The intestinal epithelium is in a dynamic equilibrium of proliferation, differentiation and apoptosis along the crypt-villus gradient. Normal intestinal homeostasis is disturbed during states of infection, inflammation and malignant transformation (adenomatous polyps, colorectal cancer). The pathogenesis of sporadic colorectal cancer involves distinct pathways with characteristic genomic and genetic alterations. Despite significant advances in leveraging our understanding of these pathways for diagnostic, prognostic, and therapeutic strategies, colorectal cancer (CRC) remains a leading cause of cancer-related mortality. This underscores a specific need to identify and understand novel, therapeutically tractable pathways in intestinal homeostasis that may drive CRC. Our work has introduced and elucidated the novel role of mRNA binding proteins in intestinal/colonic epithelial homeostasis, as well as aberrations including hyperproliferation, altered metabolism and transformation. LIN28B, an mRNA binding protein, also critical in embryonic stem cells, post- transcriptionally regulates the let-7 microRNA family and results in suppression of differentiation. In turn, Let-7 microRNAs have diverse mRNA targets, including IMP1 (Igf2 mRNA binding protein-1), another mRNA binding protein. We have demonstrated that LIN28B and IMP1 separately drive tumor-initiating cell phenotypes associated with their roles in regulating proliferation and differentiation during normal homeostasis; however, it remains unclear if LIN28B-mediated hyperproliferation, altered differentiation, and associated tumorigenesis requires IMP1. In addition, it remains unknown if the tumor promoting or metastatic roles of IMP1 depend entirely on its regulation by Let-7 downstream of LIN28B. Our overarching hypothesis of this proposal is that LIN28B and IMP1 comprise cooperative roles in controlling post-transcriptionally the pathways (some known) associated with epithelial cell fate, which may favor malignant transformation. We will pursue this hypothesis through the following interrelated Specific Aims:
Aim 1 : To evaluate the interdependence of LIN28B and IMP1 in proliferation, differentiation, and malignant transformation in vivo.
Aim 2 : To determine and validate common and divergent pathways mediated by LIN28B and IMP1 via RNA-Sequencing (?transcriptome?) and ribosome profiling (?translatome?) in vivo.
Aim 3 : To evaluate Let-7 dependent regulation of IMP1 to promote hyperproliferation and metastasis.

Public Health Relevance

There is a compelling need to understand how the normal functions resident within intestinal/colonic epithelial cells go awry to cause excessive proliferation and transformation. The manner in which mRNA binding proteins regulate such functions opens up new opportunities to unravel new approaches to risk stratification, diagnosis and therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056645-18
Application #
9605260
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hamilton, Frank A
Project Start
2000-03-01
Project End
2021-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
18
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Chatterji, Priya; Rustgi, Anil K (2018) RNA Binding Proteins in Intestinal Epithelial Biology and Colorectal Cancer. Trends Mol Med 24:490-506
Giroux, VĂ©ronique; Stephan, Julien; Chatterji, Priya et al. (2018) Mouse Intestinal Krt15+ Crypt Cells Are Radio-Resistant and Tumor Initiating. Stem Cell Reports 10:1947-1958
Andres, Sarah F; Williams, Kathy N; Rustgi, Anil K (2018) The Molecular Basis of Metastatic Colorectal Cancer. Curr Colorectal Cancer Rep 14:69-79
Chatterji, Priya; Hamilton, Kathryn E; Liang, Shun et al. (2018) The LIN28B-IMP1 post-transcriptional regulon has opposing effects on oncogenic signaling in the intestine. Genes Dev 32:1020-1034
Mizuno, Rei; Chatterji, Priya; Andres, Sarah et al. (2018) Differential Regulation of LET-7 by LIN28B Isoform-Specific Functions. Mol Cancer Res 16:403-416
Zhou, Jin; Wu, Zhong; Wong, Gabrielle et al. (2017) CDK4/6 or MAPK blockade enhances efficacy of EGFR inhibition in oesophageal squamous cell carcinoma. Nat Commun 8:13897
Heeg, Steffen; Das, Koushik K; Reichert, Maximilian et al. (2016) ETS-Transcription Factor ETV1 Regulates Stromal Expansion and Metastasis in Pancreatic Cancer. Gastroenterology 151:540-553.e14
Liu, Qi; Zhong, Xue; Madison, Blair B et al. (2015) Assessing Computational Steps for CLIP-Seq Data Analysis. Biomed Res Int 2015:196082
Asfaha, Samuel; Hayakawa, Yoku; Muley, Ashlesha et al. (2015) Krt19(+)/Lgr5(-) Cells Are Radioresistant Cancer-Initiating Stem Cells in the Colon and Intestine. Cell Stem Cell 16:627-38
Hamilton, Kathryn E; Crissey, Mary Ann S; Lynch, John P et al. (2015) Culturing adult stem cells from mouse small intestinal crypts. Cold Spring Harb Protoc 2015:354-8

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