Abstract
Tumor metastasis is the main reason for the poor prognosis of lung cancer patients. The GABAA receptor subunit GABRA3 is reportedly upregulated in lung cancer. Herein, we show that high GABRA3 protein expression in lung adenocarcinoma correlated positively with disease stage, lymphatic metastasis status and poor patient survival. In addition, GABRA3 induced MMP-2 and MMP-9 expression through activation of the JNK/AP-1 signaling pathway, which enhanced lymphatic metastasis by lung adenocarcinoma both in vitro and in vivo. These results indicate that GABRA3 promotes lymph node metastasis and may thus be an effective therapeutic target for anticancer treatment.
Keywords:
GABRA3; JNK/AP-1; MMP; lymphatic metastasis; non-small cell lung cancer.
MeSH terms
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A549 Cells
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Adenocarcinoma / enzymology*
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Adenocarcinoma / genetics
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Adenocarcinoma / mortality
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Adenocarcinoma / secondary
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Adenocarcinoma of Lung
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Animals
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Cell Movement*
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Gene Expression Regulation, Enzymologic
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Gene Expression Regulation, Neoplastic
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HEK293 Cells
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Humans
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JNK Mitogen-Activated Protein Kinases / metabolism
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Kaplan-Meier Estimate
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Lung Neoplasms / enzymology*
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Lung Neoplasms / genetics
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Lung Neoplasms / mortality
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Lung Neoplasms / pathology
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Lymphatic Metastasis
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Male
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Matrix Metalloproteinase 2 / genetics
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Matrix Metalloproteinase 2 / metabolism*
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism*
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Mice, Inbred BALB C
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Mice, Nude
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Neoplasm Invasiveness
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Neoplasm Staging
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RNA Interference
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Receptors, GABA-A / genetics
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Receptors, GABA-A / metabolism*
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Signal Transduction
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Time Factors
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Transcription Factor AP-1 / metabolism
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Transfection
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Up-Regulation
Substances
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GABRA3 protein, human
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Receptors, GABA-A
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Transcription Factor AP-1
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JNK Mitogen-Activated Protein Kinases
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MMP2 protein, human
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Matrix Metalloproteinase 2
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MMP9 protein, human
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Matrix Metalloproteinase 9