Dataset Information

SLIT2/ROBO1-miR-218-1-RET/PLAG1: a new disease pathway involved in Hirschsprung's disease.

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 PLAG1 mRNA 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.

SUBMITTER: Tang W

PROVIDER: S-EPMC4459835 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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SLIT2/ROBO1-miR-218-1-RET/PLAG1: a new disease pathway involved in Hirschsprung's disease.

Tang Weibing W Tang Junwei J He Jun J Zhou Zhigang Z Qin Yufeng Y Qin Jingjing J Li Bo B Xu Xiaoqun X Geng Qiming Q Jiang Weiwei W Wu Wei W Wang Xinru X Xia Yankai Y

Journal of cellular and molecular medicine 20150319 6

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 mRNA ...[more]

PMID: 25786906

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Project description:AimsPrevious reports indicated that the Slit2-Robo signalling pathway is involved in embryonic heart development and fibrosis in other solid organs, but its function in adult cardiac fibrosis has not been investigated. Here, we investigate the role of the Slit2-Robo1 signalling pathway in cardiac fibrosis.Methods and resultsThe right atrial tissue samples were obtained from patients with valvular heart disease complicated by atrial fibrillation during heart valve surgery and from healthy heart donors. The fibrotic animal model is created by performing transverse aortic constriction (TAC) surgery. The Robo1, Slit2, TGF-?1, and collagen I expression levels in human and animal samples were evaluated by immunohistochemistry and western blot analysis. Echocardiography measured the changes in heart size and cardiac functions of animals. Angiotensin II (Ang II), Slit2-siRNA, TGF-?1-siRNA, recombinant Slit2, and recombinant TGF-?1 were transfected to cardiac fibroblasts (CFs) respectively to observe their effects on collagen I expression level. The right atrial appendage of patients with valvular heart disease complicated by atrial fibrillation found significantly up-regulated Slit2, Robo1, TGF-?1, and collagen I expression levels. TAC surgery leads to heart enlargement, cardiac fibrosis, and up-regulation of Slit2, Robo1, TGF-?1, and collagen I expression levels in animal model. Robo1 antagonist R5 and TGF-?1 antagonist SB431542 suppressed cardiac fibrosis in TAC mice. Treatment with 100 nM Ang II in CFs caused significantly increased Slit2, Robo1, Smad2/3, TGF-?1, collagen I, PI3K, and Akt expression levels. Transfecting Slit2-siRNA and TGF-?1-siRNA, respectively, into rat CFs significantly down-regulated Smad2/3 and collagen I expression, inhibiting the effects of Ang II. Recombinant Slit2 activated the TGF-?1/Smad signalling pathway in CFs and up-regulated Periostin, Robo1, and collagen I expression.ConclusionsThe Slit2-Robo1 signalling pathway interfered with the TGF-?1/Smad pathway and promoted cardiac fibrosis. Blockade of Slit2-Robo1 might be a new treatment for cardiac fibrosis.

Dataset Information

SLIT2/ROBO1-miR-218-1-RET/PLAG1: a new disease pathway involved in Hirschsprung's disease.

Publications

SLIT2/ROBO1-miR-218-1-RET/PLAG1: a new disease pathway involved in Hirschsprung's disease.

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