Original ResearchFull Report: Basic and Translational—LiverYes-Associated Protein Up-regulates Jagged-1 and Activates the NOTCH Pathway in Human Hepatocellular Carcinoma
Section snippets
Materials and Methods
For a detailed description of methods and antibodies used in this study see the Supplemental Materials and Methods section and Supplemental Table 1.
YAP Overexpression Supports HCC Cell Viability and Migration
Comprehensive immunohistochemical analysis of human specimens revealed weak/absent hepatocellular staining for nuclear or cytoplasmic YAP in normal or cirrhotic livers, dysplastic nodules, and hepatocellular adenomas (Supplementary Figure 1A). In contrast, nuclear YAP expression significantly increased in HCC, showing moderate to high expression in up to 67% of all cases (Supplementary Figure 1B and C). Nuclear YAP expression correlated with proliferation (Ki67 staining; r = 0.3; P < .001), but
Discussion
Accumulating evidence supports the importance of the tumor-suppressive Hippo pathway and its mediator YAP in cancer.1, 3, 4, 5, 6, 7, 12, 23 Here, we show that overexpression of YAP exerts its tumor-supporting properties partly through TEAD4-dependent Jag-1 expression and subsequent activation of the Notch pathway in gastrointestinal cancers. Our in vitro data provide evidence that YAP not only regulates proliferation and apoptosis but also affects cell migration in tumor cell lines of
Acknowledgments
The authors thank M. Bissinger, U. Müller, and S. Messnard for technical assistance; and T. R. Brummelkamp (Whitehead Institute for Biomedical Research, Cambridge, MA) and F. D. Camargo (Stem Cell Program, Children's Hospital, Boston, MA) for providing the Col1A1-YAPS127A mice.
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Conflicts of interest The authors disclose no conflicts.
Funding This study was supported by grants from the Deutsche Forschungsgemeinschaft (SFB/TRR77 to K.B. and P.S., Ev168/2-1 to M.E., and Do622/2-1 to F.D.), the Helmholtz Alliance Immunotherapy of Cancer (P.S. and D.F.T.), the Virtual Liver Network (P.S. and K.B.), the Monika Kutzner Stiftung (D.F.T.), and National Institutes of Health R01CA136606 (X.C.). Also supported by the tissue bank of the National Center for Tumor Disease Heidelberg.
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Authors share co-senior authorship.