X
University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). (Translationell medicin (TRIM), Translational Medicine)ORCID iD: 0000-0001-8962-0860
2020 (English)In: Cell Communication and Signaling, ISSN 1478-811X, E-ISSN 1478-811X, Vol. 18, no 1, article id 65Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Neuroblastoma (NB) is a childhood neural crest tumor. There are two groups of aggressive NBs, one with MYCN amplification, and another with 11q chromosomal deletion; these chromosomal aberrations are generally mutually exclusive. The DLG2 gene resides in the 11q-deleted region, thus makes it an interesting NB candidate tumor suppressor gene. METHODS: We evaluated the association of DLG2 gene expression in NB with patient outcomes, stage and MYCN status, using online microarray data combining independent NB patient data sets. Functional studies were also conducted using NB cell models and the fruit fly. RESULTS: Using the array data we concluded that higher DLG2 expression was positively correlated to patient survival. We could also see that expression of DLG2 was inversely correlated with MYCN status and tumor stage. Cell proliferation was lowered in both 11q-normal and 11q-deleted NB cells after DLG2 over expression, and increased in 11q-normal NB cells after DLG2 silencing. Higher level of DLG2 increased the percentage of cells in the G2/M phase and decreased the percentage of cells in the G1 phase. We detected increased protein levels of Cyclin A and Cyclin B in fruit fly models either over expressing dMyc or with RNAi-silenced dmDLG, indicating that both events resulted in enhanced cell cycling. Induced MYCN expression in NB cells lowered DLG2 gene expression, which was confirmed in the fly; when dMyc was over expressed, the dmDLG protein level was lowered, indicating a link between Myc over expression and low dmDLG level. CONCLUSION: We conclude that low DLG2 expression level forces cell cycle progression, and that it predicts poor NB patient survival. The low DLG2 expression level could be caused by either MYCN-amplification or 11q-deletion. Video Abstract.

Place, publisher, year, edition, pages
BioMed Central, 2020. Vol. 18, no 1, article id 65
Keywords [en]
11q, DLG2, MAGUK, MYCN, Neuroblastoma
National Category
Medical Genetics Cancer and Oncology
Research subject
Translational Medicine TRIM; Bioinformatics
Identifiers
URN: urn:nbn:se:his:diva-18430DOI: 10.1186/s12964-020-00553-6PubMedID: 32312269Scopus ID: 2-s2.0-85083811841OAI: oai:DiVA.org:his-18430DiVA, id: diva2:1428974
Available from: 2020-05-07 Created: 2020-05-07 Last updated: 2020-05-08Bibliographically approved

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Keane, SimonLindlöf, AngelicaEjeskär, Katarina

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1314151617181916 of 22
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