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NDRG2 controls COX-2/PGE₂-mediated breast cancer cell migration and invasion.

Kim MJ, Kim HS, Lee SH, Yang Y, Lee MS, Lim JS - Mol. Cells (2014)

Bottom Line: Nuclear transcription factor-κB (NF-κB) signaling attenuated by NDRG2 expression resulted in a decrease in PMA-induced COX-2 expression.Consistent with these results, the migration and invasion of MCF7 cells treated with NDRG2 siRNA were significantly enhanced following treatment with PMA.Taken together, our data show that the inhibition of NF-κB signaling by NDRG2 expression is able to suppress cell migration and invasion through the down-regulation of COX-2 expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Science and the Research Center for Women's Disease, Sookmyung Women's University, Seoul 140-742, Korea.

ABSTRACT
N-myc downstream-regulated gene 2 (NDRG2), which is known to have tumor suppressor functions, is frequently down-regulated in breast cancers and potentially involved in preventing the migration and invasion of malignant tumor cells. In the present study, we examined the inhibitory effects of NDRG2 overexpression, specifically focusing on the role of cyclooxygenase-2 (COX-2) in the migration of breast cancer cells. NDRG2 overexpression in MDA-MB-231 cells inhibited the expression of the COX-2 mRNA and protein, the transcriptional activity of COX-2, and prostaglandin E2 (PGE2) production, which were induced by a treatment with phorbol-12-myristate-13-acetate (PMA). Nuclear transcription factor-κB (NF-κB) signaling attenuated by NDRG2 expression resulted in a decrease in PMA-induced COX-2 expression. Interestingly, the inhibition of COX-2 strongly suppressed PMA-stimulated migration and invasion in MDA-MB-231-NDRG2 cells. Moreover, siRNA-mediated knockdown of NDRG2 in MCF7 cells increased the COX-2 mRNA and protein expression levels and the PMA-induced COX-2 expression levels. Consistent with these results, the migration and invasion of MCF7 cells treated with NDRG2 siRNA were significantly enhanced following treatment with PMA. Taken together, our data show that the inhibition of NF-κB signaling by NDRG2 expression is able to suppress cell migration and invasion through the down-regulation of COX-2 expression.

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NDRG2 knockdown in MCF7 cells rescues wound healing, migration, and invasion abilities. (A) The cells treated with PMA for 24 h were analyzed by a transwell migration assay. (B) The cells treated with PMA for 24 h were analyzed using a Matrigel-coated transwell chamber. (C) The cells were scratched with a pipette tip (0 h), and after PMA treatment for 48 h, the plates were observed with phase-contrast microscopy. The dotted lines represent the wound margin. The relative closed-wound distance (healing) was calculated after measuring the widths of at least four wounds. (D) Schematic representation of the proposed mechanism of COX-2/PGE2-mediated migration inhibited by NDRG2 in breast cancer cells. *P < 0.05.
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f5-molcell-37-10-759: NDRG2 knockdown in MCF7 cells rescues wound healing, migration, and invasion abilities. (A) The cells treated with PMA for 24 h were analyzed by a transwell migration assay. (B) The cells treated with PMA for 24 h were analyzed using a Matrigel-coated transwell chamber. (C) The cells were scratched with a pipette tip (0 h), and after PMA treatment for 48 h, the plates were observed with phase-contrast microscopy. The dotted lines represent the wound margin. The relative closed-wound distance (healing) was calculated after measuring the widths of at least four wounds. (D) Schematic representation of the proposed mechanism of COX-2/PGE2-mediated migration inhibited by NDRG2 in breast cancer cells. *P < 0.05.

Mentions: We further investigated whether migration and invasion of tumor cells are affected by siRNA-mediated knockdown of NDRG2. The migration and invasion assay revealed that the NDRG2-siRNA transfectants treated with PMA exhibited strong increases in cell migration and invasion compared with the PMA-treated control (Figs. 5A and 5B). In addition, the wound healing assay showed that the siRNA-mediated knockdown in the MCF7 cells led to markedly increased wound healing abilities compared with the PMA-stimulated control MCF7 cells (Fig. 5C). Collectively, these results support the notion that NDRG2 may function as a negative regulator of cell migration through the suppression of COX-2 expression.


NDRG2 controls COX-2/PGE₂-mediated breast cancer cell migration and invasion.

Kim MJ, Kim HS, Lee SH, Yang Y, Lee MS, Lim JS - Mol. Cells (2014)

NDRG2 knockdown in MCF7 cells rescues wound healing, migration, and invasion abilities. (A) The cells treated with PMA for 24 h were analyzed by a transwell migration assay. (B) The cells treated with PMA for 24 h were analyzed using a Matrigel-coated transwell chamber. (C) The cells were scratched with a pipette tip (0 h), and after PMA treatment for 48 h, the plates were observed with phase-contrast microscopy. The dotted lines represent the wound margin. The relative closed-wound distance (healing) was calculated after measuring the widths of at least four wounds. (D) Schematic representation of the proposed mechanism of COX-2/PGE2-mediated migration inhibited by NDRG2 in breast cancer cells. *P < 0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4213768&req=5

f5-molcell-37-10-759: NDRG2 knockdown in MCF7 cells rescues wound healing, migration, and invasion abilities. (A) The cells treated with PMA for 24 h were analyzed by a transwell migration assay. (B) The cells treated with PMA for 24 h were analyzed using a Matrigel-coated transwell chamber. (C) The cells were scratched with a pipette tip (0 h), and after PMA treatment for 48 h, the plates were observed with phase-contrast microscopy. The dotted lines represent the wound margin. The relative closed-wound distance (healing) was calculated after measuring the widths of at least four wounds. (D) Schematic representation of the proposed mechanism of COX-2/PGE2-mediated migration inhibited by NDRG2 in breast cancer cells. *P < 0.05.
Mentions: We further investigated whether migration and invasion of tumor cells are affected by siRNA-mediated knockdown of NDRG2. The migration and invasion assay revealed that the NDRG2-siRNA transfectants treated with PMA exhibited strong increases in cell migration and invasion compared with the PMA-treated control (Figs. 5A and 5B). In addition, the wound healing assay showed that the siRNA-mediated knockdown in the MCF7 cells led to markedly increased wound healing abilities compared with the PMA-stimulated control MCF7 cells (Fig. 5C). Collectively, these results support the notion that NDRG2 may function as a negative regulator of cell migration through the suppression of COX-2 expression.

Bottom Line: Nuclear transcription factor-κB (NF-κB) signaling attenuated by NDRG2 expression resulted in a decrease in PMA-induced COX-2 expression.Consistent with these results, the migration and invasion of MCF7 cells treated with NDRG2 siRNA were significantly enhanced following treatment with PMA.Taken together, our data show that the inhibition of NF-κB signaling by NDRG2 expression is able to suppress cell migration and invasion through the down-regulation of COX-2 expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Science and the Research Center for Women's Disease, Sookmyung Women's University, Seoul 140-742, Korea.

ABSTRACT
N-myc downstream-regulated gene 2 (NDRG2), which is known to have tumor suppressor functions, is frequently down-regulated in breast cancers and potentially involved in preventing the migration and invasion of malignant tumor cells. In the present study, we examined the inhibitory effects of NDRG2 overexpression, specifically focusing on the role of cyclooxygenase-2 (COX-2) in the migration of breast cancer cells. NDRG2 overexpression in MDA-MB-231 cells inhibited the expression of the COX-2 mRNA and protein, the transcriptional activity of COX-2, and prostaglandin E2 (PGE2) production, which were induced by a treatment with phorbol-12-myristate-13-acetate (PMA). Nuclear transcription factor-κB (NF-κB) signaling attenuated by NDRG2 expression resulted in a decrease in PMA-induced COX-2 expression. Interestingly, the inhibition of COX-2 strongly suppressed PMA-stimulated migration and invasion in MDA-MB-231-NDRG2 cells. Moreover, siRNA-mediated knockdown of NDRG2 in MCF7 cells increased the COX-2 mRNA and protein expression levels and the PMA-induced COX-2 expression levels. Consistent with these results, the migration and invasion of MCF7 cells treated with NDRG2 siRNA were significantly enhanced following treatment with PMA. Taken together, our data show that the inhibition of NF-κB signaling by NDRG2 expression is able to suppress cell migration and invasion through the down-regulation of COX-2 expression.

Show MeSH
Related in: MedlinePlus