Hepatocyte growth factor upregulates E1AF that induces oral squamous cell carcinoma cell invasion by activating matrix metalloproteinase genes

Abstract

Hepatocyte growth factor (HGF) is thought to play a role in cell motility and invasion. Matrix metalloproteinases (MMPs) have been implicated in invasion and metastasis of tumor cells. We have previously reported that the Ets-oncogene family transcription factor E1AF positively regulates transcription of MMP genes in transient expression assays and that overexpression of the E1AF gene confers an invasive phenotype on breast cancer cells. Here we examined the effect of HGF on E1AF and MMP gene expression in terms of the invasive potential of the oral squamous cell carcinoma cell line HSC3. HGF stimulated expression of the E1AF gene. The levels of MMP-1, -3 and -9 mRNAs increased in cells treated with HGF and correlated with E1AF upregulation. In contrast, no obvious upregulation of MMP-1 and -9 mRNA was observed in ASE1AFHSC3 cells transfected with the antisense E1AF expression vector into parental HSC3 cells. The wild-type MMP-9 gene promoter was activated by endogenous E1AF in HSC3 cells, and chloramphenicol acetyltransferase (CAT) activities increased when HGF was added to transfected cells. On the other hand, CAT activity was reduced to almost two-thirds of the wild-type activity when HSC3 cells were transfected with a CAT reporter plasmid driven by a mutant MMP-9 promoter lacking the Ets-binding site, and induction of CAT activity was not observed upon addition of HGF. Analysis of organotypic raft cultures revealed that HSC3 cells invaded and degraded collagen gel actively upon addition of HGF. These results suggest that HGF induces expression of the Ets-related E1AF transcription factor gene whose product in turn activates MMP genes and leads to oral cancer cell invasion.

Role of Met Axis in Head and Neck Cancer

“…Consistent with in vivo data, HGF stimulation of Met-expressing HNSCC cell lines promotes an invasive phenotype [15,94]. Furthermore, activating mutations of Met are specifically selected during HNSCC metastasis [95].…”

“…Activation of Met by HGF in HNSCC cells leads to activation of Erk and Akt kinases, and Ets-related transcription factor E1AF activation, which in turn results in up-regulation of urokinase-type plasminogen activator and matrix metalloproteinases (MMP-1, 3 and 9) production [94,102]. These proteases are capable of degrading the extracellular matrix and may cooperate with MT-MMP-1 to facilitate cell migration through basement membrane, a critical step in tumor invasion.…”

ESE‐1 inhibits the invasion of oral squamous cell carcinoma in conjunction with MMP‐9 suppression

“…It is possible that the pointed domain of ESE-1 interacts with a co-suppressor or another ets factor, which mediates MMP-9 promoter suppression. Under these conditions, E1AF, an ets family transcription factor, is expressed in oral SCC cells (Hanzawa et al, 2000) and at the invasive front in colorectal cancer (Horiuchi et al, 2003). E1AF can upregulate the promoter activities of several MMP genes, including MMP-9.…”

Effects of hepatocyte growth factor on the expression of matrix metalloproteinases and their tissue inhibitors during the endometrial cancer invasion in a three-dimensional coculture

“…It has also been reported to increase the expression of MMP-9 in the proximal tubule cells of human kidneys (45) and in human epithermal cells (39) . HGF is also involved in the gene activation mechanisms for MMP-1 and MMP-9 in oral squamous cell carcinomas by up regulation of the E1AF, a transcription factor for the Ets-oncogene family (46) . In hepatocytes, HGF promotes MMP-9 expression and TNF-a activity, but has no effect on MMP-2 expression while suppressing the actions of TIMP-1 and TIMP-2 (47) .…”