The Hippo pathway in liver regeneration and tumorigenesis
Mueller, Kaly Alyse
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The Hippo signaling pathway has been implicated in both mammalian organ size regulation, as well as tumor suppression. Specifically, the Hippo pathway plays a critical role regulating the activity of transcriptional co-activator, and downstream effector, Yes-associated protein (YAP), which modulates pro-proliferative transcriptional elements. Recent investigations have demonstrated that this pathway is activated in non-regenerating livers and its inhibition leads to liver overgrowth and tumorigenesis. The majority of the existing evidence regarding the role of the Hippo pathway in hepatocyte proliferation is based on in vitro studies and knock-out animal models. However, the role of the Hippo pathway during the natural process of liver regeneration, remains unknown. Here alterations in the Hippo signaling pathway were investigated, namely its interaction with angiomotin-like 2 (AmotL2) and Set7, during liver regeneration using a 70% rat partial hepatectomy (PH) model. Overall, results indicated no significant difference between AmotL2 levels in control and regenerating tissue at various time points during liver regeneration. No significant alterations in YAP methylation during liver regeneration were found compared to control tissue. In the end, results regarding the role of both AmotL2 and Set7 provided inconclusive evidence about their roles during the regenerative process. Given the role of the Hippo pathway in hepatocyte proliferation, a hypothesis was made that this pathway may play a role in pediatric liver tumors. YAP localization was evaluated using immunohistochemical analysis in tumor sections from patients with hepatoblastoma or hepatocellular carcinoma. Once again, the results were inconclusive at the time of the preparation of this manuscript due to technical difficulties in achieving satisfactory staining of the specimens. Further studies will be directed at elucidating the role of the Hippo pathway during liver regeneration as well as developing better conditions for the immunohistochemical staining of human liver specimens.