Lgr4 is crucial for skin carcinogenesis by regulating MEK/ERK and Wnt/β-catenin signaling pathways.
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.
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Science and School of Life Science, East China Normal University, Shanghai 200241, China.
Peng
P
Xu
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Science and School of Life Science, East China Normal University, Shanghai 200241, China.
Yongyan
Y
Dang
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Science and School of Life Science, East China Normal University, Shanghai 200241, China.
Luyang
L
Wang
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Science and School of Life Science, East China Normal University, Shanghai 200241, China.
Xia
X
Liu
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Science and School of Life Science, East China Normal University, Shanghai 200241, China.
Xiaolin
X
Ren
Department of Dermatology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China.
Jun
J
Gu
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Science and School of Life Science, East China Normal University, Shanghai 200241, China.
Mingyao
M
Liu
Department of Biological Chemistry, University of California, D250 Med Sci I, Irvine, CA 92697-1700, USA. Electronic address: xdai@uci.edu.
Xing
X
Dai
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Science and School of Life Science, East China Normal University, Shanghai 200241, China. Electronic address: xyye@bio.ecnu.edu.cn.
Xiyun
X
Ye
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology* / Q000473:pathology; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010212:Papilloma / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D060449:Wnt Signaling Pathway
C530104:CCND1 protein, human; C530105:Ccnd1 protein, mouse; C411562:LGR4 protein, human; C496200:LGR4 protein, mouse; D043562:Receptors, G-Protein-Coupled; D018808:Transcription Factor AP-1; D019938:Cyclin D1; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; D013755:Tetradecanoylphorbol Acetate
ERK1/2; Lgr4; Squamous cell carcinoma; TPA; β-Catenin
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