Investigating the Role of Lin-28 in Germ Cell Tumorigenesis

Germ cell tumors arise from the tissues that make up the reproductive tract, and although rare, cause significant morbidity and mortality in the pediatric age group. This proposal will investigate the role of a gene called Lin28 in germ cell tumors. Recently, we have discovered that Lin28 blocks the production of an important class of regulators in the cell called Let-7 microRNAs, which are "tumor-suppressors" that protect against cancers of the breast, lung, and colon. In surveys of a variety of human tumors, we found that a high percentage of germ cell tumors express Lin28 and/or its close relative, Lin28B. Our preliminary data show that Lin28 can act as a cancer gene to transform a number of different cell types in the Petri dish. This proposal will test the hypothesis that hyperactivity of Lin28 drives the formation of germ cell tumors in pediatric patients by blocking the production of Let-7 tumor suppressors. We will investigate the role of Lin28 in human germ cell tumors and will produce strains of mice with hyperactive Lin28. We will test whether restoring Let-7 activity in germ cell tumors is an effective therapeutic strategy. These studies will illuminate the role of Lin28 in pediatric germ cell tumors, and hopefully lead to improved methods of diagnosis and treatment.