Keratinocyte growth factor induces gene expression signature associated with suppression of malignant phenotype of cutaneous squamous carcinoma cells

• Published in: PloS one Vol. 7; no. 3; p. e33041
• Main Authors: Toriseva, Mervi, Ala-aho, Risto, Peltonen, Sirkku, Peltonen, Juha, Grénman, Reidar, Kähäri, Veli-Matti
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.03.2012; Public Library of Science (PLoS)
• Subjects: Adenoviruses; Biology; Biotechnology; Blotting, Western; Cancer genetics; Cancer therapies; Carcinogenesis; Carcinogens; Carcinoma, Squamous Cell - metabolism; Cell adhesion & migration; Cell Line, Tumor; Cell proliferation; Chemokine CXCL10 - metabolism; Chemotherapy; Collagen; Collagenase 3; CXCL10 protein; Dermatology; Development and progression; Dual Specificity Phosphatase 6 - metabolism; Dual-Specificity Phosphatases - metabolism; Enzyme-Linked Immunosorbent Assay; Epidermal growth factor; Epithelial cells; Extracellular Matrix Proteins - metabolism; Extracellular signal-regulated kinase; Fibroblast growth factor; Fibroblast Growth Factor 7 - metabolism; Fibroblast Growth Factor 7 - pharmacology; Fibroblast growth factors; Fibroblasts; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genes; Genetic aspects; Glycoproteins - metabolism; Humans; Injuries; Insulin-Like Growth Factor Binding Protein 3 - metabolism; Insulin-like growth factor-binding protein 3; Keratinocyte growth factor; Keratinocytes; Kinases; Laboratories; Matrilin Proteins; Medicine; Messenger RNA; Mitogen-Activated Protein Kinase Phosphatases - metabolism; Mitogens; Neck; Neoplasm Invasiveness - prevention & control; Oligonucleotide Array Sequence Analysis; Otolaryngology; Phenotype; Real-Time Polymerase Chain Reaction; Skin; Skin Neoplasms - metabolism; Squamous cell carcinoma; Tumors; Wound healing; Finland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0033041

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.