Recepteur d'origine nantais tyrosine kinase is a direct target of hypoxia-inducible factor-1α-mediated invasion of breast carcinoma cells

Abstract

Hypoxia-inducible factor-1α (HIF-1α) overexpression was shown to be associated with invasion and metastasis of tumors and tumor cell line a. The identification of molecular targets that contribute to HIF-1α-mediated invasion is under intensive investigation. We iave analyzed the role of recepteur d'origine nantais (RON), a tyrosine kinase receptor for macrophage-stimulating protein (MSP) that plays a role in breast cancer cell invasion as one of the molecular targets of HIF-1α. Analysis of a panel of breast cain cer cell lines indicated a correlation between HIF-1α and RON ression. Treatment of HIF-1α- and RON- positive breastcaner cells with HIF-1α inhibitor, echinomycin, led to the inhibition of HIF-1α activity and RON expression. We have identified HIF-1α binding site on the RON promoter. Chromatin immunoprecipitation analysis and site-directed mutagenesis of the RON promoter confirmed the binding of HIF-1α to RON promoter. HIF-1α inhibitor-, echinomycin-, or short hairpin RNA-mediated selective knockdown of HIF-1α or HIF-1α target RON tyrosine kinase abrogated RON gene expression, and the RON ligand macrophage-stimulating protein mediated invasion of breast cancer cells. Consequently, the data presented herein demonstrated RON as a novel molecular target of HIF-1α and suggest a potential therapeutic role for HIF-1α or RON tyrosine kinase inhibitors in the blockade of RON tyrosine kinase-mediated invasion of carcinoma cells. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.