Abstract
Hirschsprung's disease (HSCR) is a rare congenital disease caused by impaired proliferation and migration of neural crest cells. We investigated changes in expression of microRNAs (miRNAs) and the genes they regulate in tissues of patients with HSCR. Quantitative real-time PCR and immunoblot analyses were used to measure levels of miRNA, mRNAs, and proteins in colon tissues from 69 patients with HSCR and 49 individuals without HSCR (controls). Direct interactions between miRNAs and specific mRNAs were indentified in vitro, while the function role of miR-218-1 was investigated by using miR-218 transgenic mice. An increased level of miR-218-1 correlated with increased levels of SLIT2 and decreased levels of RET and PLAG1mRNA and protein. The reductions in RET and PLAG1 by miR-218-1 reduced proliferation and migration of SH-SY5Y cells. Overexpression of the secreted form of SLIT2 inhibited cell migration via binding to its receptor ROBO1. Bowel tissues from miR-218-1 transgenic mice had nerve fibre hyperplasia and reduced numbers of gangliocytes, compared with wild-type mice. Altered miR-218-1 regulation of SLIT2, RET and PLAG1 might be involved in the pathogenesis of HSCR.
Highlights
Hirschsprung’s disease (HSCR) is a gastrointestinal disorder with an incidence of 1:200–1:5000 live births, with males being four times more affected than females in short segment HSCR [1]
It is characterized that the enteric neural crest cells (ENCCs) stop migrating and fail to reach the hindgut during embryogenesis from 5 to 12 weeks, which leads to the absence of ganglia cells in the intramural and submucosal along variable lengths of gastrointestinal tract [2]
A total of 69 human HSCR colon tissue specimens collected from HSCR patients diagnosed with HSCR disease by pathological detection were used for this study
Summary
Hirschsprung’s disease (HSCR) is a gastrointestinal disorder with an incidence of 1:200–1:5000 live births, with males being four times more affected than females in short segment HSCR [1]. The aetiological studies of HSCR have shown that the development of disease. MiRNAs are small, non-coding RNA molecules of 19–25 nucleotides which have been reported to play important roles by regulating cell differentiation, proliferation, migration and apoptosis [9]. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine Certain miRNAs have been found in the central neural system during embryonic development [13]. To our knowledge, the role of miRNAs in HSCR disease is not known yet
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