2′-O-methylation(Nm)is one of the most abundant RNA epigenetic modifications and plays a vital role in the post-transcriptional regulation of gene expression.Current Nm mapping approaches are normally limited to high...2′-O-methylation(Nm)is one of the most abundant RNA epigenetic modifications and plays a vital role in the post-transcriptional regulation of gene expression.Current Nm mapping approaches are normally limited to highly abundant RNAs and have significant technical hurdles in m RNAs or relatively rare non-coding RNAs(nc RNAs).Here,we developed a new method for enriching Nm sites by using RNA exoribonuclease and periodate oxidation reactivity to eliminate 2′-hydroxylated(2′-OH)nucleosides,coupled with sequencing(Nm-REP-seq).We revealed several novel classes of Nm-containing nc RNAs as well as m RNAs in humans,mice,and drosophila.We found that some novel Nm sites are present at fixed positions in different t RNAs and are potential substrates of fibrillarin(FBL)methyltransferase mediated by sno RNAs.Importantly,we discovered,for the first time,that Nm located at the 3′-end of various types of nc RNAs and fragments derived from them.Our approach precisely redefines the genome-wide distribution of Nm and provides new technologies for functional studies of Nm-mediated gene regulation.展开更多
Cancer immunotherapy is impaired by the intrinsic and adaptive immune resistance.Herein,a bispecific prodrug nanoparticle was engineered for circumventing immune evasion of the tumor cells by targeting multiple immune...Cancer immunotherapy is impaired by the intrinsic and adaptive immune resistance.Herein,a bispecific prodrug nanoparticle was engineered for circumventing immune evasion of the tumor cells by targeting multiple immune resistance mechanisms.A disulfide bond-linked bispecific prodrug of NLG919 and JQ1(namely NJ) was synthesized and self-assembled into a prodrug nanoparticle,which was subsequently coated with a photosensitizer-modified and tumor acidity-activatable diblock copolymer PHP for tumor-specific delivery of NJ.Upon tumor accumulation via passive tumor targeting,the polymeric shell was detached for facilitating intracellular uptake of the bispecific prodrug.NJ was then activated inside the tumor cells for releasing JQ1 and NLG919 via glutathione-mediated cleavage of the disulfide bond.JQ1 is a bromodomain-containing protein 4 inhibitor for abolishing interferon gamma-triggered expression of programmed death ligand 1.In contrast,NLG919 suppresses indoleamine-2,3-dioxygenase 1-mediated tryptophan consumption in the tumor microenvironment,which thus restores robust antitumor immune responses.Photodynamic therapy(PDT) was performed to elicit antitumor immunogenicity by triggering immunogenic cell death of the tumor cells.The combination of PDT and the bispecific prodrug nanoparticle might represent a novel strategy for blockading multiple immune evasion pathways and improving cancer immunotherapy.展开更多
Glioblastoma(GBM) therapy is severely impaired by the blood-brain barrier(BBB) and invasive tumor growth in the central nervous system.To improve GBM therapy,we herein presented a dual-targeting nanotheranostic for se...Glioblastoma(GBM) therapy is severely impaired by the blood-brain barrier(BBB) and invasive tumor growth in the central nervous system.To improve GBM therapy,we herein presented a dual-targeting nanotheranostic for second near-infrared(NIR-Ⅱ) fluorescence imaging-guided photoimmunotherapy.Firstly,a NIR-Ⅱ fluorophore MRP bearing donor-acceptor-donor(D-A-D) backbone was synthesized.Then,the prodrug nanotheranostics were prepared by self-assembling MRP with a prodrug of JQ1(JPC) and T7 ligand-modified PEG5k-DSPE.T7 can cross the BBB for tumor-targeted delivery of JPC and MRP.JQ1 could be restored from JPC at the tumor site for suppressing interferon gamma-inducible programmed death ligand 1 expression in the tumor cells.MRP could generate NIR-Ⅱ fluorescence to navigate 808 nm laser,induce a photothermal effect to trigger in-situ antigen release at the tumor site,and ultimately elicit antitumor immunogenicity.Photo-immunotherapy with JPC and MRP dual-loaded nanoparticles remarkably inhibited GBM tumor growth in vivo.The dual-targeting nanotheranostic might represent a novel nanoplatform for precise photo-immunotherapy of GBM.展开更多
CONSPECTUS:The current era has witnessed the success of immunotherapy,in particular,immune checkpoint blockade(ICB)therapy,at an unprecedented pace.However,immunotherapy often fails to unleash the antitumor immune res...CONSPECTUS:The current era has witnessed the success of immunotherapy,in particular,immune checkpoint blockade(ICB)therapy,at an unprecedented pace.However,immunotherapy often fails to unleash the antitumor immune response because of the paucity of appropriate therapeutic targets in the complex tumor microenvironment(TME)and the occurrence of intrinsic and adaptive immune resistance of tumor cells.In recent years,we have rationally engineered a set of bioinspired stimuli-activatable nanotherapeutics to circumvent cancer immune resistance and potentiate cancer immunotherapy.展开更多
The CREB1 gene encodes an exceptionally pleiotropic transcription factor that frequently dysregulated in human cancers.CREB1 can regulate tumor cell status of proliferation and/or migration;however,the molecular basis...The CREB1 gene encodes an exceptionally pleiotropic transcription factor that frequently dysregulated in human cancers.CREB1 can regulate tumor cell status of proliferation and/or migration;however,the molecular basis for this switch involvement in cell plasticity has not fully been understood yet.Here,we first show that knocking out CREB1 triggers a remarkable effect of epithelial-mesenchymal transition(EMT)and leads to the occurrence of inhibited proliferation and enhanced motility in HCT116colorectal cancer cells.By monitoring 45 cellular signaling pathway activities,we find that multiple growth-related pathways decline significantly while inflammatory pathways including NF-κB are largely upregulated in comparing between the CREB1wild-type and knocked out cells.Mechanistically,cells with CREB1 knocked out show downregulation of MYC as a result of impaired CREB1-dependent transcription of the oncogenic lnc RNA CCAT1.Interestingly,the unbalanced competition between the coactivator CBP/p300 for CREB1 and p65 leads to the activation of the NF-κB pathway in cells with CREB1 disrupted,which induces an obvious EMT phenotype of the cancer cells.Taken together,these studies identify previously unknown mechanisms of CREB1 in CRC cell plasticity via regulating lnc RNA CCAT1 and NF-κB pathways,providing a critical insight into a combined strategy for CREB1-targeted tumor therapies.展开更多
基金supported by the National Key R&D Program of China(2019YFA0802202)the National Natural Science Foundation of China(91940304,31971228,31900903,31970604,32100467,32225011)the Youth Science and Technology Innovation Talent of Guangdong Te Zhi Plan(2019TQ05Y181)。
文摘2′-O-methylation(Nm)is one of the most abundant RNA epigenetic modifications and plays a vital role in the post-transcriptional regulation of gene expression.Current Nm mapping approaches are normally limited to highly abundant RNAs and have significant technical hurdles in m RNAs or relatively rare non-coding RNAs(nc RNAs).Here,we developed a new method for enriching Nm sites by using RNA exoribonuclease and periodate oxidation reactivity to eliminate 2′-hydroxylated(2′-OH)nucleosides,coupled with sequencing(Nm-REP-seq).We revealed several novel classes of Nm-containing nc RNAs as well as m RNAs in humans,mice,and drosophila.We found that some novel Nm sites are present at fixed positions in different t RNAs and are potential substrates of fibrillarin(FBL)methyltransferase mediated by sno RNAs.Importantly,we discovered,for the first time,that Nm located at the 3′-end of various types of nc RNAs and fragments derived from them.Our approach precisely redefines the genome-wide distribution of Nm and provides new technologies for functional studies of Nm-mediated gene regulation.
基金supported by the National Natural Science Foundation of China(51873228,22074043)International Cooperation Project of Science and Technology Commission of Shanghai Municipality(20430711800,China)+1 种基金the Youth Innovation Promotion Association of CAS(2014218,China)the Fusion Grant between Fudan University and Shanghai Institute of Materia Medica,CAS(No.FU-SIMM-20182006,China)。
文摘Cancer immunotherapy is impaired by the intrinsic and adaptive immune resistance.Herein,a bispecific prodrug nanoparticle was engineered for circumventing immune evasion of the tumor cells by targeting multiple immune resistance mechanisms.A disulfide bond-linked bispecific prodrug of NLG919 and JQ1(namely NJ) was synthesized and self-assembled into a prodrug nanoparticle,which was subsequently coated with a photosensitizer-modified and tumor acidity-activatable diblock copolymer PHP for tumor-specific delivery of NJ.Upon tumor accumulation via passive tumor targeting,the polymeric shell was detached for facilitating intracellular uptake of the bispecific prodrug.NJ was then activated inside the tumor cells for releasing JQ1 and NLG919 via glutathione-mediated cleavage of the disulfide bond.JQ1 is a bromodomain-containing protein 4 inhibitor for abolishing interferon gamma-triggered expression of programmed death ligand 1.In contrast,NLG919 suppresses indoleamine-2,3-dioxygenase 1-mediated tryptophan consumption in the tumor microenvironment,which thus restores robust antitumor immune responses.Photodynamic therapy(PDT) was performed to elicit antitumor immunogenicity by triggering immunogenic cell death of the tumor cells.The combination of PDT and the bispecific prodrug nanoparticle might represent a novel strategy for blockading multiple immune evasion pathways and improving cancer immunotherapy.
基金Financial supports from the National Natural Science Foundation of China (22074043, 22174047, 32050410287)Science and Technology Commission of Shanghai Municipality (20142202800, China)+1 种基金China Postdoctoral Science Foundation (2021M700157)Shanghai Post-Doctoral Excellence Program (2021424, China)
文摘Glioblastoma(GBM) therapy is severely impaired by the blood-brain barrier(BBB) and invasive tumor growth in the central nervous system.To improve GBM therapy,we herein presented a dual-targeting nanotheranostic for second near-infrared(NIR-Ⅱ) fluorescence imaging-guided photoimmunotherapy.Firstly,a NIR-Ⅱ fluorophore MRP bearing donor-acceptor-donor(D-A-D) backbone was synthesized.Then,the prodrug nanotheranostics were prepared by self-assembling MRP with a prodrug of JQ1(JPC) and T7 ligand-modified PEG5k-DSPE.T7 can cross the BBB for tumor-targeted delivery of JPC and MRP.JQ1 could be restored from JPC at the tumor site for suppressing interferon gamma-inducible programmed death ligand 1 expression in the tumor cells.MRP could generate NIR-Ⅱ fluorescence to navigate 808 nm laser,induce a photothermal effect to trigger in-situ antigen release at the tumor site,and ultimately elicit antitumor immunogenicity.Photo-immunotherapy with JPC and MRP dual-loaded nanoparticles remarkably inhibited GBM tumor growth in vivo.The dual-targeting nanotheranostic might represent a novel nanoplatform for precise photo-immunotherapy of GBM.
基金support from the National Natural Science Foundation of China(32050410287 to M.S.,51873228 and 52111530092 to H.Y.)the International Cooperation Project of Science and Technology Commission of Shanghai Municipality(20430711800)is gratefully acknowledged.
文摘CONSPECTUS:The current era has witnessed the success of immunotherapy,in particular,immune checkpoint blockade(ICB)therapy,at an unprecedented pace.However,immunotherapy often fails to unleash the antitumor immune response because of the paucity of appropriate therapeutic targets in the complex tumor microenvironment(TME)and the occurrence of intrinsic and adaptive immune resistance of tumor cells.In recent years,we have rationally engineered a set of bioinspired stimuli-activatable nanotherapeutics to circumvent cancer immune resistance and potentiate cancer immunotherapy.
基金supported by the National Natural Science Foundation of China(31970604,31900903,31770879)the Major Research Plan of the National Natural Science Foundation of China(91940000)+3 种基金the National Key Research and Development Program of China(2017YFA0504400)in part by the Guangdong Province Key Laboratory of Computational Science(13lgjc05)the Guangdong Province Computational Science Innovative Research Team(14lgjc18)the Fundamental Research Funds for the Central Universities(20lgpy112,2021qntd26)。
文摘The CREB1 gene encodes an exceptionally pleiotropic transcription factor that frequently dysregulated in human cancers.CREB1 can regulate tumor cell status of proliferation and/or migration;however,the molecular basis for this switch involvement in cell plasticity has not fully been understood yet.Here,we first show that knocking out CREB1 triggers a remarkable effect of epithelial-mesenchymal transition(EMT)and leads to the occurrence of inhibited proliferation and enhanced motility in HCT116colorectal cancer cells.By monitoring 45 cellular signaling pathway activities,we find that multiple growth-related pathways decline significantly while inflammatory pathways including NF-κB are largely upregulated in comparing between the CREB1wild-type and knocked out cells.Mechanistically,cells with CREB1 knocked out show downregulation of MYC as a result of impaired CREB1-dependent transcription of the oncogenic lnc RNA CCAT1.Interestingly,the unbalanced competition between the coactivator CBP/p300 for CREB1 and p65 leads to the activation of the NF-κB pathway in cells with CREB1 disrupted,which induces an obvious EMT phenotype of the cancer cells.Taken together,these studies identify previously unknown mechanisms of CREB1 in CRC cell plasticity via regulating lnc RNA CCAT1 and NF-κB pathways,providing a critical insight into a combined strategy for CREB1-targeted tumor therapies.