<scp>IGF</scp>2‐derived miR‐483‐3p associated with Hirschsprung's disease by targeting <scp>FHL</scp>1

Zhi, Zhengke; Zhu, Hongxia; Lv, Xiaoyi; Lu, Changgui; Yang, Li; Wu, Feng; Zhou, Lingling; Li, Hongxing; Tang, Weibing

doi:10.1111/jcmm.13756

Cited by 14 publications

(5 citation statements)

References 46 publications

(76 reference statements)

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“…With the development of high-throughput sequencing technology and in-depth research, more and more ncRNAs, especially miRNA and lncRNA, have been found to play very important roles in epigenetic regulation and take part in the occurrence and development of multiple diseases (Moradimotlagh et al, 2019;Pan et al, 2020;Tai et al, 2020). Although there have been some reports about ncRNAs in HSCR, its mode of action and mechanism still need further study (Gunadi et al, 2019;Zhi et al, 2018). In this study, our research team detected that in the stenosis tract of HSCR patients, RMST and miR-1251 were down-regulated apparently.…”

Section: Discussionmentioning

confidence: 99%

lncRNA-RMST functioned as a SOX2 transcription co-regulator to regulate miR-1251 in the progression of Hirschsprung’s disease

Zhou¹,

Zhi²,

Chen³

et al. 2020

Preprint

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Hirschsprung’s disease (HSCR) is a congenital disorder characterized by the absence of enteric neural crest cells (ENCCs). Non-coding RNAs including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been authenticated as important regulators of biological functions. We conducted a microarray analysis and found lncRNA Rhabdomyosarcoma 2-associated transcript (RMST) was down-regulated in the stenotic segment of HSCR patients. MiR-1251 is transcribed from the intron region of RMST and was also low-expressed. When the expression of RMST or miR-1251 was reduced, the cell proliferation and migration were attenuated. However, RMST didn’t affect the expression of miR-1251 directly found in this study. Through bioinformatic analysis, transcription factor SOX2 was predicted to bind to the promoter region of miR-1251 which was confirmed by CHIP assay. Herein, we demonstrated that RMST exerted as a co-regulator of SOX2 to regulate the expression of miR-1251. Furtherly, AHNAK was proved to be the target gene of miR-1251 in this study. Taken together, we revealed the role of RMST/SOX2/miR-1251/AHNAK pathway in the occurrence of Hirschsprung’s disease and provided a potential therapeutic target for this disease.SUMMARY STATEMENTHirschsprung disease (HSCR) is characterized by a deficit in enteric neurons, however, the underlying mechanism remains unclear. This study revealed the role of lnc-RMST during the occurrence of HSCR.

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Section: Discussionmentioning

confidence: 99%

lncRNA-RMST functioned as a SOX2 transcription co-regulator to regulate miR-1251 in the progression of Hirschsprung’s disease

Zhou¹,

Zhi²,

Chen³

et al. 2020

Preprint

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“…With the development of high-throughput sequencing technology and in-depth research, more and more ncRNAs, especially miRNA and lncRNA, have been found to play very important roles in epigenetic regulation and take part in the occurrence and development of multiple diseases (22)(23)(24). Although there have been some reports about ncRNAs in HSCR, its mode of action and mechanism still need further study (25,26). In this study, our research team detected that in the stenosis tract of HSCR patients, RMST and miR-1251 were down-regulated apparently.…”

Section: Discussionmentioning

confidence: 99%

lncRNA-RMST Functioned as a SOX2 Transcription Co-regulator to Regulate miR-1251 in the Progression of Hirschsprung's Disease

Zhou

Zhi

Chen

et al. 2020

Preprint

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Background：Hirschsprung’s disease (HSCR) is a congenital colon disease characterized by the lack of ganglion cells which is closely related to impaired migration and proliferation of enteric neural crest cells (ENCCs). Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been authenticated as an important class of regulators of biological functions. In this study, a microarray analysis was conducted and found that Rhabdomyosarcoma 2-associated transcript (RMST), a newly defined lncRNA, was down-regulated in the stenotic segment of HSCR patients. MiR-1251 is transcribed from the intron region of RMST and was also low expressed in the aganglionic tract. This study aimed to clarify the roles they played in the occurrence of HSCR. Methods：qRT-PCR was applied to validate the mRNA expression of RMST, miR-1251, SOX2 and AHNAK, while western blotting was employed to evaluate the protein level of SOX2 and AHNAK in clinical samples and cells. CCK-8 and transwell assays were used to detect cell proliferation and migration after transfection. Chromatin immunoprecipitation (CHIP) was applied to confirm SOX2 could bind to the promoter region of miR-1251. RNA binding protein immunoprecipitation (RIP) was used to demonstrate the interaction between RMST and SOX2. Dul-luciferase reporter assay was performed to confirm miR-1251 could interact with AHNAK. Results: When the expression of RMST or miR-1251 was reduced, cell proliferation and migration was attenuated. However, RMST not to influence the expression of miR-1251 directly. Through bioinformatic analysis, transcription factor SOX2 was predicted to bind to the promoter region of miR-1251 which was confirmed by CHIP assay. We also demonstrated that RMST exerted as a co-regulator of SOX2 via RIP assay. AHNAK was predicted as the downstream gene of miR-1251 confirmed by the dual-luciferase reporter assay. Furtherly, rescue experiments showed RMST functioned as a transcription co-regulator of SOX2 to upregulate the expression of downstream gene AHNAK by strengthening the regulation of SOX2 on miR-1251 in HSCR.Conclusions: These findings uncovered the role of RMST/SOX2/miR-1251/AHNAK pathway during the development of Hirschsprung's disease and presented potential therapeutic targets for HSCR.

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“…SH-SY5Y cells were cultured under 37°C and 5% CO 2 in DMEM medium supplemented with 10% FBS, 100 U/mL penicillin, and 100 μg/mL streptomycin [ 10 ]. Cell models were constructed by the addition of inhibitors and agonists: a Rac1, Limk1, and Cofilin inhibitor group; a Rac1 overexpression group (the PDGF-BB group); a Rac1 overexpression group + a Limk1 inhibitor group (the P-B group); and a Rac1 overexpression group + a Cofilin inhibitor group (the P-C group).…”

Section: Methodsmentioning

confidence: 99%

The abnormal phosphorylation of the Rac1, Lim-kinase 1, and Cofilin proteins in the pathogenesis of Hirschsprung’s disease

et al. 2022

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Rac1 can affect the migration of neural crest cells by regulating the polymerization of actin and the membrane formation process. But the role of the Rac1 signaling pathway in the pathogenesis of Hirschsprung’s disease (HSCR) remains unclear. In order to investigate the mechanism of the abnormal protein phosphorylation of Rac1, Lim-kinase 1 (Limk1) and Cofilin involved in the pathogenesis of HSCR. The protein phosphorylation levels of these proteins were detected by Western blot in 30 samples of HSCR narrow segment, 30 samples of transitional segment tissues, and 14 samples of normal intestinal tissues. Subsequently, in the SH-SY5Y human neuroblastoma cell line, a Rac1, Limk1, and Cofilin inhibitor group, a Rac1 overexpression group (PDGF-BB group), a Rac1 overexpression group + a Limk1 inhibitor group (P-B group), a Rac1 overexpression group + a Cofilin inhibitor group (P-C group) were established. The results showed that the expressions of p-Rac1, p-Limk1, and p-Cofilin in HSCR narrow segment and transitional segment were lower than those in normal intestine (p < 0.05). The expression levels of p-Rac1, p-Limk1, and p-Cofilin in the relative inhibitor group were significantly lower than those in the control group (p < 0.05), and the proliferation and migration levels in the control group and Rac1 overexpression group were significantly higher than those in the Rac1, Limk1, and Cofilin inhibitor group (p < 0.05). In conclusion, the decreased phosphorylation of the Rac1/Limk1/Cofilin signaling pathway in HSCR could inhibit the proliferation and migration of SH-SY5Y cells, and this might be associated with the pathogenesis of HSCR.

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IGF2‐derived miR‐483‐3p associated with Hirschsprung's disease by targeting FHL1

Cited by 14 publications

References 46 publications

lncRNA-RMST functioned as a SOX2 transcription co-regulator to regulate miR-1251 in the progression of Hirschsprung’s disease

lncRNA-RMST functioned as a SOX2 transcription co-regulator to regulate miR-1251 in the progression of Hirschsprung’s disease

lncRNA-RMST Functioned as a SOX2 Transcription Co-regulator to Regulate miR-1251 in the Progression of Hirschsprung's Disease

The abnormal phosphorylation of the Rac1, Lim-kinase 1, and Cofilin proteins in the pathogenesis of Hirschsprung’s disease

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