Journal
ONCOGENE
Volume 30, Issue 10, Pages 1229-1240Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2010.504
Keywords
cancer signaling; Hippo pathway; YAP1 oncogene; AXL receptor kinase; HCC; hepatocellular carcinoma
Funding
- Biomedical Research Grants Council of Singapore
- National University Cancer Institute (NCIS) Centre
- National Natural Science Foundation of China [81000880]
- National Cancer Institute of NIH [CA13106]
- A*STAR
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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 alpha-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. Oncogene (2011) 30, 1229-1240; doi: 10.1038/onc.2010.504; published online 15 November 2010
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