Abstract
Keratinocyte growth factor (KGF, fibroblast growth factor-7) is a fibroblast-derived mitogen, which stimulates proliferation of epithelial cells. The expression of KGF by dermal fibroblasts is induced following injury and it promotes wound repair. However, the role of KGF in cutaneous carcinogenesis and cancer progression is not known. We have examined the role of KGF in progression of squamous cell carcinoma (SCC) of the skin. The expression of KGF receptor (KGFR) mRNA was lower in cutaneous SCCs (n = 6) than in normal skin samples (n = 6). Expression of KGFR mRNA was detected in 6 out of 8 cutaneous SCC cell lines and the levels were downregulated by 24-h treatment with KGF. KGF did not stimulate SCC cell proliferation, but it reduced invasion of SCC cells through collagen. Gene expression profiling of three cutaneous SCC cell lines treated with KGF for 24 h revealed a specific gene expression signature characterized by upregulation of a set of genes specifically downregulated in SCC cells compared to normal epidermal keratinocytes, including genes with tumor suppressing properties (SPRY4, DUSP4, DUSP6, LRIG1, PHLDA1). KGF also induced downregulation of a set of genes specifically upregulated in SCC cells compared to normal keratinocytes, including genes associated with tumor progression (MMP13, MATN2, CXCL10, and IGFBP3). Downregulation of MMP-13 and KGFR expression in SCC cells and HaCaT cells was mediated via ERK1/2. Activation of ERK1/2 in HaCaT cells and tumorigenic Ha-ras-transformed HaCaT cells resulted in downregulation of MMP-13 and KGFR expression. These results provide evidence, that KGF does not promote progression of cutaneous SCC, but rather suppresses the malignant phenotype of cutaneous SCC cells by regulating the expression of several genes differentially expressed in SCC cells, as compared to normal keratinocytes.
Highlights
Keratinocyte growth factor (KGF, fibroblast growth factor-7 (FGF-7)) is produced by cells of mesenchymal origin and by epidermal cd T cells [1,2]
In order to elucidate the role of KGF in progression of epidermal malignant tumors, we first determined the expression of KGF and KGFR mRNA in cutaneous squamous cell carcinoma (SCC) and in normal skin by quantitative real-time RT-PCR
In this study we have examined the effect of KGF, a potent epithelial cell mitogen, on cutaneous SCC cells
Summary
Keratinocyte growth factor (KGF, fibroblast growth factor-7 (FGF-7)) is produced by cells of mesenchymal origin and by epidermal cd T cells [1,2]. The expression of KGF by stromal fibroblasts is induced after injury in response to various stimuli including transforming growth factor-a, interleukin-1, and tumor necrosis factor-a [7,8,9]. The stimulatory effect of KGF on cutaneous wound healing has been demonstrated by delivery of exogenous KGF into wounds [10,11,12]. KGF has been recognized for its protective effect on normal epithelial tissues, and use of recombinant KGF has been approved for prevention and treatment of severe oral mucositis in patients with hematologic cancers receiving high-dose chemotherapy and radiation therapy followed by bone marrow transplantation. The safety and efficacy of KGF for protecting normal epithelial tissue in patients with non-hematologic malignancies treated with chemo- and radiotherapy has not been established and is under investigation [13,14,15]
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