Browsing by Subject "Liver Regeneration"
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Item The Functional Roles of the Lin28/let-7 Axis in Tissue Regeneration and Cancer(2017-04-11) Nguyen, Liem Hieu; Corey, David R.; Mendell, Joshua T.; Castrillon, Diego H.; Zhu, HaoThe 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.Item The Role of Polyploidy in the Liver and Its Implications for Cancer Therapy(2018-04-13) Zhang, Shuyuan; O'Donnell, Kathryn A.; Zhu, Hao; Brugarolas, James B.; Yu, HongtaoThe description of liver polyploidy dates back to the 1940s, but its functional roles are still largely unknown. Numerous observations and studies have suggested that liver polyploidy may participate in multiple biological processes, including regeneration, stress response, and cancer. However, little evidence has established direct causal links between polyploidy and the observed phenotypes, mainly due to the lack of appropriate tools to specifically manipulate ploidy levels without causing other permanent changes. Specifically, whether polyploidy promotes or inhibits cancer is still under debate. Inspired by a phenomenon we observed in somatically mutated mouse livers, where homozygous Apc deletions were more difficult to obtain due to hepatic polyploidy, we aimed to build inducible tools to manipulate liver ploidy levels in vivo and systematically study the role of polyploidy in liver cancer. By toggling the weaning time and levels of Anln or E2f8 genes to change liver ploidy levels, we found that liver tumorigenesis was inversely correlated with initial polyploidy levels, suggesting a tumor suppressive role for polyploidy. Moreover, the additional alleles in polyploid cells led to a reduced likelihood of loss of heterozygosity (LOH), which largely contributed to the tumor suppressive effect. These results revealed an important function of polyploidy in mammalian livers and also led us to seek related therapeutic strategies for treating liver cancer. Since hepatocyte polyploidization mainly occurs through cytokinesis failure, we hypothesized that inhibiting cytokinesis could be an effective strategy to suppress liver tumorigenesis while preserving normal liver function. Therefore, we inhibited cytokinesis via Anln knockdown in multiple models and found that liver tumor development was significantly suppressed but normal liver function and regeneration capacity were not impaired. These results suggest that cytokinesis inhibition via Anln knockdown is potentially a safe and efficacious strategy for suppressing liver cancer. Overall, we uncovered an important role of polyploidy in the liver and explored its potential applications in liver cancer therapy.