Colonic Epithelial miR-31 Associates with the Development of Crohn’s Phenotypes
| Autor: | Takahiko Toyonaga, Nicole Chaumont, Neil D. Shah, Mark J. Koruda, Matt Kanke, Greg R Gipson, Michelle Hoffner O’Connor, Elisabeth A. Wolber, Dimitri G. Trembath, Terrence S. Furey, Jasmine B. Barrow, Wendy A. Pitman, Nevzat Kazgan, Nancy L. Allbritton, Matthew S Schaner, Paul A Cotney, Francisco A. Sylvester, Omar K. Trad, Praveen Sethupathy, Benjamin P. Keith, Shruti J Saxena, Timothy S. Sadiq, Shehzad Z. Sheikh |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Oncology Biopsy Disease Inflammatory bowel disease Cohort Studies 0302 clinical medicine Crohn Disease Recurrence Medicine Intestinal Mucosa Child Colectomy Aged 80 and over 0303 health sciences Ileostomy Confounding General Medicine Middle Aged Prognosis Phenotype Up-Regulation 3. Good health mir-31 Treatment Outcome medicine.anatomical_structure Child Preschool Female 030211 gastroenterology & hepatology Research Article Adult Reoperation medicine.medical_specialty Cell type Adolescent Colon Ileum Young Adult 03 medical and health sciences Immune system Internal medicine Humans Aged 030304 developmental biology Adult patients Sequence Analysis RNA business.industry Gene Expression Profiling Cancer Epithelial Cells medicine.disease Clinical trial MicroRNAs 030104 developmental biology Cancer research Microrna profiling business Biomarkers Ex vivo |
| DOI: | 10.1101/307561 |
| Popis: | BACKGROUND. Crohn’s disease (CD) is highly heterogeneous, due in large part to variability in cellular processes that underlie the natural history of CD, thereby confounding effective therapy. There is a critical need to advance understanding of the cellular mechanisms that drive CD heterogeneity. METHODS. We performed small RNA sequencing of adult colon tissue from CD and NIBD controls. Colonic epithelial cells and immune cells were isolated from colonic tissues, and microRNA-31 (miR-31) expression was measured. miR-31 expression was measured in colonoid cultures generated from controls and patients with CD. We performed small RNA-sequencing of formalin-fixed paraffin-embedded colon and ileum biopsies from treatment-naive pediatric patients with CD and controls and collected data on disease features and outcomes. RESULTS. Small RNA-sequencing and microRNA profiling in the colon revealed 2 distinct molecular subtypes, each with different clinical associations. Notably, we found that miR-31 expression was a driver of these 2 subtypes and, further, that miR-31 expression was particularly pronounced in epithelial cells. Colonoids revealed that miR-31 expression differences are preserved in this ex vivo system. In adult patients, low colonic miR-31 expression levels at the time of surgery were associated with worse disease outcome as measured by need for an end ileostomy and recurrence of disease in the neoterminal ileum. In pediatric patients, lower miR-31 expression at the time of diagnosis was associated with future development of fibrostenotic ileal CD requiring surgery CONCLUSIONS. These findings represent an important step forward in designing more effective clinical trials and developing personalized CD therapies. FUNDING. This work was supported by CCF Career Development Award (SZS), R01-ES024983 from NIEHS (SZS and TSF), 1R01DK104828-01A1 from NIDDK (SZS and TSF), P01-DK094779-01A1 from NIDDK (SZS), P30-DK034987 from NIDDK (SZS), 1-16-ACE-47 ADA Pathway Award (PS), UNC Nutrition Obesity Research Center Pilot & Feasibility Grant P30DK056350 (PS), CCF PRO-KIIDS NETWORK (SZS and PS), UNC CGIBD T32 Training Grant from NIDDK (JBB), T32 Training Grant (5T32GM007092-42) from NIGMS (MH), and SHARE from the Helmsley Trust (SZS). The UNC Translational Pathology Laboratory is supported, in part, by grants from the National Cancer Institute (3P30CA016086) and the UNC University Cancer Research Fund (UCRF) (PS). |
| Databáze: | OpenAIRE |
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