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.
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.
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