Wnt/-catenin signaling is crucial for maintenance and activation of intestinal stem cells (ISCs). Mutations resulting in unregulated Wnt/-catenin have been linked to tumor initiation and growth. Recent evidence suggests that this pathway may also be a key mediator of the transition of ISCs to cancer stem cells (CSCs), which exhibit stem like features and contribute to metastasis and resistance to treatment. The underlying mechanisms by which canonical Wnt signaling mediates tumor formation are largely unknown, but emerging evidence suggests that deletion of APC or stabilization of -catenin results in aberrant expression of microRNAs (miRNAs). MiRNAs, a diverse class of highly conserved small non-coding RNAs (~22 nucleotides long), have been shown to play a critical role in cellular homeostasis and development and may also contribute to carcinogenesis. Whether miRNAs directly mediate the transformation of Lgr5+ ISCs has not been explored. To investigate the role of miRNAs in Wnt-mediated tumor formation, we performed global profiling of miRNA expression from intestinal crypts following stabilization of -catenin. Our analysis identified five miRNAs (let- 7e, miR-96, miR-223, miR-411 and miR-423-5p) that were differentially expressed and identified a general trend towards down-regulation of miRNAs, a phenomenon observed in human cancers. The following specific aims are designed to further investigate the role of miRNAs in the regulation of intestinal stem cells and the initiation of cancer.
Aim 1. To investigate the role of specific miRNAs, identified by global crypt profiling, on ISC behavior.
Aim 2. To determine the impact of global miRNA down-regulation on ISC behavior and adenoma formation. In summary, this proposal seeks to delineate the role of miRNAs and their targets on ISC behavior and adenoma formation. We anticipate that this could provide the basis for the development of novel Wnt-based biomarkers and therapeutics for intestinal cancer.

Public Health Relevance

The goal of this project is to identify microRNAs (miRNAs) that contribute to tumor initiation through modulation of their target messenger RNAs in intestinal stem cells. We will further characterize the molecular mechanisms by which these miRNAs function, particularly in the presence of mutations in the Wnt signaling pathway. Since, activation of the Wnt signaling pathway plays a predominant role in tumorigenesis, identification of these miRNA targets could provide the basis for the development of novel biomarkers and therapeutics for intestinal cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK107108-03
Application #
9298629
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Densmore, Christine L
Project Start
2015-08-01
Project End
2018-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Richmond, Camilla A; Rickner, Hannah; Shah, Manasvi S et al. (2018) JAK/STAT-1 Signaling Is Required for Reserve Intestinal Stem Cell Activation during Intestinal Regeneration Following Acute Inflammation. Stem Cell Reports 10:17-26
O'Connell, Amy E; Zhou, Fanny; Shah, Manasvi S et al. (2018) Neonatal-Onset Chronic Diarrhea Caused by Homozygous Nonsense WNT2B Mutations. Am J Hum Genet 103:131-137
Richmond, Camilla A; Shah, Manasvi S; Carlone, Diana L et al. (2016) Factors regulating quiescent stem cells: insights from the intestine and other self-renewing tissues. J Physiol 594:4805-13
Shah, Manasvi S; Kim, Eunjoo; Davidson, Laurie A et al. (2016) Comparative effects of diet and carcinogen on microRNA expression in the stem cell niche of the mouse colonic crypt. Biochim Biophys Acta 1862:121-34
Shah, Manasvi S; Kim, Eunjoo; Davidson, Laurie A et al. (2016) Data describing the effects of dietary bioactive agents on colonic stem cell microRNA and mRNA expression. Data Brief 6:398-404
Ariyachet, Chaiyaboot; Tovaglieri, Alessio; Xiang, Guanjue et al. (2016) Reprogrammed Stomach Tissue as a Renewable Source of Functional ? Cells for Blood Glucose Regulation. Cell Stem Cell 18:410-21
Richmond, Camilla A; Shah, Manasvi S; Carlone, Diana L et al. (2016) An enduring role for quiescent stem cells. Dev Dyn 245:718-26
Richmond, Camilla A; Shah, Manasvi S; Deary, Luke T et al. (2015) Dormant Intestinal Stem Cells Are Regulated by PTEN and Nutritional Status. Cell Rep 13:2403-2411