1. MicroRNA-4516-mediated regulation of MAPK10 relies on 3′ UTR cis-acting variants and contributes to the altered risk of Hirschsprung disease
- Author
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Hao Cai, Bei-Lin Gu, Wenjie Wu, Wei Cai, Qian Jiang, Long Li, Yang Wang, Aravinda Chakravarti, and Ze Xu
- Subjects
0301 basic medicine ,Untranslated region ,Three prime untranslated region ,Cell migration ,Disease ,Biology ,Pathogenesis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,microRNA ,Genetics ,Cancer research ,Enteric nervous system ,MAPK10 ,Genetics (clinical) - Abstract
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.
- Published
- 2020