Abstract
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 (>4-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.
Highlights
Ovarian cancer has the highest mortality rate among gynecological cancers, with a 5-year survival rate of only 27% when the disease is diagnosed at an advanced stage.[1]
GABRP significantly enhances ovarian carcinoma cell migration and invasion To elucidate the functional role of GABRP in metastasis of ovarian cancer, GABRP expression plasmid construct was transiently transfected in SK-OV-3 cells
These results indicate that GABRP plays a pivotal role in promoting the metastasis of ovarian carcinoma cells
Summary
Ovarian cancer has the highest mortality rate among gynecological cancers, with a 5-year survival rate of only 27% when the disease is diagnosed at an advanced stage.[1] The majority of ovarian cancer patients are diagnosed at an advanced stage because they show few clear symptoms, and there are no reliable diagnostic tools for early detection. Ovarian cancer is unique in that it mainly metastasizes via a transcoelomic route leading to ascites-mediated intraperitoneal dissemination rather than hematogenous dissemination.[2] The intraperitoneal dissemination occurs relatively early in the disease, which is another reason why ovarian cancer is rarely diagnosed at an early stage.[3] Because metastasis prevention is the major obstacle in the clinical management of ovarian cancer, a comprehensive understanding of the molecular mechanisms that regulate the aggressive behavior of ovarian cancer cells is required to improve treatment outcomes for ovarian cancer patients. We performed expression profiling to identify genes that were differentially expressed in the metastatic tissues, compared with the injected SK-OV-3 cells, from the xenograft mice.[4,5,6,7] Among the genes whose expression was altered more than twofold in metastatic tissues, we selected γ-aminobutyric acid (GABA)A receptor π subunit (GABRP), which was upregulated in the metastatic tissue, for further study
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