This letter addresses Pravda's innovative review,which proposes hydrogen pe-roxide as the primary pathogenic factor in ulcerative colitis(UC).Although the author presents intriguing mechanistic insights and report...This letter addresses Pravda's innovative review,which proposes hydrogen pe-roxide as the primary pathogenic factor in ulcerative colitis(UC).Although the author presents intriguing mechanistic insights and reports encouraging clinical outcomes with reducing agents,several methodological and clinical considera-tions require discussion.We examine three key aspects:The selective evidence synthesis approach;the need for rigorous clinical validation of proposed thera-pies;and the integration of this novel hypothesis with established inflammatory bowel disease pathogenesis.Given the complexity of UC,future therapeutic ad-vances may require collaborative approaches that integrate redox-based mecha-nisms into existing evidence-based frameworks rather than replacing current paradigms.展开更多
Psychological stress causes gut microbial dysbiosis and cancer progression,yet how gut microbiota determines psychological stressinduced tumor development remains unclear.Here we showed that psychological stress promo...Psychological stress causes gut microbial dysbiosis and cancer progression,yet how gut microbiota determines psychological stressinduced tumor development remains unclear.Here we showed that psychological stress promotes breast tumor growth and cancer stemness,an outcome that depends on gut microbiota in germ-free and antibiotic-treated mice.Metagenomic and metabolomic analyses revealed that psychological stress markedly alters the composition and abundance of gut microbiota,especially Akkermansia muciniphila(A.muciniphila),and decreases short-chain fatty acid butyrate.Supplement of active A.muciniphila,butyrate or a butyrateproducing high fiber diet dramatically reversed the oncogenic property and anxiety-like behavior of psychological stress in a murine spontaneous tumor model or an orthotopic tumor model.Mechanistically,RNA sequencing analysis screened out that butyrate decreases LRP5 expression to block the activation of Wnt/β-catenin signaling pathway,dampening breast cancer stemness.Moreover,butyrate as a HDAC inhibitor elevated histone H3K9 acetylation level to transcriptionally activate ZFP36,which further accelerates LRP5 mRNA decay by binding adenine uridine-rich(AU-rich)elements of LRP5 transcript.Clinically,fecal A.muciniphila and serum butyrate were inversely correlated with tumoral LRP5/β-catenin expression,poor prognosis and negative mood in breast cancer patients.Altogether,our findings uncover a microbiota-dependent mechanism of psychological stress-triggered cancer stemness,and provide both clinical biomarkers and potential therapeutic avenues for cancer patients undergoing psychological stress.展开更多
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
文摘This letter addresses Pravda's innovative review,which proposes hydrogen pe-roxide as the primary pathogenic factor in ulcerative colitis(UC).Although the author presents intriguing mechanistic insights and reports encouraging clinical outcomes with reducing agents,several methodological and clinical considera-tions require discussion.We examine three key aspects:The selective evidence synthesis approach;the need for rigorous clinical validation of proposed thera-pies;and the integration of this novel hypothesis with established inflammatory bowel disease pathogenesis.Given the complexity of UC,future therapeutic ad-vances may require collaborative approaches that integrate redox-based mecha-nisms into existing evidence-based frameworks rather than replacing current paradigms.
基金supported by the Science Fund for Creative Research Groups of the National Natural Science Foundation of China(82321003)the National Natural Science Foundation of China(82273480,82341020,82473131,82373096,82173361)+4 种基金National Key R&D Program of China(2022YFA1104002)Applied Basic Research Planning Project of Liaoning(2023JH2/101600019)Science and technology innovation team project of basic scientific research project of Liaoning Provincial Department of Education(LJ222410161065)the Science and Technology Talent Innovation Support Policy Implementation Program of Dalian-Outstanding young scientific and technological talents(2023RY013)the Shenzhen Bay Laboratory ResearchFunds(SZBL2021080601001toQL).
文摘Psychological stress causes gut microbial dysbiosis and cancer progression,yet how gut microbiota determines psychological stressinduced tumor development remains unclear.Here we showed that psychological stress promotes breast tumor growth and cancer stemness,an outcome that depends on gut microbiota in germ-free and antibiotic-treated mice.Metagenomic and metabolomic analyses revealed that psychological stress markedly alters the composition and abundance of gut microbiota,especially Akkermansia muciniphila(A.muciniphila),and decreases short-chain fatty acid butyrate.Supplement of active A.muciniphila,butyrate or a butyrateproducing high fiber diet dramatically reversed the oncogenic property and anxiety-like behavior of psychological stress in a murine spontaneous tumor model or an orthotopic tumor model.Mechanistically,RNA sequencing analysis screened out that butyrate decreases LRP5 expression to block the activation of Wnt/β-catenin signaling pathway,dampening breast cancer stemness.Moreover,butyrate as a HDAC inhibitor elevated histone H3K9 acetylation level to transcriptionally activate ZFP36,which further accelerates LRP5 mRNA decay by binding adenine uridine-rich(AU-rich)elements of LRP5 transcript.Clinically,fecal A.muciniphila and serum butyrate were inversely correlated with tumoral LRP5/β-catenin expression,poor prognosis and negative mood in breast cancer patients.Altogether,our findings uncover a microbiota-dependent mechanism of psychological stress-triggered cancer stemness,and provide both clinical biomarkers and potential therapeutic avenues for cancer patients undergoing psychological stress.
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.
