Abstract
Epidermal growth factor receptor (EGFR) overexpression and activation is critical in the initiation and progression of cancers, especially those of epithelial origin. EGFR activation is associated with the induction of divergent signal transduction pathways and a gamut of cellular processes; however, the cell-type and tissue-type specificity conferred by certain pathways remains to be elucidated. In the context of the esophageal epithelium, a prototype stratified squamous epithelium, EGFR overexpression is relevant in the earliest events of carcinogenesis as modeled in a three-dimensional organotypic culture system. We demonstrate that the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, and not the MEK/MAPK (mitogen-activated protein kinase) pathway, is preferentially activated in EGFR-mediated esophageal epithelial hyperplasia, a premalignant lesion. The hyperplasia was abolished with direct inhibition of PI3K and of AKT but not with inhibition of the MAPK pathway. With the introduction of an inducible AKT vector in both primary and immortalized esophageal epithelial cells, we find that AKT overexpression and activation is permissive for complete epithelial formation in organotypic culture, but imposes a growth constraint in cells grown in monolayer. In organotypic culture, AKT mediates changes related to cell shape and size with an expansion of the differentiated compartment.
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Acknowledgements
This work was supported by the NIH/NCI Grant P01 DE12467 (AKR, KO, TO, HN, CA, AK, AKS, MH, WED), NIH/NIDDK Center for Molecular Studies in Digestive and Liver Diseases (P30 DK50306), and the Morphology, Molecular Biology, Mouse and Cell Culture Core Facilities, NIH/NCI Grants CA 80999 and CA 25874 (both to MH), K01-DK066205 9 (HN), and F32-CA108657 and the AGA/FDHN Research Scholar Award (both to CA). We thank members of the Rustgi lab (Therese Deramaudt, Cameron Johnstone, Carmen Michaylira, Doug Stairs and Ben Rhoades) for discussions.
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
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Oyama, K., Okawa, T., Nakagawa, H. et al. AKT induces senescence in primary esophageal epithelial cells but is permissive for differentiation as revealed in organotypic culture. Oncogene 26, 2353–2364 (2007). https://doi.org/10.1038/sj.onc.1210025
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DOI: https://doi.org/10.1038/sj.onc.1210025
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