The Functional Roles of the Lin28/let-7 Axis in Tissue Regeneration and Cancer




Nguyen, Liem Hieu

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The let-7 microRNAs and their antagonists, the Lin28 RNA-binding proteins (Lin28a and Lin28b), are post-transcriptional regulators well known for their initially discovered role in controlling developmental timing, or heterochrony. Subsequent studies have further uncovered many additional cellular processes, such as differentiation, metabolism, and body size, controlled by Lin28 and let-7. Their role in pathology, however, is not as well characterized. Although several lines of in vitro evidence have implicated involvement of Lin28a/b and let-7 in cancer, their functional roles in tumor initiation and maintenance have not been vigorously demonstrated in animal models. The work in this thesis focuses on defining the in vivo functional roles of Lin28 and let-7 in the context of tissue regeneration and liver cancer. Our first study led us to discover that Lin28 overexpression is both sufficient to initiate liver cancer and necessary for its maintenance and that its oncogenic effects are mediated in part through downregulating let-7 and upregulating the Igf2-binding protein family expression levels. Subsequently, we demonstrated that overexpression of let-7g has a potent tumor suppressing effect at the expense of efficient tissue regeneration. Too little or too much let-7 resulted in compromised protection against cancer or tissue damage, respectively. Surprisingly, we found that loss of only two let-7 members, let-7b and let-7c2, render an increased regenerative capacity in liver. Lastly, in an effort to translate our findings for clinical applications, we collaborated with Daniel Siegwart's group to engineer novel lipid nanoparticles that enabled us to efficiently deliver small RNAs, such as let-7, into mice and investigate their therapeutic effects. Together, this work carefully defined the functional role of each of the main players of the Lin28/let-7 pathway in cancer. This knowledge has clinical implications because it identifies new targets for drug developments to treat liver cancer, disease that currently has very limited treatment options.

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