Abstract
G-protein-coupled receptor 48 (GPR48) is an orphan receptor belonging to the G-protein-coupled receptors family, which plays an important role in the development of various organs and cancer development and progression such as gastric cancer and colorectal cancer (CRC). However, the prognostic value of GPR48 expression in patients with CRC has not been reported. In this study, we observed that GPR48 was overexpressed in primary CRC and metastatic lymph nodes and closely correlated with tumor invasion and metastasis. Multivariate analysis indicated that high GPR48 expression was a poor prognostic factor for overall survival in CRC patients. In vitro and in vivo assays demonstrated that enforced expression of GPR48 contributed to enhance migration and invasion of cancer cells and tumor metastasis. In addition, we found that GPR48 increased nuclear β-catenin accumulation, T-cell factor 4 (TCF4) transcription activity, and expression of its target genes including Cyclin D1 and c-Myc in CRC cells. Correlation analysis showed that GPR48 expression in CRC tissues was positively associated with β-catenin expression. Upregulation of GPR48 resulted in increased phosphorylation of glycogen synthase kinase 3β, Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) in CRC cells, while inhibition of PI3K/Akt and mitogen-activated protein kinase /ERK1/2 pathways was sufficient to abolish the effect of GPR48 on β-catenin/TCF signaling. Taken together, GPR48 could serve as both a prognostic biomarker and a therapeutic target for resectable CRC patients.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics*
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
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Cell Line
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Cell Line, Tumor
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Cell Movement / genetics
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Colorectal Neoplasms / genetics*
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology*
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Female
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HCT116 Cells
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HEK293 Cells
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Humans
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Lymph Nodes / metabolism
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Lymph Nodes / pathology
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Lymphatic Metastasis / genetics
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Lymphatic Metastasis / pathology*
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MAP Kinase Signaling System / genetics
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Male
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism
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Neoplasm Invasiveness / genetics
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Neoplasm Invasiveness / pathology
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / genetics
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Prognosis
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-myb / genetics
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Proto-Oncogene Proteins c-myb / metabolism
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Receptors, G-Protein-Coupled / genetics*
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Receptors, G-Protein-Coupled / metabolism
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Signal Transduction / genetics*
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Transcription Factor 4
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Transcription, Genetic / genetics
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Up-Regulation / genetics
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beta Catenin / genetics*
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beta Catenin / metabolism
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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LGR4 protein, human
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Proto-Oncogene Proteins c-myb
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Receptors, G-Protein-Coupled
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TCF4 protein, human
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Transcription Factor 4
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Transcription Factors
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beta Catenin
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Cyclin D1
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases