Objectives:Ribosomal protein S6 kinase A2(RPS6KA2)has been identified as a potential prognostic biomarker in several cancers,including breast cancer,glioblastoma,and prostate cancer.However,its functional significance...Objectives:Ribosomal protein S6 kinase A2(RPS6KA2)has been identified as a potential prognostic biomarker in several cancers,including breast cancer,glioblastoma,and prostate cancer.However,its functional significance in ovarian cancer is not well characterized.This study was designed to explore the therapeutic relevance of modulating RPS6KA2 in the context of ovarian cancer,particularly in relation to cisplatin resistance.Methods:The expression levels of RPS6KA2 and key regulators involved in autophagy and ferroptosis were assessed using quantitative reverse transcription-PCR,immunofluorescence staining,immunohistochemistry,and western blotting.Prognostic associations were conducted using the Kaplan-Meier Plotter database.Autophagy flux assays and visualization of autophagosomes were performed to assess autophagy activity.Ferroptosis-related parameters,including intracellular iron content,glutathione(GSH)levels,reactive oxygen species(ROS)generation,and mitochondrial membrane potential,were measured to determine ferroptotic changes.In vivo experiments were carried out to determine the antitumor efficacy of RPS6KA2 modulation in combination with pathway-specific agents.Results:Using ovarian cancer cell lines and clinical tissue samples,we demonstrated that RPS6KA2 expression was significantly downregulated in cisplatin-resistant cells and tissues compared to their sensitive counterparts.Low RPS6KA2 expression correlated with unfavorable patient outcomes and enhanced chemoresistance.Mechanistically,RPS6KA2 inhibited autophagy by modulating the phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin(PI3K-AKT-mTOR)signaling pathway,which in turn increased sensitivity to cisplatin.Additionally,RPS6KA2 facilitated ferroptosis,contributing to its tumor-suppressive function.miR-512-3p was identified as a negative regulator of RPS6KA2,driving cisplatin resistance through suppression of RPS6KA2 expression.In vivo validation confirmed that combining RPS6KA2 targeting with autophagy inhibitors or ferroptosis inducers significantly enhanced cisplatin sensitivity in ovarian cancer models.Conclusion:These results collectively indicate that targeting the miR-512-3p/RPS6KA2 regulatory axis may offer a novel and effective strategy for overcoming cisplatin resistance in ovarian cancer.展开更多
[Objectives]To analyze the evolutionary rates of mitochondrial protein-coding genes across five closely related species of fruit flies,thereby providing a foundation for the molecular identification of these quarantin...[Objectives]To analyze the evolutionary rates of mitochondrial protein-coding genes across five closely related species of fruit flies,thereby providing a foundation for the molecular identification of these quarantine pests.[Methods]The newly identified species Bactrocera latizona,along with its closely related species within the same subgenus,namely B.atrifemur,B.rubigina,B.thailandica,and B.tuberculata,were selected as the subjects of this study.Utilizing the complete mitochondrial genome sequences of these five fruit fly species,the Ka/Ks ratios of 13 protein-coding genes were calculated to assess their selective pressures and degrees of conservation.[Results]The mitochondrial genome lengths of the five fruit fly species ranged from 15603 to 15972 bp.The Ka/Ks ratios of the ND4L and ND4 genes for all species were generally elevated(values of the ND4L gene all exceeding 2),suggesting accelerated evolutionary rates.In contrast,the COX1 gene exhibited the lowest Ka/Ks ratio,indicating it is the most conserved gene among those analyzed.The majority of genes displayed Ka/Ks ratios below 1,implying they are under purifying selection.[Conclusions]Among the mitochondrial genes of five fruit fly species,COX1 is the most conserved,whereas ND4L exhibits the highest rate of evolution.These findings offer theoretical support for the development of molecular markers and the species identification of fruit flies.展开更多
基金supported by the Academic Leader Training Programof Pudong New Area Health System in Shanghai(Grant No.PWRd2021-13)Shanghai Municipal Health Commission(Grant No.202340094).
文摘Objectives:Ribosomal protein S6 kinase A2(RPS6KA2)has been identified as a potential prognostic biomarker in several cancers,including breast cancer,glioblastoma,and prostate cancer.However,its functional significance in ovarian cancer is not well characterized.This study was designed to explore the therapeutic relevance of modulating RPS6KA2 in the context of ovarian cancer,particularly in relation to cisplatin resistance.Methods:The expression levels of RPS6KA2 and key regulators involved in autophagy and ferroptosis were assessed using quantitative reverse transcription-PCR,immunofluorescence staining,immunohistochemistry,and western blotting.Prognostic associations were conducted using the Kaplan-Meier Plotter database.Autophagy flux assays and visualization of autophagosomes were performed to assess autophagy activity.Ferroptosis-related parameters,including intracellular iron content,glutathione(GSH)levels,reactive oxygen species(ROS)generation,and mitochondrial membrane potential,were measured to determine ferroptotic changes.In vivo experiments were carried out to determine the antitumor efficacy of RPS6KA2 modulation in combination with pathway-specific agents.Results:Using ovarian cancer cell lines and clinical tissue samples,we demonstrated that RPS6KA2 expression was significantly downregulated in cisplatin-resistant cells and tissues compared to their sensitive counterparts.Low RPS6KA2 expression correlated with unfavorable patient outcomes and enhanced chemoresistance.Mechanistically,RPS6KA2 inhibited autophagy by modulating the phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin(PI3K-AKT-mTOR)signaling pathway,which in turn increased sensitivity to cisplatin.Additionally,RPS6KA2 facilitated ferroptosis,contributing to its tumor-suppressive function.miR-512-3p was identified as a negative regulator of RPS6KA2,driving cisplatin resistance through suppression of RPS6KA2 expression.In vivo validation confirmed that combining RPS6KA2 targeting with autophagy inhibitors or ferroptosis inducers significantly enhanced cisplatin sensitivity in ovarian cancer models.Conclusion:These results collectively indicate that targeting the miR-512-3p/RPS6KA2 regulatory axis may offer a novel and effective strategy for overcoming cisplatin resistance in ovarian cancer.
文摘[Objectives]To analyze the evolutionary rates of mitochondrial protein-coding genes across five closely related species of fruit flies,thereby providing a foundation for the molecular identification of these quarantine pests.[Methods]The newly identified species Bactrocera latizona,along with its closely related species within the same subgenus,namely B.atrifemur,B.rubigina,B.thailandica,and B.tuberculata,were selected as the subjects of this study.Utilizing the complete mitochondrial genome sequences of these five fruit fly species,the Ka/Ks ratios of 13 protein-coding genes were calculated to assess their selective pressures and degrees of conservation.[Results]The mitochondrial genome lengths of the five fruit fly species ranged from 15603 to 15972 bp.The Ka/Ks ratios of the ND4L and ND4 genes for all species were generally elevated(values of the ND4L gene all exceeding 2),suggesting accelerated evolutionary rates.In contrast,the COX1 gene exhibited the lowest Ka/Ks ratio,indicating it is the most conserved gene among those analyzed.The majority of genes displayed Ka/Ks ratios below 1,implying they are under purifying selection.[Conclusions]Among the mitochondrial genes of five fruit fly species,COX1 is the most conserved,whereas ND4L exhibits the highest rate of evolution.These findings offer theoretical support for the development of molecular markers and the species identification of fruit flies.
