Lin28 is a highly conserved RNA binding protein that modifies gene expression via direct binding of mRNAs and by blocking the processing of the let-7 family of tumor suppressor microRNAs. In vertebrates, Lin28a and its paralog Lin28b are highly expressed in stem and progenitor cells of the early embryo, and play important roles in the balance of self-renewal, proliferation, and differentiation. Over-expression of Lin28 has been detected in a wide array of malignancies, including colon, breast, kidney, liver, leukemia, and several pediatric embryonal tumors such as Neuroblastoma and Wilms tumor (WT). Wilms tumor is the fourth most common type of childhood cancer and the most common type of pediatric kidney cancer, affecting 1 in 10,000 children in North America.WT is particularly interesting as it arises from multipotent embryonic kidney precursor cells that fail to differentiate, providing a window into the mechanisms of early renal development and potentially into the properties of embryonic kidney stem cells. The general goal of this dissertation project is to inform the molecular pathogenesis of Wilms tumor, and to interrogate the Lin28/let-7 pathway as an exemplar of the large variety of human tumors in which this pathway has been implicated.
This proposal will provide insights into the role of Lin28/let-7 pathway in a childhood kidney cancer, Wilms' tumor. Dysregulation of the pathway has been documented in a growing list of various cancers, especially those that are highly aggressive and carry the worst prognosis. It is my hope that discovery of Wilms' specific pathways or targets would add considerable depth to our understanding of the large variety of human tumors in which Lin28/let-7 axis has been implicated and may ultimately be important for defining therapeutic approaches.