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Investigation of the Transcriptional Role of a RUNX1 Intronic Silencer by CRISPR/Cas9 Ribonucleoprotein in Acute Myeloid Leukemia Cells
Published on: September 1, 2019
RUNX3 interacts with MYCN and facilitates protein degradation in neuroblastoma
11] Division of Biochemistry and Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba, Japan [2] Department of Molecular Biology and Oncology, Chiba University Graduate School of Medicine, Chiba, Japan [3] Department of Thoracic Surgery, Forth Hospital of Hebei Medical University, Hebei, PRC.
Abstract:
RUNX3, a runt-related transcription factor, has a crucial role in dorsal root ganglion neurogenesis. Recent studies have suggested that RUNX3 acts as a tumor suppressor in stomach, colon and breast cancer. However, the biological role of RUNX3 in neuroblastoma remains elusive. Here we report that high levels of RUNX3 expression contribute to the favorable outcome in patients with neuroblastoma, whereas low levels of RUNX3 expression result in poor outcome. Array-based analysis suggested that the allelic loss at chromosome 1p36 is one of the reasons why expression of RUNX3 is downregulated in advanced neuroblastomas. Interestingly, the several patients survived from neuroblastoma with both high mRNA expressions of MYCN and RUNX3, suggesting that RUNX3 high expression might overcome the aggressive behavior of MYCN. Exogenous expression of RUNX3 strongly inhibits cell proliferation and migration in neuroblastoma cell lines. Furthermore, RUNX3 reduces the stability of MYCN protein in MYCN-amplified neuroblastoma cell lines, and this RUNX3-mediated MYCN degradation may depend on the physical interaction between RUNX3 and MYCN. Thus, our findings provide a tumor-suppressing mechanism by which RUNX3 inhibits the MYCN activity in neuroblastoma.
Insights
High RUNX3 expression correlates with better outcomes in neuroblastoma, potentially overcoming MYCN
Area of Science:
- Neuro-oncology
- Cancer biology
- Molecular genetics
Background:
- RUNX3 (runt-related transcription factor 3) is implicated in neurogenesis and acts as a tumor suppressor in several cancers.
- The role of RUNX3 in neuroblastoma, a pediatric cancer, is not well understood.
Purpose of the Study:
- To investigate the biological role and prognostic significance of RUNX3 in neuroblastoma.
- To elucidate the molecular mechanisms underlying RUNX3's function in neuroblastoma, particularly in relation to MYCN.
Main Methods:
- Analysis of RUNX3 expression levels in neuroblastoma patient cohorts.
- Array-based analysis to identify genetic alterations associated with RUNX3 downregulation.
- In vitro studies involving exogenous RUNX3 expression in neuroblastoma cell lines.
- Investigation of the interaction between RUNX3 and MYCN protein stability.
Main Results:
- High RUNX3 expression is associated with favorable patient outcomes, while low expression indicates poor prognosis.
- Allelic loss at chromosome 1p36 contributes to RUNX3 downregulation in advanced neuroblastomas.
- RUNX3 overexpression inhibits neuroblastoma cell proliferation and migration.
- RUNX3 reduces MYCN protein stability, suggesting a mechanism to counteract MYCN's oncogenic activity.
Conclusions:
- RUNX3 functions as a tumor suppressor in neuroblastoma.
- RUNX3's favorable prognostic role may stem from its ability to inhibit MYCN activity.
- RUNX3 represents a potential therapeutic target for neuroblastoma treatment.
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