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

Abstract

Background

Hirschsprung disease (HSCR) is a life-threatening congenital disorder in which the enteric nervous system (ENS) 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.

Methods

We 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.

Results

Three 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. Additionally, knock-down of MAPK10 rescued the effect of miR-4516 on the migration of human neural cells.

Conclusion

Our 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.