The RNA-binding protein LIN28B has been implicated in a variety of cancers, with their expression correlating with an aggressive phenotype, enhanced metastasis and poor prognosis. When expression is directed to the mouse intestinal epithelium we find that LIN28B causes intestinal hypertrophy, loss of Paneth cells, crypt fission and intestinal adenocarcinoma formation. LIN28B specifically targets and repress the Let-7 family of miRNAs. LIN28B inhibits Let-7 microRNA (miRNA) maturation through sequestration of pri-miRNAs n the nucleolus, which is inaccessible to microprocessor machinery. By rescuing Let-7 levels with an inducible Let- 7a transgenic mouse model, we determined that the LIN28B phenotypes noted above are due to Let-7 dependent actions of LIN28B. Furthermore, we find that LIN28B mediated downregulation of Let-7 results in the upregulation of Igf mRNA binding protein-1 (IMP1), and thus, we will investigate the role of the interplay between LIN28B and IMP-1 in intestinal homeostasis and cancer. Since Let-7-independent mechanisms of LIN28B function have been reported, we have pursued ribonucleoprotein cross-linking, immunoprecipitation, and high-throughput sequencing (RNP CLIP-Seq) to identify mRNAs and miRNAs that are targeted directly by LIN28B.This reveals that LIN28B binds to mRNAs involved in metabolic processes, splicing, and regulation of the actin cytoskeleton. Thus, we identify a new pathway of LIN28B-Let7-IMP1 in colon carcinogenesis that adds to our knowledge of underlying molecular mechanisms, but also provides a platform in translational opportunities by using LIN28B as a biomarker for disease progression, and targeting this pathway therapeutically.

Public Health Relevance

The intestinal/colonic epithelia undergo an exquisite program of proliferation and differentiation that is continuously renewed, and yet, subjct to insults such as infection, inflammation and transformation. This project seeks to understand and elucidate how LIN28b and IMP1, two RNA binding proteins, affect differentiation and transformation, using state of the art in vitro and in vivo approaches. The insights gained will hopefully have new translational applications in diagnosis, prognosis and therapy in patients.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01DK056645-14A1
Application #
8695677
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Hamilton, Frank A
Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
Madison, Blair B; Jeganathan, Arjun N; Mizuno, Rei et al. (2015) Let-7 Represses Carcinogenesis and a Stem Cell Phenotype in the Intestine via Regulation of Hmga2. PLoS Genet 11:e1005408
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; Chatterji, Priya; Lundsmith, Emma T et al. (2015) Loss of Stromal IMP1 Promotes a Tumorigenic Microenvironment in the Colon. Mol Cancer Res 13:1478-86
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
Schnepp, Robert W; Khurana, Priya; Attiyeh, Edward F et al. (2015) A LIN28B-RAN-AURKA Signaling Network Promotes Neuroblastoma Tumorigenesis. Cancer Cell 28:599-609
Kim, Jihun; Fox, Cameron; Peng, Shouyong et al. (2014) Preexisting oncogenic events impact trastuzumab sensitivity in ERBB2-amplified gastroesophageal adenocarcinoma. J Clin Invest 124:5145-58
Watanabe, Hideo; Ma, Qiuping; Peng, Shouyong et al. (2014) SOX2 and p63 colocalize at genetic loci in squamous cell carcinomas. J Clin Invest 124:1636-45
Hamilton, Kathryn E; Noubissi, Felicite K; Katti, Prateek S et al. (2013) IMP1 promotes tumor growth, dissemination and a tumor-initiating cell phenotype in colorectal cancer cell xenografts. Carcinogenesis 34:2647-54

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