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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

Higher miR-124 expression correlates with better prognosis for breast cancer patients receiving chemotherapy.Overall survival of breast cancer patients who received (left panel) or did not receive chemotherapy (right panel) stratified by expression of miR-124. Log-rank test P values are shown. Data were generated using the Kaplan Meier plotter [16].
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pone.0128472.g006: Higher miR-124 expression correlates with better prognosis for breast cancer patients receiving chemotherapy.Overall survival of breast cancer patients who received (left panel) or did not receive chemotherapy (right panel) stratified by expression of miR-124. Log-rank test P values are shown. Data were generated using the Kaplan Meier plotter [16].

Mentions: We demonstrated that miR-124 overexpression reduced DNA SB repair, which may increase sensitivity to SB-inducing chemotherapeutic agents. The translational relevance of this finding was then examined by analysis of publically available data from a large breast cancer patient cohort study [16, 36]. The measurement of micro-RNAs expression in this cohort was based on chip-based experiments to detect expression in tumor tissues. We analyzed the association between overall survival and miR-124 expression level by the Kaplan-Meier plot. To this end, as many other studies using this dataset, we identified the median level of miR-124 expression in all patients, and defined those with higher/lower miR-124 expression using the median level as a cutoff [37]. Higher miR-124 expression in tumors—presumably resulting in reduced SB repair and greater sensitivity to chemotherapy—was significantly associated with better survival (left panels of Fig 6) in the subgroup of patients who received chemotherapy. In contrast, patients who did not receive chemotherapy did not show such an association (right panels of Fig 6). The statistical power of this analysis was evaluated using the Cox-proportion hazard model, resulting in an (1-β), i.e. statistical power, of 0.941, which means our sample size was statistically adequate to address this association. Though, in this dataset, the information of the drugs used in chemotherapy is not clearly indicated, the treatment protocols of breast cancer are relatively standardized in individual oncology clinics in different countries. Based on the guideline of NCCN Clinical Practice Guidelines in Oncology, the most common drug used for chemotherapy of breast cancer patients is Adriamycin (Doxorubicin), a drug causing DNA SBs.


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)

Higher miR-124 expression correlates with better prognosis for breast cancer patients receiving chemotherapy.Overall survival of breast cancer patients who received (left panel) or did not receive chemotherapy (right panel) stratified by expression of miR-124. Log-rank test P values are shown. Data were generated using the Kaplan Meier plotter [16].
© Copyright Policy
Related In: Results  -  Collection

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

pone.0128472.g006: Higher miR-124 expression correlates with better prognosis for breast cancer patients receiving chemotherapy.Overall survival of breast cancer patients who received (left panel) or did not receive chemotherapy (right panel) stratified by expression of miR-124. Log-rank test P values are shown. Data were generated using the Kaplan Meier plotter [16].
Mentions: We demonstrated that miR-124 overexpression reduced DNA SB repair, which may increase sensitivity to SB-inducing chemotherapeutic agents. The translational relevance of this finding was then examined by analysis of publically available data from a large breast cancer patient cohort study [16, 36]. The measurement of micro-RNAs expression in this cohort was based on chip-based experiments to detect expression in tumor tissues. We analyzed the association between overall survival and miR-124 expression level by the Kaplan-Meier plot. To this end, as many other studies using this dataset, we identified the median level of miR-124 expression in all patients, and defined those with higher/lower miR-124 expression using the median level as a cutoff [37]. Higher miR-124 expression in tumors—presumably resulting in reduced SB repair and greater sensitivity to chemotherapy—was significantly associated with better survival (left panels of Fig 6) in the subgroup of patients who received chemotherapy. In contrast, patients who did not receive chemotherapy did not show such an association (right panels of Fig 6). The statistical power of this analysis was evaluated using the Cox-proportion hazard model, resulting in an (1-β), i.e. statistical power, of 0.941, which means our sample size was statistically adequate to address this association. Though, in this dataset, the information of the drugs used in chemotherapy is not clearly indicated, the treatment protocols of breast cancer are relatively standardized in individual oncology clinics in different countries. Based on the guideline of NCCN Clinical Practice Guidelines in Oncology, the most common drug used for chemotherapy of breast cancer patients is Adriamycin (Doxorubicin), a drug causing DNA SBs.

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