Abstract
Hirschsprung’s disease (HSCR), the most common congenital malformation of the gut, is regulated by multiple signal transduction pathways. Several components of these pathways are important targets for microRNAs (miRNAs). Multiple miRNAs have been associated with the pathophysiology of HSCR, and serum miRNAs profiles of HSCR patients have been reported, but miRNA expression in HSCR colon tissue is almost completely unexplored. Using microarray technology, we screened colon tissue to detect miRNAs whose expression profiles were altered in HSCR and identify targets of differentially expressed miRNAs. Following filtering of low-intensity signals, data normalization, and volcano plot filtering, we identified 168 differentially expressed miRNAs (104 up-regulated and 64 down-regulated). Fifty of these mRNAs represent major targets of dysegulated miRNAs and may thus important roles in the pathophysiology of HSCR. Pathway analysis revealed that 7 of the miRNA targets encode proteins involved in regulation of cell proliferation and migration via RET and related signaling pathways (MAPK and PI3K/AKT). Our results identify miRNAs that play key roles in the pathophysiology of the complex multi-factorial disease HSCR.
Highlights
Identification of miRNAs differentially expressed in colonic lesions of Hirschsprung’s disease (HSCR) patients
RNA was isolated from stenotic colon segments of HSCR patients (n = 6, three males and three female, labeled as 3, 4, 10, 13, 16, and 20), control colon segments from HSCR patients (n = 3, one female and two males, labeled as 3con, 4con, and 10con) and normal tissue from control subjects (n = 3, one males and two females, labeled as 2, 6, and 21)
After removing transcripts not associated with pathology of HSCR from the list of possible targets, we found that 13 of the 168 miRNAs targeted 50 potentially relevant mRNAs, whereas the other 155 miRNAs did not have any experimentally evaluated molecular targets associated with HSCR pathology (Tables 2 and 3)
Summary
Colon tissue specimens were obtained from the Department of Pediatric Surgery, Chingqing Children's Hospital, with the approval of the Institutional Review Board of Children’s Hospital of Chongqing Medical University and with the written consent of all patients or legal gurdians. Samples from a total of 76 HSCR patients (39 males and 37 females) were collected at Chongqing Children’s Hospital from March 2013 to September 2013. HSCR patients were aged from 13 days to 4 years old and all were diagnosed by barium enema and anorectic manometer evaluation before surgical procedures and pathological analysis for definitive diagnosis. Three agematched control colon tissues were collected from patients with colorectal trauma or undergoing anorectal colostomy at Chongqing Children’s Hospital. Full-thickness tissues were obtained and immediately stored in liquid nitrogen
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