Increased miR-214 expression suppresses cell migration and proliferation in Hirschsprung disease by interacting with PLAGL2

Wu, Liang; Yuan, Wenzheng; Chen, Jinhuang; Zhou, Zili; Shu, Yan; Ji, Jintong; Liu, Zhengyi; Tang, Qiang; Zhang, Xudan; Shu, Xuefeng

doi:10.1038/s41390-019-0324-9

Cited by 22 publications

(15 citation statements)

References 36 publications

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“…The regulation of PLAGL2 expression by miRNAs has also been reported. For example, miR-214 was found to target the 3'UTR of PLAGL2 mRNA and down-regulated PLAGL2 expression in neuroblastoma cells [50]. miR-449a, miR-486-5p and let-7 were found to target the 3'UTR of PLAGL2 mRNA in other cancer cell types [46,49,51,52].…”

Section: Discussionmentioning

confidence: 99%

The PLAGL2/MYCN/miR-506-3p interplay regulates neuroblastoma cell fate and associates with neuroblastoma progression

Zhao

Shelton

Oviedo

et al. 2020

J Exp Clin Cancer Res

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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.

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Section: Discussionmentioning

confidence: 99%

The PLAGL2/MYCN/miR-506-3p interplay regulates neuroblastoma cell fate and associates with neuroblastoma progression

Zhao

Shelton

Oviedo

et al. 2020

J Exp Clin Cancer Res

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“…Analysis of miRNA-214 expression with the pleiomorphic adenoma gene-like zinc finger 2 ( PLAGL2 ) gene target from the colon tissue of HSCR patients has also been investigated, showing increased levels of miR-214 expression in the aganglionic colon segment, which inhibits cell migration and proliferation directly by deregulating the expression of the target gene PLAGL2 [ 144 ]. In other studies, it has been found that the level of miR-369-3p expression in the aganglionic colon segment increased compared with the normal colon.…”

Section: Enteric Nervous System (Ens)mentioning

confidence: 99%

Literature review: enteric nervous system development, genetic and epigenetic regulation in the etiology of Hirschsprung's disease

Diposarosa

Bustam

Sahiratmadja

et al. 2021

Heliyon

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Hirschsprung's disease (HSCR) is a developmental disorder of the enteric nervous system (ENS) derived from neural crest cells (NCCs), which affects their migration, proliferation, differentiation, or preservation in the digestive tract, resulting in aganglionosis in the distal intestine. The regulation of both NCCs and the surrounding environment involves various genes, signaling pathways, transcription factors, and morphogens. Therefore, changes in gene expression during the development of the ENS may contribute to the pathogenesis of HSCR.This review discusses several mechanisms involved in the development of ENS, confirming that deviant genetic and epigenetic patterns, such as DNA methylation, histone modification, and microRNA (miRNA) regulation, can contribute to the development of neurocristopathy. Specifically, the epigenetic regulation of miRNA expression and its relationship to cellular interactions and gene activation through various major pathways in Hirschsprung's disease will be discussed.

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“…Different research studies have related miRNAs, lncRNA and circRNA to HSCR [28,37,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121]. These associations have been based on either their differential expression in HSCR tissues, an aberrant expression of their target genes and, finally, alterations in migration, proliferation and/or apoptosis processes of NCCs during development (Table 1).…”

Section: Ncrnamentioning

confidence: 99%

Epigenetic Mechanisms in Hirschsprung Disease

Torroglosa

Villalba‐Benito

Lasa

et al. 2019

IJMS

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Hirschsprung disease (HSCR, OMIM 142623) is due to a failure of enteric precursor cells derived from neural crest (EPCs) to proliferate, migrate, survive or differentiate during Enteric Nervous System (ENS) formation. This is a complex process which requires a strict regulation that results in an ENS specific gene expression pattern. Alterations at this level lead to the onset of neurocristopathies such as HSCR. Gene expression is regulated by different mechanisms, such as DNA modifications (at the epigenetic level), transcriptional mechanisms (transcription factors, silencers, enhancers and repressors), postranscriptional mechanisms (3′UTR and ncRNA) and regulation of translation. All these mechanisms are finally implicated in cell signaling to determine the migration, proliferation, differentiation and survival processes for correct ENS development. In this review, we have performed an overview on the role of epigenetic mechanisms at transcriptional and posttranscriptional levels on these cellular events in neural crest cells (NCCs), ENS development, as well as in HSCR.

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Increased miR-214 expression suppresses cell migration and proliferation in Hirschsprung disease by interacting with PLAGL2

Cited by 22 publications

References 36 publications

The PLAGL2/MYCN/miR-506-3p interplay regulates neuroblastoma cell fate and associates with neuroblastoma progression

The PLAGL2/MYCN/miR-506-3p interplay regulates neuroblastoma cell fate and associates with neuroblastoma progression

Literature review: enteric nervous system development, genetic and epigenetic regulation in the etiology of Hirschsprung's disease

Epigenetic Mechanisms in Hirschsprung Disease

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