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- 학술저널
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- 2017.1
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Metastasis is a major cause of therapeutic failure in ovarian cancer. To elucidate molecular mechanisms of ovarian cancer metastasis, we previously established a metastatic xenograft mouse model using human ovarian carcinoma SK-OV-3 cells. Using gene expression profiling, we found that γ-aminobutyric acid (GABA)A receptor π subunit (GABRP) expression was upregulated (44-fold) in metastatic tissues from our xenograft mice compared with SK-OV-3 cells. Importantly, GABRP knockdown diminished the migration and invasion of SK-OV-3 cells, and reduced extracellular signal-regulated kinase (ERK) activation while overexpression of GABRP exhibited significantly increased cell migration, invasion and ERK activation. Moreover, treatment with the mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) inhibitor U0126 similarly suppressed the migration and invasion of SK-OV-3 cells, implying that GABRP promotes these cellular behaviors by activating the MAPK/ERK pathway. Using genome-wide DNA methylation profiling, we identified hypomethylated CpG sites in the GABRP promoter in metastatic tissues from the xenograft mice compared with SK-OV-3 cells. Treatment with a DNA methyltransferase inhibitor demonstrated that methylation at − 963 bp from the GABRP transcription start site (−963 CpG site) was critical for the epigenetic regulation of GABRP. Finally, we analyzed human ovarian cancer patient samples and showed DNA hypomethylation at the GABRP − 963 CpG site in advanced stage, but not early-stage, primary tumors compared with their paired normal tissues. These findings suggest that GABRP enhances the aggressive phenotype of ovarian cancer cells, and that the DNA methylation status of the GABRP − 963 CpG site may be useful for predicting the metastatic potential in ovarian cancer patients.
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참고문헌 (23)
참고문헌 신청
American Cancer Society / 2015 / Cancer Facts & Figures 2015 / American Cancer Society
Azuma H / 2003 / γ-Aminobutyric acid as a promoting factor of cancer metastasis;induction of matrix metalloproteinase production is potentially its underlying mechanism / C
Barker J / 1997 / GABAergic cells and signals in CNS development / Perspect Dev Neurobiol 5 : 305 ~ 322
Benjamini Y / 1995 / Controlling the false discovery rate : a practical and powerful approach to multiple testing / J R Statist Soc B 57 : 289 ~ 300
Bormann J / 2000 / The ‘ABC’of GABA receptors / Trends Pharmacol Sci 21 : 16 ~ 19
Azuma H / 2003 / γ-Aminobutyric acid as a promoting factor of cancer metastasis;induction of matrix metalloproteinase production is potentially its underlying mechanism / C
Barker J / 1997 / GABAergic cells and signals in CNS development / Perspect Dev Neurobiol 5 : 305 ~ 322
Benjamini Y / 1995 / Controlling the false discovery rate : a practical and powerful approach to multiple testing / J R Statist Soc B 57 : 289 ~ 300
Bormann J / 2000 / The ‘ABC’of GABA receptors / Trends Pharmacol Sci 21 : 16 ~ 19
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