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AXL receptor kinase is a mediator of YAP-dependent oncogenic functions in hepatocellular carcinoma

Oncogene volume 30, pages 1229–1240 (2011)Cite this article

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Abstract

Yes-associated protein (YAP) is a downstream effector of the Hippo signaling pathway, which controls organ expansion and tissue development. We have recently defined the tumorigenic potential and clinical significance of the YAP1 oncogene in human hepatocellular carcinoma (HCC). The present study aims to define the tumorigenic properties of YAP in HCC and elucidate the related downstream signaling mechanism. In a gain-of-function study, we demonstrated that ectopic increased expression of YAP in the immortalized non-tumorigenic hepatocyte cell line MIHA confers tumorigenic and metastatic potentials, as evidenced by (1) enhanced aptitudes in cell viability, anchorage-independent growth, migration and invasion; (2) tumor formation in a xenograft mouse model; and (3) induction of HCC biomarker α-fetoprotein and activation of mitogen-activated protein kinase. Furthermore, we have identified AXL, a receptor tyrosine kinase, as a key downstream target that drives YAP-dependent oncogenic functions. RNAi-mediated knockdown of AXL expression decreased the ability of YAP-expressing MIHA cells and of the primary HCC cell line to proliferate and invade. These results indicate that AXL is a mediator of YAP-dependent oncogenic activities and implicates it as a potential therapeutic target for HCC.

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Acknowledgements

We thank Dr Yuk-Tat Chan (Queen Mary Hospital, HK) for the AFP assay and Dr Stella Sun (University of Hong Kong)) for technical assistance on cell line maintenance.

Sources of support: The work was supported by grants to JML from the Biomedical Research Grants Council of Singapore and by the National University Cancer Institute (NCIS) Centre Grant; WH was supported by the A*STAR and MX by the National Natural Science Foundation of China (Grant No. 81000880). SWL is an investigator in the Howard Hughes Medical Institute and Dr Lowe's work is supported by a program grant (CA13106) from the National Cancer Institute of NIH.

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Author notes

  1. M Z Xu, S W Chan and A M Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, the Affiliated Nanjing First Hospital, Nanjing Medical University, Nanjing, PR China

    M Z Xu, J Chen & J M Luk

  2. Department of Surgery, Queen Mary Hospital, University of Hong Kong, Hong Kong, PR China

    M Z Xu, A M Liu, K F Wong, S T Fan, R T Poon & J M Luk

  3. Cancer and Developmental Cell Biology Division, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore

    S W Chan & W Hong

  4. Department of Pharmacology, Department of Surgery, and Cancer Science Institute, National University of Singapore, Singapore

    A M Liu, K F Wong & J M Luk

  5. Department of Cell Biology, Helmholtz Center for Infection Research, Braunschweig, Germany

    L Zender

  6. Howard Hughes Medical Institute and CSHL Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA

    S W Lowe

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  1. M Z Xu
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Correspondence to J M Luk.

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Xu, M., Chan, S., Liu, A. et al. AXL receptor kinase is a mediator of YAP-dependent oncogenic functions in hepatocellular carcinoma. Oncogene 30, 1229–1240 (2011). https://doi.org/10.1038/onc.2010.504

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