HGF and ligation of alphavbeta5 integrin induce a novel, cancer cell-specific gene expression required for cell scattering

Abstract

Hepatocyte growth factor (HGF), a cytokine involved in tumorigenesis and most metastases, initiates cell migration by binding to the protooncogene c-Met receptor. In epithelial carcinoma cells, c-Met activation causes the breakdown of E-cadherin cell-cell contacts leading to cell spreading. While the breakdown of E-cadherin contacts is immediate, HGF-induced migration requires transcription. To test the hypothesis that this de novo mRNA synthesis includes cancer cell-specific transcripts, we performed subtraction hybridization to isolate HGF-induced transcripts from an endometrial epithelial carcinoma cell line, RL95-2 (RL95), known to migrate but not to proliferate with HGF treatment. One novel cDNA we call Mig-7 is induced by HGF in endometrial epithelial carcinoma cell lines RL95 and HEC-1A before migration ensues. Ovarian, oral squamous cell, and colon metastatic tumors but not normal tissues express Mig-7. HGF did not induce Mig-7 in normal primary endometrial epithelial cells. In addition, blocking antibodies to alphavbeta5 integrin inhibited HGF induction of Mig-7 in RL95 cells. Most importantly, Mig-7-specific antisense oligonucleotides inhibited scattering of RL95 cells in vitro. These results are the first to demonstrate that Mig-7 expression may be used as a cancer cell-specific target to inhibit cell scattering.