Aim:Malignant pleural mesothelioma is a chemoresistant tumor,and biphasic and sarcomatoid histologies portend the worst prognosis for malignant pleural mesothelioma(MPM)patients.We obtained the microRNA expression pro...Aim:Malignant pleural mesothelioma is a chemoresistant tumor,and biphasic and sarcomatoid histologies portend the worst prognosis for malignant pleural mesothelioma(MPM)patients.We obtained the microRNA expression profile of three biphasic-sarcomatoid MPM cell lines to identify commonly expressed microRNAs and evaluate the effect of butein,a chemo-sensitizing compound,on this microRNA subset.Methods:Nanostring-based microRNA profiling and analysis through the ROSALIND platform were employed to identify the commonly modulated microRNAs and their targets.MicroRNA-mimic transfection,Luciferase assay,and Western blotting were employed to show specific perturbation of TWIST1 levels by miR-186-5p.Sphere-forming assays,invasion assay,and metabolic profiling were used to assess the biological consequences of the butein-instigated miR-186-5p-mediated perturbation of TWIST1 levels.TGCA analysis was used to search for the correlation between TWIST1 and miR-186-5p levels in biphasic and epithelioid MPM specimens.Results:We identified a set of perturbed microRNAs,common to three biphasic/sarcomatoid MPM cell lines,after butein treatment.When focusing on miR-186-5p,we unraveled a butein-ignited and miR-186-5p-mediated modulation of TWIST1 levels which affected the 3D anchorage-independent growth,cisplatin resistance,invasion,and bioenergetics of the MPM cell lines tested.We showed that miR-186-5p and TWIST1 levels are anti-correlated in biphasic MPM specimens from TCGA.Conclusion:We unraveled a novel mechanism of action of butein,which attenuated the pro-tumorigenic features of MPM at least through a miR-186-5p-TWIST1 axis.We suggest that those activities converge into the chemo-sensitizing effect of this compound and may be of translational relevance.展开更多
基金partially supported by an AIRC and Marie Curie Actions-People-COFUND fellowship.
文摘Aim:Malignant pleural mesothelioma is a chemoresistant tumor,and biphasic and sarcomatoid histologies portend the worst prognosis for malignant pleural mesothelioma(MPM)patients.We obtained the microRNA expression profile of three biphasic-sarcomatoid MPM cell lines to identify commonly expressed microRNAs and evaluate the effect of butein,a chemo-sensitizing compound,on this microRNA subset.Methods:Nanostring-based microRNA profiling and analysis through the ROSALIND platform were employed to identify the commonly modulated microRNAs and their targets.MicroRNA-mimic transfection,Luciferase assay,and Western blotting were employed to show specific perturbation of TWIST1 levels by miR-186-5p.Sphere-forming assays,invasion assay,and metabolic profiling were used to assess the biological consequences of the butein-instigated miR-186-5p-mediated perturbation of TWIST1 levels.TGCA analysis was used to search for the correlation between TWIST1 and miR-186-5p levels in biphasic and epithelioid MPM specimens.Results:We identified a set of perturbed microRNAs,common to three biphasic/sarcomatoid MPM cell lines,after butein treatment.When focusing on miR-186-5p,we unraveled a butein-ignited and miR-186-5p-mediated modulation of TWIST1 levels which affected the 3D anchorage-independent growth,cisplatin resistance,invasion,and bioenergetics of the MPM cell lines tested.We showed that miR-186-5p and TWIST1 levels are anti-correlated in biphasic MPM specimens from TCGA.Conclusion:We unraveled a novel mechanism of action of butein,which attenuated the pro-tumorigenic features of MPM at least through a miR-186-5p-TWIST1 axis.We suggest that those activities converge into the chemo-sensitizing effect of this compound and may be of translational relevance.
