Abstract
Background Hepatoblastoma (HB) is the most common pediatric liver malignancy, occurring mainly during the first 4 years of life. Recent studies unraveled the frequent, coordinated activation of Wnt/beta-catenin and YAP/Hippo (where YAP is yes-associated protein) pathways in human HB samples. Furthermore, it was found that concomitant overexpression of activated forms of beta-catenin and YAP in ...
Abstract
Background Hepatoblastoma (HB) is the most common pediatric liver malignancy, occurring mainly during the first 4 years of life. Recent studies unraveled the frequent, coordinated activation of Wnt/beta-catenin and YAP/Hippo (where YAP is yes-associated protein) pathways in human HB samples. Furthermore, it was found that concomitant overexpression of activated forms of beta-catenin and YAP in the mouse liver triggers HB formation in YAP/beta-catenin mice. Cyclin-dependent kinases 9 (CDK9) is an elongating kinase, which has been shown to mediate YAP-driven tumorigenesis. The role of CDK9 in HB molecular pathogenesis has not been investigated to date. Methods CDK9 expression was determined in human HB lesions, HB cell lines, and YAP/beta-catenin mouse livers. CDK9 was silenced in human HB cell lines and the effects on growth rate and YAP targets were analyzed. Hydrodynamic transfection of YAPS127A and increment N90-beta-catenin together with either shCdk9 or control shLuc (where Luc is luciferase) plasmids was employed to assess the requirement of Cdk9 for HB development in vivo. Results Nuclear immunoreactivity for CDK9 protein was more pronounced in human HB samples and YAP/beta-catenin mouse HB tumor tissues than in corresponding surrounding nontumorous liver tissues. CDK9 protein was also expressed in human HB cell lines. Silencing of CDK9 in human HB cell lines did not lead to consistent effects on HB cell growth or YAP target gene expression. Surprisingly, silencing of Cdk9 led to accelerated liver tumorigenesis in YAP/beta-catenin mice. Conclusion CDK9 is not a major downstream mediator of YAP oncogenic function in HB development and progression.
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