Abstract
Lgr4 is a member of the leucine-rich, G protein-coupled receptor family of proteins, and has recently been shown to augment Wnt/β-catenin signaling via binding to Wnt agonists R-spondins. It plays an important role in skin development, but its involvement in skin tumorigenesis is unclear. Here, we report that mice deficient for Lgr4 are resistant to 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced keratinocyte proliferation and papilloma formation. We show that TPA treatment activates MEK1, ERK1/2 and downstream effector AP-1 in wild-type (WT) epidermal cells and mice, but not in cells or mice where Lgr4 is depleted. Wnt/β-catenin signaling is also dramatically activated by TPA treatment, and this activation is abolished when Lgr4 is deleted. We provide evidences that blocking both MEK1/ERK1/2 and Wnt/β-catenin pathways prevents TPA-induced increase in the expression of Ccnd1 (cyclin D1), a known Wnt/β-catenin target gene, and that the activation of MEK1/ERK1/2 pathway lies upstream of Wnt/β-catenin signal pathway. Collectively, our findings identify Lgr4 as a critical positive factor for skin tumorigenesis by mediating the activation of MEK1/ERK1/2 and Wnt/β-catenin pathways.
Keywords:
ERK1/2; Lgr4; Squamous cell carcinoma; TPA; β-Catenin.
Copyright © 2016. Published by Elsevier Ireland Ltd.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Cell Proliferation
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Cell Transformation, Neoplastic / chemically induced
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Cell Transformation, Neoplastic / pathology
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Genetic Predisposition to Disease
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Humans
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Keratinocytes / enzymology*
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Keratinocytes / pathology
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MAP Kinase Kinase 1 / metabolism*
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Mice, Knockout
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Neoplasms, Experimental / chemically induced
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Neoplasms, Experimental / enzymology*
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Neoplasms, Experimental / genetics
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Neoplasms, Experimental / pathology
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Papilloma / chemically induced
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Papilloma / enzymology*
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Papilloma / genetics
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Papilloma / pathology
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Phenotype
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RNA Interference
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Receptors, G-Protein-Coupled / deficiency
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism*
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Skin Neoplasms / chemically induced
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Skin Neoplasms / enzymology*
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Skin Neoplasms / genetics
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Skin Neoplasms / pathology
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Tetradecanoylphorbol Acetate
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Time Factors
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Transcription Factor AP-1 / metabolism
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Transfection
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Wnt Signaling Pathway*
Substances
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CCND1 protein, human
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Ccnd1 protein, mouse
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LGR4 protein, human
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LGR4 protein, mouse
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Receptors, G-Protein-Coupled
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Transcription Factor AP-1
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Cyclin D1
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Extracellular Signal-Regulated MAP Kinases
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MAP Kinase Kinase 1
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MAP2K1 protein, human
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Map2k1 protein, mouse
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Tetradecanoylphorbol Acetate