Objective Long non-coding RNAs(lncRNAs)are critical in the pathogenesis of hematological malignancies,including acute myeloid leukemia(AML).However,the specific role and underlying mechanisms of the lncRNA chromosome ...Objective Long non-coding RNAs(lncRNAs)are critical in the pathogenesis of hematological malignancies,including acute myeloid leukemia(AML).However,the specific role and underlying mechanisms of the lncRNA chromosome 9 open reading frame 139(C9orf139)in AML remain unclear.This study aimed to investigate the role and molecular mechanism of C9orf139 in AML development.Methods AML-related sequencing and microarray data were retrieved from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)databases.Significant lncRNAs and mRNAs influencing AML progression were identified and analyzed.A competing endogenous RNA network involving lncRNA–microRNA(miRNA)3–mRNA interactions was subsequently constructed.The expression levels of C9orf139,miR-24-3p,and human TAO kinase 1(TAOK1)were assessed via real-time fluorescent quantitative polymerase chain reaction(PCR).Cell proliferation was evaluated via the Cell Counting Kit-8(CCK8)assay,whereas Transwell assays were used to assess cell invasion and migration.Apoptosis was measured by Annexin V Fluorescein Isothiocyanate(FITC)double staining.Tumor formation in nude mice was assessed to examine the effect of C9orf139 on in vivo tumor growth.The C9orf139-miR-24-3p-TAOK1 regulatory axis was validated via dual luciferase reporter assays and RNA-binding protein immunoprecipitation(RIP).Western blot assays were used to assess the expression and phosphorylation of key proteins in the mitogen-activated protein kinase(MAPK)signaling pathway.Results Bioinformatics analysis identified C9orf139 and TAOK1 as differentially expressed genes that play key roles in AML pathogenesis.The C9orf139-miR-24-3p-TAOK1 axis was tightly linked to AML development,as confirmed by clinical sample analysis.In vitro,C9orf139 downregulation resulted in reduced proliferation,invasion,and migration and enhanced the apoptosis of AML cells.In vivo,the inhibition of C9orf139 significantly impaired tumor growth in nude mice.The regulatory axis was further validated.C9orf139 knockdown reduced the phosphorylation levels of the key MAPK pathway proteins,including Raf,mitogen-activated protein kinase kinase(MEK),and extracellular regulated protein kinase(ERK).Conclusion C9orf139 regulates AML progression by activating the MAPK signaling pathway through the C9orf139-miR-24-3p-TAOK1 axis.展开更多
Interleukin 17(IL-17)is an important cytokine that can induce tissue inflammation and is involved in the pathogenesis of numerous autoimmune diseases.However,the regulation of its signaling transduction has not been w...Interleukin 17(IL-17)is an important cytokine that can induce tissue inflammation and is involved in the pathogenesis of numerous autoimmune diseases.However,the regulation of its signaling transduction has not been well described.In this study,we report that thousand and one kinase 1(TAOK1)functions as a negative regulator of IL-17-mediated signal transduction and inflammation.TAOK1 knockdown promotes IL-17-induced cytokine and chemokine expression and the activation of mitogen-activated protein kinases and nuclear factor-κB.We further demonstrate that TAOK1 interacts with IL-17 receptor A(IL-17RA)independent of its kinase activity,and TAOK1 dose-dependently prevents the formation of the IL-17R-Act1(nuclear factor activator 1,also known as tumor necrosis factor receptor-associated factor 3 interacting protein 2)complex.Consistent with this,TAOK1 deficiency exacerbates colitis in the 2,4,6-trinitrobenzenesulfonic acid-induced experimental model of inflammatory bowel disease,likely by its promotion of the IL-17-mediated signaling pathway.TAOK1 expression is decreased in the colons of ulcerative colitis patients.In conclusion,these findings suggest that TAOK1 is involved in the development of IL-17-related autoimmune disorders.展开更多
基金supported by the Youth Talent Science and Technology Project of Health Commission of Changzhou(QN202223)the Education Research Project of Nanjing Medical University(2023ZC086)the Changzhou Medical Center(CMCB202422).
文摘Objective Long non-coding RNAs(lncRNAs)are critical in the pathogenesis of hematological malignancies,including acute myeloid leukemia(AML).However,the specific role and underlying mechanisms of the lncRNA chromosome 9 open reading frame 139(C9orf139)in AML remain unclear.This study aimed to investigate the role and molecular mechanism of C9orf139 in AML development.Methods AML-related sequencing and microarray data were retrieved from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)databases.Significant lncRNAs and mRNAs influencing AML progression were identified and analyzed.A competing endogenous RNA network involving lncRNA–microRNA(miRNA)3–mRNA interactions was subsequently constructed.The expression levels of C9orf139,miR-24-3p,and human TAO kinase 1(TAOK1)were assessed via real-time fluorescent quantitative polymerase chain reaction(PCR).Cell proliferation was evaluated via the Cell Counting Kit-8(CCK8)assay,whereas Transwell assays were used to assess cell invasion and migration.Apoptosis was measured by Annexin V Fluorescein Isothiocyanate(FITC)double staining.Tumor formation in nude mice was assessed to examine the effect of C9orf139 on in vivo tumor growth.The C9orf139-miR-24-3p-TAOK1 regulatory axis was validated via dual luciferase reporter assays and RNA-binding protein immunoprecipitation(RIP).Western blot assays were used to assess the expression and phosphorylation of key proteins in the mitogen-activated protein kinase(MAPK)signaling pathway.Results Bioinformatics analysis identified C9orf139 and TAOK1 as differentially expressed genes that play key roles in AML pathogenesis.The C9orf139-miR-24-3p-TAOK1 axis was tightly linked to AML development,as confirmed by clinical sample analysis.In vitro,C9orf139 downregulation resulted in reduced proliferation,invasion,and migration and enhanced the apoptosis of AML cells.In vivo,the inhibition of C9orf139 significantly impaired tumor growth in nude mice.The regulatory axis was further validated.C9orf139 knockdown reduced the phosphorylation levels of the key MAPK pathway proteins,including Raf,mitogen-activated protein kinase kinase(MEK),and extracellular regulated protein kinase(ERK).Conclusion C9orf139 regulates AML progression by activating the MAPK signaling pathway through the C9orf139-miR-24-3p-TAOK1 axis.
基金supported by grants from the National Key Research and Development Program of China(2016YFA0502201)the National Natural Science Foundation of China(81571550,81671613)+2 种基金the Natural Science Foundation of Zhejiang Province(LY18H100001,LY15H100001)the‘Double First-rate’project initiatives,the Shanghai Key Laboratory of Cell Engineering(14DZ2272300)the Shanghai Leading Academic Discipline Project(B905).
文摘Interleukin 17(IL-17)is an important cytokine that can induce tissue inflammation and is involved in the pathogenesis of numerous autoimmune diseases.However,the regulation of its signaling transduction has not been well described.In this study,we report that thousand and one kinase 1(TAOK1)functions as a negative regulator of IL-17-mediated signal transduction and inflammation.TAOK1 knockdown promotes IL-17-induced cytokine and chemokine expression and the activation of mitogen-activated protein kinases and nuclear factor-κB.We further demonstrate that TAOK1 interacts with IL-17 receptor A(IL-17RA)independent of its kinase activity,and TAOK1 dose-dependently prevents the formation of the IL-17R-Act1(nuclear factor activator 1,also known as tumor necrosis factor receptor-associated factor 3 interacting protein 2)complex.Consistent with this,TAOK1 deficiency exacerbates colitis in the 2,4,6-trinitrobenzenesulfonic acid-induced experimental model of inflammatory bowel disease,likely by its promotion of the IL-17-mediated signaling pathway.TAOK1 expression is decreased in the colons of ulcerative colitis patients.In conclusion,these findings suggest that TAOK1 is involved in the development of IL-17-related autoimmune disorders.
