Aberrant RNA splicing produces alternative isoforms of genes to facilitate tumor progression,yet how this process is regulated by oncogenic signal remains largely unknown.Here,we unveil that non-canonical activation o...Aberrant RNA splicing produces alternative isoforms of genes to facilitate tumor progression,yet how this process is regulated by oncogenic signal remains largely unknown.Here,we unveil that non-canonical activation of nuclear AURKA promotes an oncogenic RNA splicing of tumor suppressor RBM4 directed by m^(6)A reader YTHDC1 in lung cancer.Nuclear translocation of AURKA is a prerequisite for RNA aberrant splicing,specifically triggering RBM4 splicing from the full isoform(RBM4-FL)to the short isoform(RBM4-S)in a kinase-independent manner.展开更多
Background:Increasing studies have reported that oncogenes regulate components of the immune system,suggesting that this is a mechanism for tumorigenesis.Aurora kinase A(AURKA),a serine/threonine kinase,is involved in...Background:Increasing studies have reported that oncogenes regulate components of the immune system,suggesting that this is a mechanism for tumorigenesis.Aurora kinase A(AURKA),a serine/threonine kinase,is involved in cell mitosis and is essential for tumor cell proliferation,metastasis,and drug resistance.However,the mechanism by which AURKA is involved in immune response regulation is unclear.Therefore,this study aimed to investigate the role of AURKA in immune regulation in triple-negative breast cancer(TNBC).Methods:Peripheral blood mononuclear cells(PBMCs)were co-cultured with TNBC cells.The xCELLigence Real-Time Cell Analyzer-MP system was used to detect the killing efficiency of immune cells on TNBC cells.The expression of immune effector molecules was tested by quantitative real-time polymerase chain reaction(qRT-PCR)to evaluate immune function.Furthermore,to validate AURKA-regulated immune response in vivo,4T1 murine breast cancer cell line with AURKA overexpression or downregulation was engrafted into BALB/c mice.The distribution and proportion of immune cells in tumors were further evaluated by immunohistochemistry and flow cytometry.Results:Downregulation of AURKA in TNBC cells increased immune response by activating CD8^(+)T cell proliferation and activity.Nuclear rather than cytoplasmic AURKA-derived programmed death-ligand 1(PD-L1)expression was independent of its kinase activity.Mechanistic investigations showed that nuclear AURKA increased PD-L1 expression via an MYC-dependent pathway.PD-L1 overexpression mostly reversed AURKA silencing-induced expression of immune effector molecules,including interleukin-(IL-2),interferon-γ(IFN-γ),and perforin.Moreover,AURKA expression was negatively correlated with the enrichment and activity of tumor-infiltrating CD8^(+)T cells in 4T1 engrafted BALB/c mouse model.Conclusions:Nuclear AURKA elevated PD-L1 expression via an MYCdependent pathway and contributed to immune evasion in TNBC.Therapies targeting nuclear AURKA may restore immune responses against tumors.展开更多
基金We thank Quentin Liu’s lab members for their critical comments and technical support.We thank Eric W.-F.Lam for his critical reading of the manuscript and insightful suggestions.This research work was supported by the National Natural Science Foundation of China(No.81820108024 to Q.L.,No.81630005 to Q.L.,No.81830088 to Y.W.,No.81873441 to B.-L.J.,No.82103659 to S.-S.L.,No.8210113819 to Y.-F.Q.,No.81972786 to J.X.,No.82003141 to F.P.,No.82002960 to B.C.,No.31801100 to X.-.D.D.)National Key R&D Program of China(2019YFA0110300 to Q.L.and 2017YFA0505600-04 to Q.L.)+12 种基金Program for Changjiang Scholars and Innovative Research Team in University of Ministry of Education of China(No.IRT_17R15)Innovative Research Team in University of Liaoning(No.LT2017001 to Q.L.)Heilongjiang Postdoctoral Fund(No.LBH-Z20074 to S.-S.L.)Harbin Medical University Doctor Green Seedling Ground-breaking Project(No.QMPT-1909 to S.-S.L.)the Natural Science Foundation of Liaoning(No.2019-BS-081 to F.P.)the“Seedling cultivation”program for young scientific and technological talents of Liaoning(No.LZ2020044 to F.P.,No.LZ2019067 to B.C.)Dalian Science and Technology program-The central government guiding local funding projects for scientific and technological development(2021 to F.P.)Dalian High-level Talents Innovation Support Program-Young Science and Technology Star(2021RQ004 to B.C.)the program for climbing Scholars of Liaoning,the Science and Technology Innovation Foundation of Dalian(No.2020JJ25CY008 to Q.L.)International Scientific and Technological Cooperation of Dalian(2015F11GH095 to Q.L.)the Natural Science Foundation of Guangdong(2016A030311038 and 2017A030313608 to Q.L.)the Science and Technology Planning Project of Guangzhou(No.201804020044 to Q.L.)the Scientific Research Project of Guangzhou(No.201904010492 to B.-L.J.).
文摘Aberrant RNA splicing produces alternative isoforms of genes to facilitate tumor progression,yet how this process is regulated by oncogenic signal remains largely unknown.Here,we unveil that non-canonical activation of nuclear AURKA promotes an oncogenic RNA splicing of tumor suppressor RBM4 directed by m^(6)A reader YTHDC1 in lung cancer.Nuclear translocation of AURKA is a prerequisite for RNA aberrant splicing,specifically triggering RBM4 splicing from the full isoform(RBM4-FL)to the short isoform(RBM4-S)in a kinase-independent manner.
基金National Natural Science Foundation of China,Grant/Award Numbers:81702621,81630005,81820108024,81972594,82003141,82002960,31801100,81703062National Key Research and Development Program,Grant/Award Number:2016YFC1303001+2 种基金Natural Science Foundation of Liaoning Province,Grant/Award Numbers:20180550618,2019-BS-081Guangdong Basic and Applied Basic Research Foundation,Grant/Award Numbers:2018A0303130299,2020A1515010608“Seedling cultivation”programfor young scientific and technological talents of Liaoning,Grant/Award Numbers:LZ2020044,LZ2019067。
文摘Background:Increasing studies have reported that oncogenes regulate components of the immune system,suggesting that this is a mechanism for tumorigenesis.Aurora kinase A(AURKA),a serine/threonine kinase,is involved in cell mitosis and is essential for tumor cell proliferation,metastasis,and drug resistance.However,the mechanism by which AURKA is involved in immune response regulation is unclear.Therefore,this study aimed to investigate the role of AURKA in immune regulation in triple-negative breast cancer(TNBC).Methods:Peripheral blood mononuclear cells(PBMCs)were co-cultured with TNBC cells.The xCELLigence Real-Time Cell Analyzer-MP system was used to detect the killing efficiency of immune cells on TNBC cells.The expression of immune effector molecules was tested by quantitative real-time polymerase chain reaction(qRT-PCR)to evaluate immune function.Furthermore,to validate AURKA-regulated immune response in vivo,4T1 murine breast cancer cell line with AURKA overexpression or downregulation was engrafted into BALB/c mice.The distribution and proportion of immune cells in tumors were further evaluated by immunohistochemistry and flow cytometry.Results:Downregulation of AURKA in TNBC cells increased immune response by activating CD8^(+)T cell proliferation and activity.Nuclear rather than cytoplasmic AURKA-derived programmed death-ligand 1(PD-L1)expression was independent of its kinase activity.Mechanistic investigations showed that nuclear AURKA increased PD-L1 expression via an MYC-dependent pathway.PD-L1 overexpression mostly reversed AURKA silencing-induced expression of immune effector molecules,including interleukin-(IL-2),interferon-γ(IFN-γ),and perforin.Moreover,AURKA expression was negatively correlated with the enrichment and activity of tumor-infiltrating CD8^(+)T cells in 4T1 engrafted BALB/c mouse model.Conclusions:Nuclear AURKA elevated PD-L1 expression via an MYCdependent pathway and contributed to immune evasion in TNBC.Therapies targeting nuclear AURKA may restore immune responses against tumors.
