Expression of the FGFR2c mesenchymal splicing variant in human keratinocytes inhibits differentiation and promotes invasion.

Abstract

The altered isoform switching of the fibroblast growth factor receptor 2 (FGFR2) and aberrant expression of the mesenchymal FGFR2c isoform in epithelial cells is involved in cancer progression. We have recently described that the ectopic expression of FGFR2c in normal human keratinocytes induces epithelial-mesenchymal transition and leads to invasiveness and anchorage-independent growth. Here, we extended our analysis to the effects of this FGFR2c forced expression on human keratinocyte differentiation and stratification. Our findings demonstrated that, differently from cells overexpressing the epithelial splicing variant FGFR2b, keratinocytes ectopically expressing FGFR2c are not able to form a monolayer and display decreased expression of early differentiation markers. This impaired ability to enter the differentiation program is related to the up-modulation of the transcription factor ΔNp63. In addition, FGFR2c-expressing keratinocytes undergo defective stratification and invasion of the collagen matrix in 3D organotypic cultures, further suggesting their tumorigenic potential. Taken together, our results support the hypothesis that the receptor switching and the consequent appearance of the mesenchymal FGFR2c variant in the epithelial context would drive early steps of carcinogenesis, unbalancing the p63/FGFR interplay, and altering the paracrine response to the microenvironment.

• Authors: Danilo Ranieri, Benedetta Rosato, Monica Nanni, Francesca Belleudi, Maria Rosaria Torrisi
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 57 Issue 2 Pg. 272-283 (02 2018) ISSN: 1098-2744 [Electronic] United States
• PMID: 29068468 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc.

Chemical References

• Protein Isoforms
• FGFR2 protein, human
• Receptor, Fibroblast Growth Factor, Type 2

Topics

• Cell Differentiation (genetics)
• Cell Line
• Epithelial Cells (metabolism, pathology)
• Epithelial-Mesenchymal Transition (genetics)
• Gene Expression Regulation (genetics)
• Humans
• Keratinocytes (metabolism, pathology)
• Neoplasm Invasiveness (genetics, pathology)
• Protein Isoforms (genetics)
• RNA Splicing (genetics)
• Receptor, Fibroblast Growth Factor, Type 2 (genetics)
• Signal Transduction (genetics)