MicroRNA-939 inhibits cell proliferation via targeting LRSAM1 in Hirschsprung’s disease

Chen, Guanglin; Du, Chunxia; Shen, Ziyang; Peng, Lei; Xie, Hua; Zang, Rujin; Li, Hongxing; Xia, Yankai; Tang, Weibing

doi:10.18632/aging.101331

Cited by 15 publications

(13 citation statements)

References 34 publications

(31 reference statements)

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“…It has been confirmed that some protein coding genes participate in the pathogenesis of HSCR, including RET, EDNRB, PHOX2B, SOX10, etc [3,4]. To date, some noncoding RNAs have also been proven to take part in the biological processes of HSCR, such as microRNA-939, lncRNA HOTTIP and LOC100507600 [5][6][7]. However, the underlying pathogenesis of HSCR occurrence still remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of circ-PRKCI inhibits cell migration and proliferation in Hirschsprung disease by suppressing the expression of miR-1324 target PLCB1

Zhou

Jiang

et al. 2018

Cell CycleHas correction 2018-12-27 Has erratum 2018-12-27

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Circular RNAs (circRNAs) are a novel class of noncoding RNAs (ncRNAs), which have been shown to participate in intracellular RNA regulatory networks and play vital roles in many pathological processes. Recently, circular RNA_PRKCI (circ-PRKCI) has been reported to regulate cell proliferation, migration and invasion in several human cancers. Hirschsprung disease (HSCR) is a well-known congenital gut motility disorder which roots in the aberrance of cranial-caudal neural crest cell migration. In this study, we investigated whether circ-PRKCI may affect cell migration and proliferation in HSCR. Quantitative reverse transcription PCR (qRT-PCR) was performed to detect the expression of circ-PRKCI in 48 HSCR aganglionic tissues and 48 normal bowel tissues. Luciferase reporter assay and RNA immunoprecipitation (RIP) assay verified the direct interaction between miR-1324 and PLCB1 or circ-PRKCI. Cell counting Kit-8 (CCK-8) and Ethynyldeoxyuridine (EdU) assays were employed to appraise the effects of miR-1324 or circ-PRKCI on cell proliferative potential, while transwell was performed to detect the migration in vitro. We found that circ-PRKCI was significantly down-regulated in HSCR aganglionic tissues. Morever, knockdown of circ-PRKCI suppressed cell proliferation and migration in vitro. Mechanistically, we confirmed that circ-PRKCI functioned as a molecular sponge for miR-1324 to upregulate the expression of PLCB1. In conclusion, our present study revealed the important role of circ-PRKCI-miR-1324-PLCB1 regulatory network in HSCR, providing a novel insight for the pathogenesis of HSCR.

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“…9 However, the dysregulation of miRNAs in HSCR 10,11 has not been stated thoroughly to date. Benefiting from the microarray of miRNAs which was performed in our previous study, 12 a great deal of up-or down-regulated miRNAs were sought out in HSCR samples compared with the normal ones. Among them, miR-483-3p gained our attention because it was found down-regulated in HSCR and transcribed from its host gene IGF2.…”

Section: Introductionmentioning

confidence: 99%

IGF2‐derived miR‐483‐3p associated with Hirschsprung's disease by targetingFHL1

Zhi

Zhu

et al. 2018

J Cell Mol MedHas erratum 2019-1-28

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HSCR (Hirschsprung's disease) is a serious congenital defect, and the aetiology of it remains unclear. Many studies have highlighted the significant roles of intronic miRNAs and their host genes in various disease, few was mentioned in HSCR although. In this study, miR‐483‐3p along with its host gene IGF2 (Insulin‐like growth factor 2) was found down‐regulated in 60 HSCR aganglionic colon tissues compared with 60 normal controls. FHL1 (Four and a half LIM domains 1) was determined as a target gene of miR‐483‐3p via dual‐luciferase reporter assay, and its expression was at a higher level in HSCR tissues. Here, we study cell migration and proliferation in human 293T and SH‐SY5Y cell lines by performing Transwell and CCK8 assays. In conclusion, the knockdown of miR‐483‐3p and IGF2 both suppressed cell migration and proliferation, while the loss of FHL1 leads to opposite outcome. Furthermore, miR‐483‐3p mimics could rescue the negative effects on cell proliferation and migration caused by silencing IGF2, while the FHL1 siRNA may inverse the function of miR‐483‐3p inhibitor. This study revealed that miR‐483‐3p derived from IGF2 was associated with Hirschsprung's disease by targeting FHL1 and may provide a new pathway to understand the aetiology of HSCR.

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“…Numerous miRNAs have been proved to be associated with HSCR, including miR‐206 (Sharan et al., ), miR‐939 (Chen et al., ), miR‐483‐5p (Wang et al., ), miR‐195 (Lei et al., ), miR‐369‐3p (Pan et al., ) and miR‐192/215 (Zhu et al., ) by suppressing cell proliferation. However, the models used in these studies were SK‐N‐BE(2) (Chen et al., ) or SH‐SY5Y (Chen et al., ; Lei et al., ; Pan et al., ; Sharan et al., ; Wang et al., ; Zhu et al., ) cell lines rather than animal models or ENCCs themselves. In our study, we used BAC treated mouse models of HSCR and isolated ENCCs to directly investigate ENCCs proliferation, because HSCR mouse model has been proved to be very similar to the most commonly encountered HSCR in humans (Yoneda et al., ).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of microRNA‐431‐5p promotes enteric neural crest cell proliferation via targetingLRSAM1 in Hirschsprung's disease

Cao²,

Wang

et al. 2019

Develop. Growth Differ.

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Background Hirschsprung's disease (HSCR) is characterized by missing of enteric neurons in the terminal areas of the whole gut, which is causally related to poor proliferation of enteric neural crest cells (ENCCs). Our aim is to explore how miR‐431‐5p interacts with its target gene in regulation of proliferation of ENCCs in HSCR. Methods Mouse model of HSCR was established by Benzalkonium chloride (BAC) treatment. Quantitative Real‐time PCR and western blotting were performed to determine the miR‐431‐5p and the LRSAM1 expression in colon tissues of the HSCR group (n = 8) and the control group (n = 8) and in ENCCs isolated from colon tissues. CCK‐8 assay was performed to detect the proliferation of ENCCs of HSCR. ENCCs after transfection with miR‐431‐5p mimics or miR‐431‐5p inhibitor. Luciferase reporter assay was conducted to clarify the connections between miR‐431‐5p and LRSAM1. Results Upregulation of miR‐431‐5p and downregulation of LRSAM1 were found in ENCCs of HSCR. Downregulation of miR‐431‐5p could promote cell proliferation of ENCCs. LRSAM1 was proved to be the target gene of miR‐431‐5p by luciferase reporter assay. Moreover, proliferation of ENCCs was increased in the miR‐431‐5p inhibitor group and was suppressed after knocking down LRSAM1. Conclusion Downregulation of miR‐431‐5p promoted proliferation of ENCCs via targeting LRSAM1, which provides an innovative and candidate target for treatment of HSCR.

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“…The postnatal down-regulation of LNX2 protein levels in the brain [13] despite the continued expression of LNX2 mRNA [6], suggests that either high rates of protein turnover or other mechanisms operating at the level of protein translation may control adult LNX2 protein levels. Possible regulatory mechanisms could include the repression of translation by non-coding RNAs and one report has identified a miRNA, miR-939, that may target Lnx2 message [38].…”

Section: Lnx1/2 Protein Expressionmentioning

confidence: 99%

LNX1/LNX2 proteins: functions in neuronal signalling and beyond

Young

2018

Neuronal Signaling

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Ligand of NUMB Protein X1 and X2 (LNX1 and LNX2) are E3 ubiquitin ligases, named for their ability to interact with and promote the degradation of the cell fate determinant protein NUMB. On this basis they are thought to play a role in modulating NUMB/NOTCH signalling during processes such as cortical neurogenesis. However, LNX1/2 proteins can bind, via their four PDZ (PSD95, DLGA, ZO-1) domains, to an extraordinarily large number of other proteins besides NUMB. Many of these interactions suggest additional roles for LNX1/2 proteins in the nervous system in areas such as synapse formation, neurotransmission and regulating neuroglial function. Twenty years on from their initial discovery, I discuss here the putative neuronal functions of LNX1/2 proteins in light of the anxiety-related phenotype of double knockout mice lacking LNX1 and LNX2 in the central nervous system (CNS). I also review what is known about non-neuronal roles of LNX1/2 proteins, including their roles in embryonic patterning and pancreas development in zebrafish and their possible involvement in colorectal cancer (CRC), osteoclast differentiation and immune function in mammals. The emerging picture places LNX1/2 proteins as potential regulators of multiple cellular signalling processes, but in many cases the physiological significance of such roles remains only partly validated and needs to be considered in the context of the tight control of LNX1/2 protein levels in vivo.

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“…MiRNAs are small non-coding RNA molecules that post-transcriptionally modulate gene expression by promoting mRNA degradation and/or repressing translation, and thus play key roles in various physiological and pathological conditions, including neuronal differentiation, plasticity, development, survival and central nervous system disorders 12 13. More recent studies have focused on the miRNA-mediated regulation of cell migration in the ENS, and dozens of miRNAs are demonstrated to be linked to HSCR aetiology 14 15. Interestingly, recent work reveals that miR-4516 may be involved in the mechanism of suppression of cell migration, and actually loss of miR-4516 expression contributes to accelerated migration in keratinocytes 16 17…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-4516-mediated regulation of MAPK10 relies on 3′ UTR cis-acting variants and contributes to the altered risk of Hirschsprung disease

Wang¹,

Jiang²,

Chakravarti

et al. 2020

J Med Genet

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BackgroundHirschsprung disease (HSCR) is a life-threatening congenital disorder in which the enteric nervous system is completely missing from the distal gut. Recent studies have shown that miR-4516 markedly inhibits cell migration, and as one of its potential targets, MAPK10 functions as a modifier for developing HSCR. We thus aimed to evaluate the role of miR-4516 and MAPK10 in HSCR and how they contribute to the pathogenesis of HSCR.MethodsWe examined 13 genetic variants using the MassArray system in a case–control study (n=1015). We further investigated miR-4516-mediated regulation of MAPK10 in HSCR cases and human neural cells, the effects of cis-acting elements in MAPK10 on miR-4516-mediated modulation and cell migration process.ResultsThree positive 3′ UTR variants in MAPK10 were associated with altered HSCR susceptibility. We also showed that miR-4516 directly regulates MAPK10 expression, and this regulatory mechanism is significantly affected by the 3′ UTR cis-acting elements of MAPK10. In addition, knock-down of MAPK10 rescued the effect of miR-4516 on the migration of human neural cells.ConclusionOur findings indicate a key role of miR-4516 and its direct target MAPK10 in HSCR risk, and highlight the general importance of cis- and posttranscriptional modulation for HSCR pathogenesis.

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MicroRNA-939 inhibits cell proliferation via targeting LRSAM1 in Hirschsprung’s disease

Cited by 15 publications

References 34 publications

Down-regulation of circ-PRKCI inhibits cell migration and proliferation in Hirschsprung disease by suppressing the expression of miR-1324 target PLCB1

IGF2‐derived miR‐483‐3p associated with Hirschsprung's disease by targetingFHL1

Downregulation of microRNA‐431‐5p promotes enteric neural crest cell proliferation via targetingLRSAM1 in Hirschsprung's disease

LNX1/LNX2 proteins: functions in neuronal signalling and beyond

MicroRNA-4516-mediated regulation of MAPK10 relies on 3′ UTR cis-acting variants and contributes to the altered risk of Hirschsprung disease

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