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The Effect of MicroRNA-124 Overexpression on Anti-Tumor Drug Sensitivity.

Chen SM, Chou WC, Hu LY, Hsiung CN, Chu HW, Huang YL, Hsu HM, Yu JC, Shen CY - PLoS ONE (2015)

Bottom Line: In the present study, we found that overexpression of miR-124 was associated with reduced DNA repair capacity in cultured cancer cells and increased sensitivity of cells to DNA-damaging anti-tumor drugs, specifically those that cause the formation of DNA strand-breaks (SBs).The translational relevance of this role of miR-124 in anti-tumor drug sensitivity is suggested by the finding that increased miR-124 expression correlates with better breast cancer prognosis, specifically in patients receiving chemotherapy.These findings suggest that miR-124 could potentially be used as a therapeutic agent to improve the efficacy of chemotherapy with DNA-damaging agents.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

ABSTRACT
MicroRNAs play critical roles in regulating various physiological processes, including growth and development. Previous studies have shown that microRNA-124 (miR-124) participates not only in regulation of early neurogenesis but also in suppression of tumorigenesis. In the present study, we found that overexpression of miR-124 was associated with reduced DNA repair capacity in cultured cancer cells and increased sensitivity of cells to DNA-damaging anti-tumor drugs, specifically those that cause the formation of DNA strand-breaks (SBs). We then examined which DNA repair-related genes, particularly the genes of SB repair, were regulated by miR-124. Two SB repair-related genes, encoding ATM interactor (ATMIN) and poly (ADP-ribose) polymerase 1 (PARP1), were strongly affected by miR-124 overexpression, by binding of miR-124 to the 3¢-untranslated region of their mRNAs. As a result, the capacity of cells to repair DNA SBs, such as those resulting from homologous recombination, was significantly reduced upon miR-124 overexpression. A particularly important therapeutic implication of this finding is that overexpression of miR-124 enhanced cell sensitivity to multiple DNA-damaging agents via ATMIN- and PARP1-mediated mechanisms. The translational relevance of this role of miR-124 in anti-tumor drug sensitivity is suggested by the finding that increased miR-124 expression correlates with better breast cancer prognosis, specifically in patients receiving chemotherapy. These findings suggest that miR-124 could potentially be used as a therapeutic agent to improve the efficacy of chemotherapy with DNA-damaging agents.

No MeSH data available.


Related in: MedlinePlus

MiR-124 overexpression increases sensitivity to specific anti-tumor drugs/treatments.(A) Survival of breast cancer cells (MDA-MB-231) stably transfected with the empty lentivirus vector (vector control, VC) or the miR-124-overexpressing construct (miR-124) after the indicated treatments. (B) Survival of osteosarcoma cells (U-2 OS) stably transfected with the empty lentivirus vector (vector control, VC) or the miR-124-overexpressing construct (miR-124) after the indicated treatments. *Significant difference (P < 0.05) between the miR-124 and VC-transfected cells.
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pone.0128472.g002: MiR-124 overexpression increases sensitivity to specific anti-tumor drugs/treatments.(A) Survival of breast cancer cells (MDA-MB-231) stably transfected with the empty lentivirus vector (vector control, VC) or the miR-124-overexpressing construct (miR-124) after the indicated treatments. (B) Survival of osteosarcoma cells (U-2 OS) stably transfected with the empty lentivirus vector (vector control, VC) or the miR-124-overexpressing construct (miR-124) after the indicated treatments. *Significant difference (P < 0.05) between the miR-124 and VC-transfected cells.

Mentions: To assess the effects of miR-124 expression on drug sensitivity, we constructed a lentiviral miR-124 overexpression vector for use in an MB-MDA-231 cell survival assay. To determine the efficiency of miR-124 on regulation of cellular response to anti-cancer drugs, we used both transient transfection, transfecting different dosages of miR-124 into MDA-MB-231 cells, and stable transfection, in which the clones expressing high and low levels of miR-124 were selected for experiments. The results show that higher level of miR-124 expression resulted in higher sensitivity of cell to drugs (S1 Fig). Based on this, we examined six common anti-tumor drugs/treatments, including CPT, ETO, DOX, IR, TMZ, and 5-FU. Cell death increased more in the miR-124-overexpressing cells than in the vector control group after CPT, ETO, DOX, or IR treatment (Fig 2A and Fig. A in S2 Fig). However, the effect of miR-124 seemed to be specific to the type of damage because we did not observe any differences between the miR-124-overexpressing and vector control groups in the TMZ or 5-FU treatments (Fig 2A). These findings suggested that miR-124 overexpression increased sensitivity to drugs/treatments, especially those that induce DNA damage.


The Effect of MicroRNA-124 Overexpression on Anti-Tumor Drug Sensitivity.

Chen SM, Chou WC, Hu LY, Hsiung CN, Chu HW, Huang YL, Hsu HM, Yu JC, Shen CY - PLoS ONE (2015)

MiR-124 overexpression increases sensitivity to specific anti-tumor drugs/treatments.(A) Survival of breast cancer cells (MDA-MB-231) stably transfected with the empty lentivirus vector (vector control, VC) or the miR-124-overexpressing construct (miR-124) after the indicated treatments. (B) Survival of osteosarcoma cells (U-2 OS) stably transfected with the empty lentivirus vector (vector control, VC) or the miR-124-overexpressing construct (miR-124) after the indicated treatments. *Significant difference (P < 0.05) between the miR-124 and VC-transfected cells.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4482746&req=5

pone.0128472.g002: MiR-124 overexpression increases sensitivity to specific anti-tumor drugs/treatments.(A) Survival of breast cancer cells (MDA-MB-231) stably transfected with the empty lentivirus vector (vector control, VC) or the miR-124-overexpressing construct (miR-124) after the indicated treatments. (B) Survival of osteosarcoma cells (U-2 OS) stably transfected with the empty lentivirus vector (vector control, VC) or the miR-124-overexpressing construct (miR-124) after the indicated treatments. *Significant difference (P < 0.05) between the miR-124 and VC-transfected cells.
Mentions: To assess the effects of miR-124 expression on drug sensitivity, we constructed a lentiviral miR-124 overexpression vector for use in an MB-MDA-231 cell survival assay. To determine the efficiency of miR-124 on regulation of cellular response to anti-cancer drugs, we used both transient transfection, transfecting different dosages of miR-124 into MDA-MB-231 cells, and stable transfection, in which the clones expressing high and low levels of miR-124 were selected for experiments. The results show that higher level of miR-124 expression resulted in higher sensitivity of cell to drugs (S1 Fig). Based on this, we examined six common anti-tumor drugs/treatments, including CPT, ETO, DOX, IR, TMZ, and 5-FU. Cell death increased more in the miR-124-overexpressing cells than in the vector control group after CPT, ETO, DOX, or IR treatment (Fig 2A and Fig. A in S2 Fig). However, the effect of miR-124 seemed to be specific to the type of damage because we did not observe any differences between the miR-124-overexpressing and vector control groups in the TMZ or 5-FU treatments (Fig 2A). These findings suggested that miR-124 overexpression increased sensitivity to drugs/treatments, especially those that induce DNA damage.

Bottom Line: In the present study, we found that overexpression of miR-124 was associated with reduced DNA repair capacity in cultured cancer cells and increased sensitivity of cells to DNA-damaging anti-tumor drugs, specifically those that cause the formation of DNA strand-breaks (SBs).The translational relevance of this role of miR-124 in anti-tumor drug sensitivity is suggested by the finding that increased miR-124 expression correlates with better breast cancer prognosis, specifically in patients receiving chemotherapy.These findings suggest that miR-124 could potentially be used as a therapeutic agent to improve the efficacy of chemotherapy with DNA-damaging agents.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

ABSTRACT
MicroRNAs play critical roles in regulating various physiological processes, including growth and development. Previous studies have shown that microRNA-124 (miR-124) participates not only in regulation of early neurogenesis but also in suppression of tumorigenesis. In the present study, we found that overexpression of miR-124 was associated with reduced DNA repair capacity in cultured cancer cells and increased sensitivity of cells to DNA-damaging anti-tumor drugs, specifically those that cause the formation of DNA strand-breaks (SBs). We then examined which DNA repair-related genes, particularly the genes of SB repair, were regulated by miR-124. Two SB repair-related genes, encoding ATM interactor (ATMIN) and poly (ADP-ribose) polymerase 1 (PARP1), were strongly affected by miR-124 overexpression, by binding of miR-124 to the 3¢-untranslated region of their mRNAs. As a result, the capacity of cells to repair DNA SBs, such as those resulting from homologous recombination, was significantly reduced upon miR-124 overexpression. A particularly important therapeutic implication of this finding is that overexpression of miR-124 enhanced cell sensitivity to multiple DNA-damaging agents via ATMIN- and PARP1-mediated mechanisms. The translational relevance of this role of miR-124 in anti-tumor drug sensitivity is suggested by the finding that increased miR-124 expression correlates with better breast cancer prognosis, specifically in patients receiving chemotherapy. These findings suggest that miR-124 could potentially be used as a therapeutic agent to improve the efficacy of chemotherapy with DNA-damaging agents.

No MeSH data available.


Related in: MedlinePlus