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The loss of DLG2 isoform 7/8, but not isoform 2, is critical in advanced staged neuroblastoma
University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). (Translationell medicin TRIM, Translational Medicine)ORCID iD: 0000-0002-0471-6896
Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
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
2021 (English)In: Cancer Cell International, E-ISSN 1475-2867, Vol. 21, no 1, article id 170Article in journal (Refereed) Published
Abstract [en]

Background: Neuroblastoma is a childhood neural crest tumor showing large clinical and genetic heterogeneity, one form displaying 11q-deletion is very aggressive. It has been shown that 11q-deletion results in decreased expression of DLG2, a gene residing in the deleted region. DLG2 has a number of different isoforms with the main difference is the presence or absence of a L27 domain. The L27 domain containing DLG proteins can form complexes with CASK/MPP and LIN7 protein family members, which will control cell polarity and signaling. Methods: We evaluated the DLG gene family and the LIN7 gene family for their expression in differently INSS staged neuroblastoma from publically available data and primary tumors, we included two distinct DLG1 and DLG2 N-terminal transcript isoforms encoding L27 domains for their expression. Functionality of DLG2 isoforms and of LIN7A were evaluated in the 11q-deleted neuroblastoma cell line SKNAS. Results: In neuroblastoma only two DLG2 isoforms were expressed: isoform 2 and isoform 7/8. Using the array data we could determine that higher expression of DLG members that contain L27 domains correlated to better survival and prognosis. Whilst DLG1 showed a decrease in both isoforms with increased INSS stage, only the full length L27 containing DLG2 transcripts DLG2-isoform 7/8 showed a decrease in expression in high stage neuroblastoma. We could show that the protein encoded by DLG2-isoform 7 could bind to LIN7A, and increased DLG2-isoform 7 gene expression increased the expression of LIN7A, this reduced neuroblastoma cell proliferation and viability, with increased BAX/BCL2 ratio indicating increased apoptosis. Conclusion: We have provided evidence that gene expression of the L27 domain containing DLG2-isoform 7/8 but not L27 domain lacking DLG2-isoform 2 is disrupted in neuroblastoma, in particular in the aggressive subsets of tumors. The presence of the complete L27 domain allows for the binding to LIN7A, which will control cell polarity and signaling, thus affecting cancer cell viability. 

Place, publisher, year, edition, pages
Springer Nature, 2021. Vol. 21, no 1, article id 170
Keywords [en]
DLG, DLG2, Isoform, L27, LIN7A, Neuroblastoma
National Category
Cancer and Oncology Cell and Molecular Biology
Research subject
Translational Medicine TRIM
Identifiers
URN: urn:nbn:se:his:diva-19546DOI: 10.1186/s12935-021-01851-wISI: 000629888200003PubMedID: 33726762Scopus ID: 2-s2.0-85102533029OAI: oai:DiVA.org:his-19546DiVA, id: diva2:1539670
Note

CC BY 4.0

The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

© 2021, The Author(s).

© 2021 BioMed Central Ltd unless otherwise stated. Part of Springer Nature.

Correspondence: Katarina.ejeskar@his.se

Available from: 2021-03-25 Created: 2021-03-25 Last updated: 2023-09-08Bibliographically approved

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Keane, SimonEjeskär, Katarina

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