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An engineered DNA aptamer-based PROTAC for precise therapy of p53-R175H hotspot mutant-driven cancer

Science Bulletin 2024年第13期69卷 2122-2135页

作者： Lingping Kong Fanlu Meng Ping Zhou Ruixin Ge Xiaoshan Geng Zhihao Yang Guo Li Linlin Zhang Jing Wang Jinfeng Ma Cheng Dong Jun Zhou Sijin Wu Diansheng Zhong Songbo Xie Department of Medical Oncology Tianjin Medical University General HospitalTianjin 300052China Center for Cell Structure and Function Collaborative Innovation Center of Cell Biology in Universities of ShandongCollege of Life SciencesShandong Normal UniversityJinan 250014China The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics Key Laboratory of Immune Microenvironment and Disease(Ministry of Education)School of Basic Medical SciencesTianjin Medical UniversityTianjin 300070China Tianjin Key laboratory of Lung Cancer Metastasis and tumor microenvironment Lung Cancer InstituteTianjin Medical University General HospitalTianjin 300052China Haihe laboratory of Cell Ecosystem State Key Laboratory of Medicinal Chemical BiologyCollege of Life SciencesNankai UniversityTianjin 300071China Wisdom Lake Academy of Pharmacy Xi’an Jiaotong-Liverpool UniversitySuzhou 215028China Department of Ophthalmology Tianjin Medical University General HospitalLaboratory of Molecular OphthalmologyTianjin Key Laboratory of Ocular TraumaTianjin Medical UniversityTianjin 300052China

Targeting oncogenic mutant p53 represents an attractive strategy for cancer treatment due to the high frequency of gain-of-function mutations and ectopic expression in various cancer *** extensive efforts,the absence of a druggable active site for small molecules has rendered these mutants therapeutically *** we develop a selective and effective proteolysis-targeting chimera(PROTAC)for p53-R175H,a common hotspot mutant with dominant-negative and oncogenic *** a novel iterative molecular docking-guided post-SELEX(systematic evolution of ligands by exponential enrichment)approach,we rationally engineer a high-performance DNA aptamer with improved affinity and specificity for *** this resulting aptamer as a binder for PROTACs,we successfully developed a selective p53-R175H degrader,named ***53m induces the ubiquitin–protea some-dependent degradation of p53-R175H while sparing wildtype ***,dp53m demonstrates significant antitumor efficacy in p53-R175H-driven cancer cells both in vitro and in vivo,without ***,dp53m significantly and synergistically improves the sensitivity of these cells to cisplatin,a commonly used chemotherapy *** findings provide evidence of the potential therapeutic value of dp53m in p53-R175H-driven cancers.

关键词： P53 Aptamer PROTAC Cancer Drug resistance

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Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis

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Bone Research 2024年第2期12卷 421-437页

作者： Hongzhen Chen Xuekun Fu Xiaohao Wu Junyi Zhao Fang Qiu Zhenghong Wang Zhuqian Wang Xinxin Chen Duoli Xie Jie Huang Junyu Fan Xu Yang Yi Song Jie Li Dongyi He Guozhi Xiao Aiping Lu Chao Liang Department of Systems Biology School of Life SciencesSouthern University of Science and TechnologyGuangdong Provincial Key Laboratory of Cell Microenvironment and Disease ResearchShenzhen Key Laboratory of Cell MicroenvironmentShenzhen 518055China Institute of Integrated Bioinfomedicine and Translational Science(IBTS) School of Chinese MedicineHong Kong Baptist UniversityHong Kong SAR 999077China Department of Biochemistry School of MedicineSouthern University of Science and TechnologyGuangdong Provincial Key Laboratory of Cell Microenvironment and Disease ResearchShenzhen Key Laboratory of Cell MicroenvironmentShenzhen 518055China Division of Immunology and Rheumatology Stanford UniversityStanfordCA 94305USA VA Palo Alto Health Care System Palo AltoCA 94304USA Institute of Plant and Food Science Department of BiologySouthern University of Science and TechnologyShenzhen 518055China Department of Rheumatology Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghai University of Traditional Chinese MedicineShanghaiChina Department of Computational Biology St.Jude Children’s Research HospitalMemphisTNUSA Department of laboratory Medicine Peking University Shenzhen HospitalShenzhenChina Guangdong-Hong Kong-Macao Joint Lab on Chinese Medicine and Immune Disease Research Guangzhou 510006China Shanghai University of Traditional Chinese Medicine Shanghai 200032China State Key laboratory of Proteomics National Center for Protein Sciences(Beijing)Beijing Institute of Lifeomics100850 BeijingChina

Rheumatoid arthritis(RA)is an autoimmune *** studies hold an opinion that gut microbiota is environmentally acquired and associated with RA ***,accumulating evidence demonstrates that genetics also shape the gut *** is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis(CIA),while the others are resistant to ***,we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice.C57BL/6J mice and healthy human individuals have enriched *** than DBA/1J mice and RA *** of *** prevents CIA in DBA/1J *** identify that *** mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of ***-like synoviocytes(FLSs)in RA are activated to undergo tumor-like *** disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1,resulting in reduced FOXK1 stability,blocked interferon signaling and deactivation of *** treat CIA mice with propionate and show that propionate attenuates ***,a combination of propionate with anti-TNF etanercept synergistically relieves *** results suggest that *** or propionate could be an alternative or complementary approach to the current therapies.

关键词： HDAC3 cytes interferon

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Human umbilical cord mesenchymal stem cell-derived exosomes loaded into a composite conduit promote functional recovery after peripheral nerve injury in rats

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Neural Regeneration Research 2024年第4期19卷 900-907页

作者： Haoshuai Tang Junjin Li Hongda Wang Jie Ren Han Ding Jun Shang Min Wang Zhijian Wei Shiqing Feng Department of Othopaedics Tianjin Medical University General Hospital International Science and Technology Cooperation Base of Spinal Cord Injury Tianjin Key Laboratory of Spine and Spinal Cord InjuryDepartment of OrthopedicsTianjin Medical University General Hospital Tianjin Key laboratory of Lung Cancer Metastasis and tumor microenvironment Tianjin Lung Cancer InstituteTianjin Medical University General Hospital Department of Othopaedics Qilu Hospital of Shandong UniversityShandong University Centre for OthopedicsAdvanced Medical Research InstituteShandong University Orthopedic Research Center of Shandong University&Advanced Medical Research Institute Cheeloo College of MedicineShandong University

Complete transverse injury of peripheral nerves is challenging to *** secreted by human umbilical cord mesenchymal stem cells are considered to play an important role in intercellular communication and regulate tissue *** previous studies,a collagen/hyaluronic acid sponge was shown to provide a suitable regeneration environment for Schwann cell proliferation and to promote axonal *** three-dimensional(3D)composite conduit contains a collagen/hyaluronic acid inner sponge enclosed in an electrospun hollow poly(lactic-co-glycolic acid)***,whether there is a synergy between the 3D composite conduit and exosomes in the repair of peripheral nerve injury remains *** this study,we tested a comprehensive strategy for repairing long-gap(10 mm)peripheral nerve injury that combined the 3D composite conduit with human umbilical cord mesenchymal stem cell-derived *** effectiveness was evaluated by sciatic functional index,sciatic nerve compound muscle action potential recording,recovery of muscle mass,measuring the cross-sectional area of the muscle fiber,Masson trichrome staining,and transmission electron microscopy of the regenerated nerve in *** results showed that transplantation of the 3D composite conduit loaded with human umbilical cord mesenchymal stem cell-derived exosomes promoted peripheral nerve regeneration and restoration of motor function,similar to autograft *** CD31-positive endothelial cells were observed in the regenerated nerve after transplantation of the loaded conduit than after transplantation of the conduit without exosomes,which may have contributed to the observed increase in axon regeneration and distal nerve ***,the use of a 3D composite conduit loaded with human umbilical cord mesenchymal stem cell-derived exosomes represents a promising cell-free therapeutic option for the treatment of peripheral nerve injury.

关键词： axon growth collagen exosome human umbilical cord mesenchymal stem cells hyaluronic acid muscular atrophy nerve guidance conduits peripheral nerve regeneration

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Hepatic Zbtb18 (Zinc Finger and BTB Domain Containing 18) alleviates hepatic steatohepatitis via FXR (Farnesoid X Receptor)

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Signal Transduction and Targeted Therapy 2024年第2期9卷 766-781页

作者： Lei Zhang Jiabing Chen Xiaoying Yang Chuangpeng Shen Jiawen Huang Dong Zhang Naihua Liu Chaonan Liu Yadi Zhong Yingjian Chen Kaijia Tang Jingyi Guo Tianqi Cui Siwei Duan Jiayu Li Shangyi Huang Huafeng Pan Huabing Zhang Xiaoqiang Tang Yongsheng Chang Yong Gao State Key laboratory of Traditional Chinese Medicine Syndrome Science and Technology Innovation CenterGuangzhou University of Chinese MedicineGuangzhouChina Key laboratory of Immune microenvironment and Disease(Ministry of Education) Tianjin Key Laboratory of Cellular Homeostasis and DiseaseDepartment of Physiology and PathophysiologyTianjin Medical UniversityTianjinChina Jiangsu Key laboratory of Immunity and Metabolism Department of Pathogen Biology and ImmunologyJiangsu International Laboratory of Immunity and MetabolismXuzhou Medical UniversityXuzhouChina Department of Endocrinology The First Clinical CollegeGuangzhou University of Chinese MedicineGuangdongChina The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine ShenzhenChina Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of tumor Nanjing University of Chinese MedicineNanjingChina Department of Biochemistry and Molecular Biology Metabolic Disease Research CenterSchool of Basic MedicineAnhui Medical UniversityHefeiChina Key laboratory of Birth Defects and Related Diseases of Women and Children of MOE State Key Laboratory of BiotherapyWest China Second University HospitalSichuan UniversityChengduChina

A lasting imbalance between fatty acid synthesis and consumption leads to non-alcoholic fatty liver disease(NAFLD),coupled with hepatitis and insulin *** the details of the underlying mechanisms are not fully ***,we unraveled that the expression of the transcription factor Zbtb18 is markedly decreased in the livers of both patients and murine models of *** Zbtb18 knockout promoted NAFLD features like impaired energy expenditure and fatty acid oxidation(FAO),and induced insulin ***,hepatic Zbtb18 overexpression alleviated hepato-steatosis,insulin resistance,and hyperglycemia in mice fed on a high-fat diet(HFD)or in diabetic ***,in vitro and in vivo mechanistic studies revealed that Zbtb18 transcriptional activation of Farnesoid X receptor(FXR)mediated FAO and Clathrin Heavy Chain(CLTC)protein hinders NLRP3 inflammasome *** key mechanism by which hepatocyte’s Zbtb18 expression alleviates NAFLD and consequent liver fibrosis was further verified by FXR’s deletion and forced expression in mice and cultured mouse primary hepatocytes(MPHs).Moreover,CLTC deletion significantly abrogated the hepatic Zbtb18 overexpression-driven inhibition of NLRP3 inflammasome activity in ***,Zbtb18 transcriptionally activates the FXR-mediated FAO and CLTC expression,which inhibits NLRP3 inflammasome’s activity alleviating inflammatory stress and insulin resistance,representing an attractive remedy for hepatic steatosis and fibrosis.

关键词： hepatic Hepatic impaired

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Screening for metastasis-related genes in mouse melanoma cells through sequential tail vein injection

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Biophysics Reports 2024年第1期10卷 15-21页

作者： Qinggang Hao Rui Dong Weiyu Bai Dong Chang Xinyi Yao Yingru Zhang Huangying Xu Huiyan Li Xiang Kui Feng Wang Yan Wang Chengqin Wang Yujie Lei Yan Chen Junling Shen Lei Sang Yan Bai Jianwei Sun Center for Life Sciences Yunnan Key Laboratory of Cell Metabolism and Diseases State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan School of Life Sciences Yunnan University Key laboratory of tumor Immunological Prevention and Treatment of Yunnan Province Yan'an Hospital Affiliated to Kunming Medical University Shandong Provincial Key laboratory of Animal resistance Biology Collaborative Innovation Center of Cell Biology in Universities of Shandong Center for Cell Structure and Function Institute of Biomedical Science College of Life Sciences Shandong Normal University Department of Pathology The Second Affiliated Hospital of Kunming Medical University State Key laboratory of Bioactive Molecules and Druggability Assessment Institute of Genomic Medicine College of Pharmacy Jinan University Department of Pathology School of Basic Medicine Qingdao University Department of Thoracic Surgery Yunnan Cancer Hospital & The Third Affiliated Hospital of Kunming Medical University & Yunnan Cancer Center

tumor metastasis, responsible for approximately 90% of cancer-associated mortality, remains poorly understood. Here in this study, we employed a melanoma lung metastasis model to screen for metastasis-related genes. By sequential tail vein injection of mouse melanoma B16F10 cells and the subsequently derived cells from lung metastasis into BALB/c mice, we successfully obtained highly metastatic B16F15 cells after five rounds of in vivo screening. RNA-sequencing analysis of B16F15 and B16F10 cells revealed a number of differentially expressed genes, some of these genes have previously been associated with tumor metastasis while others are novel discoveries. The identification of these metastasis-related genes not only improves our understanding of the metastasis mechanisms, but also provides potential diagnostic biomarkers and therapeutic targets for metastatic melanoma.

关键词： Melanoma Lung metastasis model Gene screening Tail vein injection

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Nanomedicine targeting ferroptosis to overcome anticancer therapeutic resistance

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Science China(Life Sciences) 2024年第1期67卷 19-40页

作者： Jing Cai Xiaoding Xu Phei Er Saw Guangdong Provincial Key laboratory of Malignant tumor Epigenetics and Gene Regulation Guangdong-Hong Kong Joint Laboratory for RNA MedicineMedical Research CenterSun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Nanhai Translational Innovation Center of Precision Immunology Sun Yat-sen Memorial HospitalSun Yat-sen UniversityFoshan 528200China

A potential reason for the failure of tumor therapies is treatment *** to chemotherapy,radiotherapy,and immunotherapy continues to be a major obstacle in clinic,resulting in tumor recurrence and *** major mechanisms of therapy resistance are inhibitions of cell deaths,like apoptosis and necrosis,through drug inactivation and excretion,repair of DNA damage,tumor heterogeneity,or changes in tumor microenvironment,*** studies have shown that ferroptosis play a major role in therapies resistance by inducing phospholipid peroxidation and iron-dependent cell *** ferroptosis inducers in combination with clinical treatment techniques have been used to enhance the effect in tumor ***,versatile ferroptosis nanoinducers exhibit an extensive range of functions in reversing therapy resistance,including directly triggering ferroptosis and feedback ***,we provide a detailed description of the design,mechanism,and therapeutic application of ferroptosis-mediated synergistic tumor *** also discuss the prospect and challenge of nanomedicine in tumor therapy resistance by regulating ferroptosis and combination therapy.

关键词： ferroptosis cancer therapy therapy resistance nanoinducers

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Cancer stem cell-immune cell crosstalk in the tumor microenvironment for liver cancer progression

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Frontiers of Medicine 2024年第3期18卷 430-445页

作者： Yue Ma Hongwei Lv Fuxue Xing Wei Xiang Zixin Wu Qiyu Feng Hongyang Wang Wen Yang Cancer Research Center First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei230027China National Center for Liver Cancer Naval Medical University(Second Military Medical University)Shanghai201805China International Co-operation laboratory on Signal Transduction Eastern Hepatobiliary Surgery HospitalNaval Medical University(Second Military Medical University)Shanghai200438China Shanghai Key laboratory of Hepato-biliary tumor Biology Shanghai200438China Key laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer Ministry of EducationShanghai200438China

Crosstalk between cancer cells and the immune microenvironment is determinant for liver cancer progression.A tumor subpopulation called liver cancer stem cells(CSCs)significantly accounts for the initiation,metastasis,therapeutic resistance,and recurrence of liver *** evidence demonstrates that the interaction between liver CSCs and immune cells plays a crucial role in shaping an immunosuppressive microenvironment and determining immunotherapy *** review sheds light on the bidirectional crosstalk between liver CSCs and immune cells for liver cancer progression,as well as the underlying molecular mechanisms after presenting an overview of liver CSCs characteristic and their ***,we discuss the potential application of liver CSCs-targeted immunotherapy for liver cancer treatment.

关键词： liver cancer cancer stem cell immune cell immunotherapy

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HIF-1α signaling: Essential roles in tumorigenesis and implications in targeted therapies

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Genes & Diseases 2024年第1期11卷 234-251页

作者： Yan Zhao Cheng Xing Yating Deng Can Ye Hongling Peng Department of Hematology The Second Xiangya HospitalCentral South UniversityChangshaHunan 410011China Hunan Key laboratory of tumor Models and Individualized Medicine The Second Xiangya HospitalCentral South UniversityChangshaHunan 410011China Hunan Engineering Research Center of Cell Immunotherapy for Hematopoietic Malignancies The Second Xiangya HospitalCentral South UniversityChangshaHunan 410011China

The hypoxic microenvironment is an essential characteristic of most malignant ***,hypoxia-inducible factor-1 alpha(HIF-1a)is a key regulatory factor of cellular adaptation to hypoxia,and many critical pathways are correlated with the biological activity of organisms via *** the intra-tumoral hypoxic environment,HIF-1αis highly expressed and contributes to the malignant progression of tumors,which in turn results in a poor prog-nosis in ***,it has been indicated that HiF-1αinvolves in various critical pro-cesses of life events and tumor development via regulating the expression of HiF-1a target genes,such as cell proliferation and apoptosis,angiogenesis,glucose metabolism,immune response,therapeutic resistance,*** from solid tumors,accumulating evidence has re-vealed that HiF-1αis also closely associated with the development and progression of hemato-logical malignancies,such as leukemia,lymphoma,and multiple *** inhibition of HiF-1a can facilitate an increased sensitivity of patients with malignancies to relevant ther-apeutic *** the review,we elaborated on the basic structure and biological functions of HIF-1a and summarized their current role in various *** is expected that they will have future potential fortargeted therapy.

关键词： Angiogenesis Hematological malignancies Hypoxia-inducible factor-1 alpha(HIF-1α) Immune escape Targeted therapy

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基于工程化的DNA适配体PROTAC用于p53-R175H驱动癌症的精准治疗（英文）

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Science Bulletin 2024年第13期 2122-2135页

作者：孔令平孟凡路周萍葛瑞鑫耿小珊杨志豪李果张琳琳王竞马金峰董诚周军吴思晋钟殿胜谢松波 Department of Medical Oncology Tianjin Medical University General Hospital Center for Cell Structure and Function Collaborative Innovation Center of Cell Biology in Universities of Shandong College of Life Sciences Shandong Normal University The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) School of Basic Medical Sciences Tianjin Medical University Tianjin Key laboratory of Lung Cancer Metastasis and tumor microenvironment Lung Cancer Institute Tianjin Medical University General Hospital Haihe laboratory of Cell Ecosystem State Key Laboratory of Medicinal Chemical Biology College of Life Sciences Nankai University Wisdom Lake Academy of Pharmacy Xi'an Jiaotong-Liverpool University Department of Ophthalmology Tianjin Medical University General Hospital Laboratory of Molecular Ophthalmology Tianjin Key Laboratory of Ocular Traum1 Tianjin Medical University

Targeting oncogenic mutant p53 represents an attractive strategy for cancer treatment due to the high frequency of gain-of-function mutations and ectopic expression in various cancer types. Despite extensive efforts, the absence of a druggable active site for small molecules has rendered these mutants therapeutically non-actionable. Here we develop a selective and effective proteolysis-targeting chimera(PROTAC) for p53-R175H, a common hotspot mutant with dominant-negative and oncogenic *** a novel iterative molecular docking-guided post-SELEX(systematic evolution of ligands by exponential enrichment) approach, we rationally engineer a high-performance DNA aptamer with improved affinity and specificity for p53-R175H. Leveraging this resulting aptamer as a binder for PROTACs, we successfully developed a selective p53-R175H degrader, named dp53m. dp53m induces the ubiquitin–protea some-dependent degradation of p53-R175H while sparing wildtype p53. Importantly, dp53m demonstrates significant antitumor efficacy in p53-R175H-driven cancer cells both in vitro and in vivo, without toxicity. Moreover, dp53m significantly and synergistically improves the sensitivity of these cells to cisplatin, a commonly used chemotherapy drug. These findings provide evidence of the potential therapeutic value of dp53m in p53-R175H-driven cancers.

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Role of cancer stem cell ecosystem on breast cancer metastasis and related mouse models

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Zoological Research 2024年第3期45卷 506-517页

作者： Xilei Peng Haonan Dong Lixing Zhang Suling Liu Fudan University Shanghai Cancer Center&Institutes of Biomedical Sciences/State Key laboratory of Genetic Engineering/Cancer Institutes/Department of Oncology/Key laboratory of Breast Cancer in Shanghai/Shanghai Key laboratory of Medical Epigenetics/Shanghai Key laboratory of Radiation Oncology/International Co-laboratory of Medical Epigenetics and Metabolism Ministry of Science and Technology/Shanghai Medical College/Fudan UniversityShanghai 200032China

Breast cancer metastasis is responsible for most breast cancer-related deaths and is influenced by many factors within the tumor ecosystem,including tumor cells and *** cancer stem cells(BCSCs)constitute a small population of cancer cells with unique characteristics,including their capacity for self-renewal and *** have shown that BCSCs not only drive tumorigenesis but also play a crucial role in promoting metastasis in breast *** tumor microenvironment(TME),composed of stromal cells,immune cells,blood vessel cells,fibroblasts,and microbes in proximity to cancer cells,is increasingly recognized for its crosstalk with BCSCs and role in BCSC survival,growth,and dissemination,thereby influencing metastatic ***,a thorough understanding of BCSCs and the TME is critical for unraveling the mechanisms underlying breast cancer *** this review,we summarize current knowledge on the roles of BCSCs and the TME in breast cancer metastasis,as well as the underlying regulatory ***,we provide an overview of relevant mouse models used to study breast cancer metastasis,as well as treatment strategies and clinical trials addressing BCSC-TME interactions during ***,this study provides valuable insights for the development of effective therapeutic strategies to reduce breast cancer metastasis.

关键词： Breast cancer Metastasis Cancer stem cell Ecosystem tumor microenvironment Mouse model

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