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

Oncogene. 2011 Mar 10;30(10):1229-40. doi: 10.1038/onc.2010.504. Epub 2010 Nov 15.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Cell Cycle Proteins
  • Cell Line
  • Cell Movement / genetics
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Gene Expression
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Knockdown Techniques
  • Humans
  • Immunoblotting
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Male
  • Mice
  • Mice, Nude
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Small Interfering
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transfection
  • Transplantation, Heterologous

Substances

  • Cell Cycle Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Transcription Factors
  • YY1AP1 protein, human
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase