Reactivation of Embryonic Growth Programs in Liver Cancer
Heterochronic genes encode products whose expression changes throughout time in tissues and temporally regulates developmental changes, organ growth, and regenerative capacity. For example, many heterochronic genes are expressed in fetal, but not adult, tissues such that they promote the rapid growth of fetal tissues and are shut off postnatally. Cancers can reactivate these heterochronic genes in adult tissues to enable neoplastic proliferation. We have uncovered important roles for heterochronic genes by using murine models that allow temporally specific gain or loss of Lin28 and let-7.
We previously showed that adult reactivation of Lin28a promotes regeneration capabilities reminiscent of embryonic tissue (Nguyen et al., 2014). Lin28’s ability to temporally integrate embryonic metabolism, cell proliferation, and tissue growth also contributes to its oncogenic activities. We are currently determining the functions and mechanisms of the oncofetal RNA-binding protein Imp3 (aka Igf2bp3), a well-known downstream target of let-7 and Lin28. Our goal is to define the mechanisms downstream of Imp3 that are therapeutically relevant.
