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Genes & Diseases 2024年第4期11卷 39-41页

作者： Tong Qiao Beining Yin Jun Liang Li Wei Department of Thoracic Surgery Henan Provincial People's HospitalZhengzhouHenan 450000China Reproductive Medicine Center The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China Department of Breast Surgery Henan Provincial People's HospitalZhengzhouHenan 450000China

Due to the profound heterogeneity exhibited amongst patients with lung adenocarcinoma(LUAD),considerable variances in clinical efficacy emerge.1 For the aims of precision medicine,a clinical instrument to delineate distinct disease phenotypes and anticipate susceptibility to intervention is imperative.Cellular cytotoxicity mediated through T lymphocytes constitutes a pivotal mechanism of anti-tumoral immunity and the foundation for cancer immunotherapy.?Numerous genes regulating the sensitivity of tumor cells to killing mediated by T lymphocytes(GSTKKs)are conducive to satisfying the aforesaid medical necessity.

关键词： clinical mediated adenocarcinoma

Estrogen-mediated downregulation of HIF-1αsignaling in B lymphocytes influences postmenopausal bone loss

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Bone Research 2022年第2期10卷 326-337页

作者： Xianyi Meng Zhen Lin Shan Cao Iga Janowska Koshiro Sonomoto Darja Andreev Knab Katharina Jinming Wen Karl Xaver Knaup Michael Sean Wiesener Gerhard Krönke Marta Rizzi Georg Schett Aline Bozec Department of Internal Medicine 3 Friedrich-Alexander-University Erlangen-Nürnberg(FAU)and Universitätsklinikum ErlangenErlangen 91054Germany Deutsches Zentrum fur Immuntherapie(DYI) Erlangen 91054Germany Department of Rheumatology and Clinical Immunology Faculty of MedicineMedical Center-University of FreiburgFreiburg 79106Germany Department of Internal Medicine 4 Friedrich-Alexander-University Erlangen-Nürnberg(FAU)and Universitätsklinikum ErlangenErlangen 91054Germany

In the bone marrow, B cells and bone-resorbing osteoclasts colocalize and form a specific microenvironment. How B cells functionally influence osteoclasts and bone architecture is poorly understood. Using genetically modified mice and highthroughput analyses, we demonstrate that prolonged HIF-1α signaling in B cells leads to enhanced RANKL production and osteoclast formation. In addition, deletion of HIF-1α in B cells prevents estrogen deficiency-induced bone loss in mice.Mechanistically, estrogen controls HIF-1α protein stabilization through HSP70-mediated degradation in bone marrow B cells.The stabilization of HIF-1α protein in HSP70-deficient bone marrow B cells promotes RANKL production and osteoclastogenesis.Induction of HSP70 expression by geranylgeranylacetone(GGA) administration alleviates ovariectomy-induced osteoporosis.Moreover, RANKL gene expression has a positive correlation with HIF1 A expression in human B cells. In conclusion, HIF-1αsignaling in B cells is crucial for the control of osteoclastogenesis, and the HSP70/HIF-1α axis may serve as a new therapeutic target for osteoporosis.

关键词： mediated lymphocytes stabilization

TRAF3 activates STING-mediated suppression of EV-A71 and target of viral evasion

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Signal Transduction and Targeted Therapy 2023年第3期8卷 1296-1309页

作者： Wenwen Zheng Zhenbang Zhou Yajuan Rui Runxin Ye Fengyan Xia Fei Guo Xiaoman Liu Jiaming Su Meng Lou Xiao-Fang Yu Cancer Institute(Key Laboratory of Cancer Prevention and Intervention China National Ministry of Education)The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China National Health Commission of the People’s Republic of China Key Laboratory of Systems Biology of Pathogens Institute of Pathogen Biology and Center for AIDS ResearchChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Cancer Center Zhejiang UniversityHangzhouZhejiang 310058China

Innate immunity represents one of the main host responses to viral infection.1,2,3 STING(Stimulator of interferon genes),a crucial immune adapter functioning in host cells,mediates cGAS(Cyclic GMP-AMP Synthase)sensing of exogenous and endogenous DNA fragments and generates innate immune responses.4 Whether STING activation was involved in infection and replication of enterovirus remains largely unknown.In the present study,we discovered that human enterovirus A71(EV-A71)infection triggered STING activation in a cGAS dependent manner.EV-A71 infection caused mitochondrial damage and the discharge of mitochondrial DNA into the cytosol of infected cells.However,during EV-A71 infection,cGAS-STING activation was attenuated.EV-A71 ^(pro)teins were screened and the viral ^(pro)tease 2A^(pro) had the greatest capacity to inhibit cGAS-STING activation.We identified TRAF3 as an important factor during STING activation and as a target of 2A^(pro).Supplement of TRAF3 rescued cGAS-STING activation suppression by 2A^(pro).TRAF3 supported STING activation mediated TBK1 phosphorylation.Moreover,we found that 2A^(pro) ^(pro)tease activity was essential for inhibiting STING activation.Furthermore,EV-D68 and CV-A16 infection also triggered STING activation.The viral ^(pro)tease 2A^(pro) from EV-D68 and CV-A16 also had the ability to inhibit STING activation.As STING activation prior to EV-A71 infection generated cellular resistance to EV-A71 replication,blocking EV-A71-mediated STING suppression represents a new anti-viral target.

关键词： mediated TRAF3 immunity

Nucleolin promotes tumor growth in colorectal cancer by enhancing hnRNPA1-mediated PKM2 alternative splicing

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Genes & Diseases 2023年第6期10卷 2237-2240页

作者： Xue Wang Han Cheng Die Hu Ying Chen Waseem Hassan Jing Zhao Jiuming Li Zhaohui Huang Laboratory of Cancer Epigenetics Wuxi School of MedicineJiangnan UniversityWuxiJiangsu 214062China Wuxi Cancer Institute Affiliated Hospital of Jiangnan UniversityWuxiJiangsu 214062China Wuxi School of Medicine Jiangnan UniversityWuxiJiangsu 214062China Department of Pharmacy COMSATS University IslamabadLahore CampusLahore 54000Pakistan

Emerging evidence indicates that metabolism reprogramming plays an important role in cancer progression.RNAbinding protein nucleolin(NCL)was reported to function as an important oncogenic factor in multiple cancer types.However,the role and mechanism of NCL in cancer metabolism are unknown.In this study,we found that NCL directly interacted with hnRNPA1 and promoted CRC cell proliferation by enhancing aerobic glycolysis.Mechanistically,NCL bound PKM pre-mRNA and increased hnRNPA1-mediated PKM alternative splicing,resulting in increased PKM2 expression and tumor growth.A seed-mediated growth approach was used to synthesize gold nanostars(GNS),which were further modified with aptamer AS1411(an NCL ligand),GE11(an EGFR ligand),and nuclear localization signal to obtain functionalized nanoparticles(GNSAS1411-GE11).GNS-AS1411-GE11 efficiently enter the nucleus of CRC cells and blocked the glycolysis-promoting effects of NCL,inhibiting the growth of CRC xenograft.Targeting NCL is a promising strategy for treating CRC.

关键词： PKM2 metabolism mediated

Highlighted multi-modifications of enzymes:a novel succinylation mediated by histone acetyltransferase 1 in tumors

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Cancer Biology & Medicine 2022年第2期19卷 133-135页

作者： Xiaodong Zhang Chunyu Hou Guang Yang Department of Gastrointestinal Cancer Biology Liver Cancer CenterTianjin Medical University Cancer Institute&HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerTianjin 300060China

Histone acetyltransferase 1 serves as a succinyl transferase in tumors Protein post-translational modification(PTM)as an important research field has attracted increasing attention.Recently,our group has reported that histone acetyltransferase 1(HAT1)succinylated histones and non-histones and promoted tumorigenesis1.HAT1 plays a role in different biological processes,including cell cycle progression,glucose metabolism,histone production,and DNA damage repair2.We found that HAT1 succinylated histone H3 on K122.For a non-histone,HAT1 catalyzed the succinylation of phosphoglycerate mutase 1(PGAM1)on K99 to increase its enzyme activity,promoting glycolysis in cancer cells.Functionally,HAT1-mediated succinylation contributed to tumorigenesis.Our finding provided new insight into the mechanism of how a histone acetyltransferase HAT1 modulated succinylation during cancer development.

关键词： metabolism mediated tumors

SDHA: a key player in T cell-mediated intestinal disease severity

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Cellular & Molecular Immunology 2022年第2期19卷 139-141页

作者： José M.Izquierdo Centro de Biología Molecular Severo Ochoa.Consejo Superior de Investigaciones Científicas Universidad Autónoma de Madrid(CSIC/UAM)C/Nicolás Cabrera 1Campus de Cantoblanco28049MadridSpain

In their recent article in Nature Immunology,Fujiwara et al.identified reduced mitochondrial respiration and increased succinate levels in intestinal epithelial cells(IECs)from several distinct models of T cell-mediated colitis.Their observations point to a specific link between alterations in the mitochondrial complex II component SDHA and the severity of T cell-mediated intestinal diseases and suggest that SDHA dysfunction could be a diagnostic and/or prognostic biomarker in T cell-mediated immunopathology.

关键词： severity alterations mediated

Black phosphorus-based photothermal therapy with aCD47-mediated immune checkpoint blockade for enhanced cancer immunotherapy

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Light(Science & Applications) 2020年第1期9卷 479-493页

作者： Zhongjian Xie Minhua Peng Ruitao Lu Xiangying Meng Weiyuan Liang Zhongjun Li Meng Qiu Bin Zhang Guohui Nie Ni Xie Han Zhang Paras N.Prasad Shenzhen International Institute for Biomedical Research Shenzhen 518116 GuangdongPR China Shenzhen Institutes of Advanced Technology Chinese Academy of SciencesShenzhen 518055 GuangdongPR China School of Basic Medical Sciences Guangzhou Medical UniversityGuangzhou 511436 GuangdongPR China Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province Institute of Microscale Optoelectronicsand Otolaryngology Department and Biobank of the First Affiliated HospitalShenzhen Second People’s HospitalHealth Science CenterShenzhen UniversityShenzhen 518060PR China Key Laboratory of Marine Chemistry Theory and Technology(Ocean University of China) Ministry of EducationQingdao 266100PR China Department of Chemistry Institute for LasersPhotonicsand BiophotonicsUniversity at BuffaloStateUniversity of New YorkBuffaloNYUSA

Here,we describe a combination strategy of black phosphorus(BP)-based photothermal therapy together with anti-CD47 antibody(aCD47)-based immunotherapy to synergistically enhance cancer treatment.Tumour resistance to immune checkpoint blockades in most cancers due to immune escape from host surveillance,along with the initiation of metastasis through immunosuppressive cells in the tumour microenvironment,remains a significant challenge for cancer immunotherapy.aCD47,an agent for CD47/SIRPαaxis blockade,induces modest phagocytic activity and a low response rate for monotherapy,resulting in failures in clinical trials.We showed that BP-mediated ablation of tumours through photothermal effects could serve as an effective strategy for specific immunological stimulation,improving the inherently poor immunogenicity of tumours,which is particularly useful for enhancing cancer immunotherapy.BP in combination with aCD47 blockade activates both innate and adaptive immunities and promotes local and systemic anticancer immune responses,thus offering a synergistically enhanced effect in suppression of tumour progression and in inducing abscopal effects for inhibition of metastatic cancers.Our combination strategy provides a promising platform in which photothermal agents could help to enhance the therapeutic efficacy of immunotherapy.

关键词： immunotherapy cancer mediated

Development of a Haploid-Inducer mediated Genome Editing System for Accelerating Maize Breeding

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Molecular Plant 2019年第4期12卷 597-602页

作者： Baobao Wang Lei Zhu Binbin Zhao Yongping Zhao Yurong Xie Zhigang Zheng Yaoyao Li Juan Sun Haiyang Wang Biotechnology Research Institute Chinese Academy of Agricultural Sciences Beijing 100081 China School of Life Sciences State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources South China Agricultural University Guangzhou 510642 China

Crop breeding aims to generate pure in bred lines with multiple desired traits. Doubled haploid (DH) and genome editing using CRISPR/Cas9 are two powerful game-changing technologies in crop breeding. However, both of them still fall short for rapid generation of pure elite lines with integrated favorable traits. Here, we report the development of a Haploid-Inducer mediated Genome Editing (IMGE) approach, which utilizes a maize haploid inducer line carrying a CRISPR/Cas9 cassette targeting for a desired agronomic trait to pollinate an elite maize in bred line and to generate genome-edited haploids in the elite maize background. Homozygous pure DH lines with the desired trait improvement could be generated within two generations, thus bypassing the lengthy procedure of repeated crossing and backcrossing used in conventional breeding for integrating a desirable trait into elite commercial backgrounds.

关键词： maize, doubled haploids (DH) CRSIPR/Cas9 haploid-inducer mediated genome editing (IMGE) crop breeding

Macrophage-derived small extracellular vesicles promote biomimetic mineralized collagen-mediated endogenous bone regeneration

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International Journal of Oral Science 2020年第4期12卷 317-326页

作者： Anqi Liu Shanshan Jin Cuicui Fu Shengji Cui Ting Zhang Lisha Zhu Yu Wang Steve G.F.Shen Nan Jiang Yan Liu Department of Oral and Maxillofacial Surgery Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai Key Laboratory of StomatologyShanghaiChina Laboratory of Biomimetic Nanomaterials Department of OrthodonticsPeking University School and Hospital of StomatologyNational Engineering Laboratory for Digital and Material Technology of StomatologyBeijing Key Laboratory of Digital StomatologyBeijingChina Department of Oral Biochemistry Academic Centre for Dentistry Amsterdam(ACTA)University of Amsterdam(UvA)and Vrije Universiteit Amsterdam(VU)Gustav Mahlerlaan 3004AmsterdamThe Netherlands Shanghai University of Medicine and Health Sciences ShanghaiChina Central Laboratory Peking University School and Hospital of StomatologyNational Engineering Laboratory for Digital and Material Technology of StomatologyBeijing Key Laboratory of Digital StomatologyBeijingChina

Macrophages play an important role in material-related immune responses and bone formation,but the functionality of macrophage-derived extracellular vesicles(EVs)in material-mediated bone regeneration is still unclear.Here,we evaluated intracellular communication through small extracellular vesicles(sEVs)and its effects on endogenous bone regeneration mediated by biomimetic intrafibrillarly mineralized collagen(IMC).After implantation in the bone defect area,IMC generated more neobone and recruited more mesenchymal stem cells(MSCs)than did extrafibrillarly mineralized collagen(EMC).More CD63+CD90+and CD63+CD163+cells were detected in the defect area in the IMC group than in the EMC group.To determine the functional roles of sEVs,extracellular vesicles from macrophages cultured on different mineralized collagen were isolated,and they showed no morphological differences.However,macrophage-derived sEVs in the IMC group showed an enhanced Young’s modulus and exerted beneficial effects on the osteogenic differentiation of bone marrow MSCs by increasing the expression of the osteoblastic differentiation markers BMP2,BGLAP,COL1,and OSX and calcium nodule formation.Mechanistically,sEVs from IMC-treated macrophages facilitated MSC osteogenesis through the BMP2/Smad5 pathway,and blocking sEV secretion with GW4869 significantly impaired MSC proliferative,immunomodulative and osteogenic potential.Taken together,these findings show that macrophage-derived sEVs may serve as an emerging functional tool in biomaterial-mediated endogenous bone regeneration.

关键词： endogenous CD63 mediated

m6A RNA methylation-mediated HNF3γ reduction rendershepatocellular carcinoma dedifferentiation and sorafenibresistance

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Signal Transduction and Targeted Therapy 2021年第1期6卷 144-157页

作者： Tengfei Zhou Shichao Li Daimin Xiang Junyu Liu Wen Sun Xiuliang Cui Beifang Ning Xiao Li Zhuo Cheng Weiqi Jiang Cheng Zhang Xijun Liang Liang Li Xin Cheng Liu Hui Hongyang Wang Jin Ding International Cooperation Laboratory on Signal Transduction Eastern Hepatobiliary Surgery Hospital/InstituteThe Second Military Medical UniversityShanghaiChina Department of Gastroenterology Changzheng HospitalThe Second Military Medical UniversityShanghaiChina Shanghai Institutes for Biological Sciences Chinese Academy of SciencesShanghaiChina The Third Department of Hepatic Surgery Eastern Hepatobiliary Surgery HospitalThe Second Military Medical UniversityShanghaiChina National Center for Liver Cancer ShanghaiChina Tongji University School of Medicine ShanghaiChina

Hepatocyte nuclear factor 3γ(HNF3γ)is a hepatocyte nuclear factor,but its role and clinical significance in hepatocellular carcinoma(HCC)remain unclear.Herein,we report that HNF3γexpression is downregulated in patient HCC and inversely correlated with HCC malignancy and patient survival.Moreover,our data suggested that the HNF3γreduction in HCC could be mediated by METTL14-dependent m6A methylation of HNF3γmRNA.HNF3γexpression was increased during hepatic differentiation and decreased in dedifferentiated HCC cells.Interestingly,HNF3γdelivery promoted differentiation of not only HCC cells but also liver CSCs,which led to suppression of HCC growth.Mechanistic analysis suggested an HNF3γ-centered regulatory network that includes essential liver differentiation-associated transcription factors and functional molecules,which could synergistically facilitate HCC cell differentiation.More importantly,enforced HNF3γexpression sensitized HCC cells to sorafenib-induced growth inhibition and cell apoptosis through transactivation of OATP1B1 and OATP1B3 expression,which are major membrane transporters for sorafenib uptake.Clinical investigation showed that patient-derived HCC xenografts with high HNF3γexpression exhibited a sorafenib response and patients with high HCC HNF3γlevels benefited from sorafenib therapy.Together,these results suggest that HNF3γplays an essential role in HCC differentiation and may serve as a therapeutic target and predictor of sorafenib benefit in patients.

关键词： sorafenib hepatocellular mediated