The loss of DLG2 isoform 7/8, but not isoform 2, is critical in advanced staged neuroblastoma
Related Experiment Video
Updated: Nov 12, 2025
Live-3D-Cell Immunocytochemistry Assays of Pediatric Diffuse Midline Glioma
Published on: November 11, 2021
Simon Keane1, Tommy Martinsson2, Per Kogner3
1Translational Medicine, School of Health Sciences, University of Skövde, Skövde, Sweden.
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.
Insights
The L27 domain in DLG2-isoform 7/8 is disrupted in aggressive neuroblastoma, impacting cell signaling and viability. Its presence correlates with better prognosis in childhood neural crest tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Neuroblastoma is a heterogeneous childhood neural crest tumor.
- Aggressive forms often exhibit 11q-deletion, leading to reduced DLG2 gene expression.
- DLG2 isoforms differ by the presence or absence of a L27 domain, crucial for protein complex formation and cell signaling.
Purpose of the Study:
- To investigate the expression and functional significance of DLG gene family members, specifically DLG1 and DLG2 isoforms with L27 domains, in neuroblastoma.
- To evaluate the role of DLG2 isoforms and LIN7A in the aggressive 11q-deleted neuroblastoma cell line SKNAS.
Main Methods:
- Expression analysis of DLG and LIN7 gene families in neuroblastoma using public data and primary tumors.
- Inclusion of two distinct DLG1 and DLG2 N-terminal transcript isoforms encoding L27 domains.
- Functional evaluation of DLG2 isoforms and LIN7A in the SKNAS cell line.
Main Results:
- Only DLG2-isoform 2 and DLG2-isoform 7/8 were expressed in neuroblastoma.
- Higher expression of L27 domain-containing DLG members correlated with improved survival and prognosis.
- DLG2-isoform 7/8 expression decreased in high-stage neuroblastoma, and its protein product bound LIN7A, reducing cell proliferation and increasing apoptosis.
Conclusions:
- DLG2-isoform 7/8 gene expression, but not DLG2-isoform 2, is disrupted in neuroblastoma, especially in aggressive subtypes.
- The intact L27 domain of DLG2-isoform 7/8 facilitates LIN7A binding, influencing cell polarity, signaling, and cancer cell viability.
