Differential And Cooperative Roles Of β‐Catenin And Yap During Hepatoblastoma Pathogenesis

Abstract

Hepatoblastoma (HB) is the most frequent pediatric liver tumor. In our previous study we demonstrated that coordinated activation of Yap and β‐catenin is a major mechanism in promoting HB development. However, the individual contribution of Yap and β‐catenin and how they may interact to contribute to induce HB remains unknown. Here, instead of co‐delivering yap and β‐catenin sleeping beauty plasmids with transposase, we hydrodynamically delivered either Yap first followed 3 days or 7 days later by β‐catenin or vice versa. The mouse livers were harvested at 6 weeks, 7 weeks, and 9 weeks after the second injection for comparing tumor size and phenotype to the Yap‐b‐catenin co‐injected group. There was no difference in the liver phenotype when Yap injection preceded β‐catenin compared to Yap‐β‐catenin co‐injection. However, the tumors were significantly smaller and fewer when β‐catenin injection preceded Yap as compared to the co‐delivery group at the early time‐points (6 & 7 weeks). Intriguingly, there was no difference in tumors between all 3 groups at late stage (9 weeks). Lastly, when Yap with defective TEAD binding and b‐catenin or b‐catenin with defective TCF4 binding and Yap were co‐delivered, there was alleviation of tumorigenesis. In summary, Yap is important early in reprograming hepatocyte to hepatoblasts, while both Yap and β‐catenin with preserved ability to bind their canonical transcription factors are required for tumor growth and progression through activation of downstream targets.