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dc.contributor.authorZhao, Zhenze ( )
dc.contributor.authorShelton, Spencer D. ( )
dc.contributor.authorOviedo, Alejandro ( )
dc.contributor.authorBaker, Amy L. ( )
dc.contributor.authorBryant, Collin P. ( )
dc.contributor.authorOmidvarnia, Soroush ( )
dc.contributor.authorDu, Liqin ( )
dc.date.accessioned2020-03-11T17:58:41Z
dc.date.available2020-03-11T17:58:41Z
dc.date.issued2020
dc.identifier.citationZhao, Z., Shelton, S. D., Oviedo, A., Baker, A. L., Bryant, C. P., Omidvarnia, S., & Du, L. (2020). The PLAGL2/MYCN/miR-506-3p interplay regulates neuroblastoma cell fate and associates with neuroblastoma progression. Journal of Experimental and Clinical Cancer Research, 39(1).en_US
dc.identifier.issn1756-9966
dc.identifier.urihttps://digital.library.txstate.edu/handle/10877/9382
dc.description.abstract

Background: The oncogene MYCN is critical for tumorigenesis of several types of cancers including neuroblastoma. We previously reported that miR-506-3p repressed MYCN expression in neuroblastoma cells. However, the mechanism underlying such regulation was undetermined since there is no miR-506-3p target site in MYCN 3’UTR.

Methods: By a systematic investigation combining microarray, informatics and luciferase reporter assay, we identified that the transcriptional factor pleiomorphic adenoma gene-like 2 (PLAGL2) is a direct target of miR-506-3p that mediates its regulation on MYCN expression. Using CHIP-PCR and luciferase reporter assay, we validated the transcriptional regulation of MYCN by PLAGL2 and we further demonstrated the transcriptional regulation of PLAGL2 by MYCN. We examined the function of PLAGL2 in regulating neuroblastoma cell fate by cell viability assay, colony formation and Western blotting of differentiation markers. We examined the effect of retinoic acid, the differentiation agent used in neuroblastoma therapy, on miR-506-3p, PLAGL2 and MYCN expressions by quantitative PCR and Western blots. We investigated the clinical relevance of PLAGL2 expression by examining the correlation of tumor PLAGL2 mRNA levels with MYCN mRNA expression and patient survival using public neuroblastoma patient datasets.

Results: We found that miR-506-3p directly down-regulated PLAGL2 expression, and we validated a PLAGL2 binding site in the MYCN promoter region responsible for promoting MYCN transcription, thereby establishing a mechanism through which miR-506-3p regulates MYCN expression. Conversely, we discovered that MYCN regulated PLAGL2 transcription through five N-Myc-binding E-boxes in the PLAGL2 promoter region. We further confirmed the reciprocal regulation between endogenous PLAGL2 and MYCN in multiple neuroblastoma cell lines. Moreover, we found that PLAGL2 knockdown induced neuroblastoma cell differentiation and reduced cell proliferation, and combined knockdown of PLAGL2 and MYCN showed a synergistic effect. More strikingly, we found that high tumor PLAGL2 mRNA levels were significantly correlated with high MYCN mRNA levels and poor patient survival in neuroblastoma patients. Furthermore, we found that retinoic acid increased expression of miR-506-3p and repressed expression of MYCN and PLAGL2.

Conclusions: Our findings altogether suggest that the interplay network formed by PLAGL2, MYCN and miR-506-3p is an important mechanism in regulating neuroblastoma cell fate, determining neuroblastoma prognosis, and mediating the therapeutic function of retinoic acid.

en_US
dc.formatText
dc.format.extent20 pages
dc.format.medium1 file (.pdf)
dc.language.isoen_USen_US
dc.publisherBioMed Centralen_US
dc.sourceJournal of Experimental and Clinical Cancer Research, 2020, Vol. 39, No. 1.
dc.subjectmiR-506-3pen_US
dc.subjectNeuroblastoma
dc.subjectPLAGL2
dc.subjectMYCN
dc.subjectRetinoic acid
dc.subjectCell differentiation
dc.titleThe PLAGL2/MYCN/miR-506-3p Interplay Regulates Neuroblastoma Cell Fate and Associates with Neuroblastoma Progressionen_US
txstate.documenttypeArticle
dc.rights.license© The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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.
txstate.departmentChemistry and Biochemistry


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