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Road of no return——loss of TP53 paves a defined evolution path from gastric preneoplasia-to-cancer

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Cancer Biology & Medicine 2023年第12期20卷 885-890页

作者： Liwei An Yi Han Shi Jiao zhaocai zhou State Key Laboratory of Genetic Engineering Zhongshan HospitalSchool of Life SciencesFudan UniversityShanghai 200438China Department of Stomatology Shanghai Tenth People’s HospitalDepartment of Biochemistry and Molecular BiologyTongji University School of MedicineShanghai 200072China

Gastric cancer(GC),the fifth-and fourth-leading causes of morbidity and mortality worldwide,still lacks effective diagnoses and ***,China accounts for nearly 50%of the newly diagnosed and death cases of GC *** directly exposed to external food intake,extremely acidic content,and microorganisms,such as Helicobacter pylori and Epstein-Barr virus(EBV),stomach homeostasis is easily perturbed and ***,the gastric epithelium is composed of multiple cell types,including chief,parietal,pit,and stem *** lineages of these gastric epithelial cells are rather plastic,giving rise to a high degree of GC heterogeneity.

关键词： stomach Gastric homeostasis

Modeling human gastric cancers in immunocompetent mice

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Cancer Biology & Medicine 2024年第7期21卷 553-570页

作者： Weihong Zhang Shilong Wang Hui Zhang Yan Meng Shi Jiao Liwei An zhaocai zhou Department of Stomatology Department of Medical UltrasoundShanghai Tenth People's HospitalTongji University Cancer CenterTongji University School of MedicineShanghai 200072China State Key Laboratory of Genetic Engineering School of Life SciencesZhongshan HospitalFudan UniversityShanghai 200032China Collaborative Innovation Center for Cancer Personalized Medicine School of Public HealthNanjing Medical UniversityNanjing 211166China

Gastric cancer(GC)is a major cause of cancer-related mortality *** is determined by multiple(epi)genetic and environmental factors;can occur at distinct anatomic positions of the stomach;and displays high heterogeneity,with different cellular origins and diverse histological and molecular *** heterogeneity has hindered efforts to fully understand the pathology of GC and develop efficient *** the past decade,great progress has been made in the study of GC,particularly in molecular subtyping,investigation of the immune microenvironment,and defining the evolutionary path and *** mouse models,particularly immunocompetent models that mimic the cellular and molecular features of human GC,in combination with organoid culture and clinical studies,have provided powerful tools for elucidating the molecular and cellular mechanisms underlying GC pathology and immune evasion,and the development of novel therapeutic ***,we first briefly introduce current progress and challenges in GC study and subsequently summarize immunocompetent GC mouse models,emphasizing the potential application of genetically engineered mouse models in antitumor immunity and immunotherapy studies.

关键词： Gastric cancer heterogeneity mouse model GEMM immunocompetent

Exploration of the shared gene signatures and molecular mechanisms between periodontitis and inflammatory bowel disease:evidence from transcriptome data

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Gastroenterology Report 2023年第1期11卷 412-423页

作者： Chi Zhan zhaocai zhou Yaxian Huang Shuheng Huang Zhengmei Lin FengHe Zhi Song Hospital of Stomatology Guangdong Provincial Key Laboratory of StomatologyGuanghua School of StomatologySun Yat-sen UniversityGuangzhouGuangdongP.R.China Guangzhou First People’s Hospital School of MedicineSouth China University of TechnologyGuangzhouGuangdongP.R.China

Background:Periodontitis disease(PD)is associated with a systemic disorder of inflammatory bowel disease(IBD).The immune response is the common feature of the two conditions,but the more precise mechanisms remain ***:Differential expressed genes(DEGs)analysis and weighted gene co-expression network analysis(WGCNA)were performed on PD and Crohn’s disease(CD)data sets to identify crosstalk genes linking the two *** proportions of infiltrating immune cells were calculated by using Single-sample Gene Set Enrichment *** addition,a data set of isolated neutrophils from the circulation was performed via WGCNA to obtain PD-related key ***,single-cell gene set enrichment scores were computed for the key module and grouped neutrophils according to score order in the IBD scRNA-seq data ***-cell gene enrichment analysis was used to further explore the biological process of the ***:A total of 13 crosstalk genes(IL1B,CSF3,CXCL1,CXCL6,FPR1,FCGR3B,SELE,MMP7,PROK2,SRGN,FCN1,TDO2 and CYP24A1)were identified via DEGs analysis and WGCNA by combining PD and CD data *** enrichment analysis showed that these genes were involved in interleukin-10 signaling and inflammatory *** immune infiltration analysis showed a significant difference in the proportion of neutrophils in PD and CD compared with healthy *** were scored based on the expression of a periodontitis-related gene set in the scRNA-seq data set of *** enrichment analysis demonstrated that inflammatory response,TNFa signaling via NF-jB and interferon-gamma response were upregulated in the high-score group,which expressed more pro-inflammatory cytokines and chemokines compared with the low-score ***:This study reveals a previously unrecognized mechanism linking periodontitis and IBD through crosstalk genes and neutrophils,which provides a theoretical framework for future research.

关键词： periodontitis inflammatory bowel disease neutrophils immune infiltration inflammation bioinformatics

Germinal center kinases in immune regulation

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Cellular & Molecular Immunology 2012年第6期9卷 439-445页

作者： Hailei Yin Zhubing Shi ShiJiao Cuicui Chen Wenjia Wang Mark I Greene zhaocai zhou Department of Trauma and Orthopaedics General Hospital of Jinan Military RegionJinanChina No.401 Hospital of People Liberation Army QingdaoChina State Key Laboratory of Cell Biology Institute of Biochemistry and Cell BiologyShangha nst tutes for Biological SciencesChinese Academy of SciencesShanghaiChina Department of Pathology and Laboratory Medicine University of PennsylvaniaPhiladelphiaPAUSA

Germinal center kinases （GCKs） participate in a variety of signaling pathways needed to regulate cellular functions including apoptosis, cell proliferation, polarity and migration. Recent studies have shown that GCKs are participants in both adaptive and innate immune regulation. However, the differential activation and regulatory mechanisms of GCKs, as well as upstream and downstream signaling molecules, remain to be fully defined. It remains unresolved whether and how GCKs may cross-talk with existing signaling pathways. This review stresses the progresses in research of GCKs relevant to the immune system.

关键词： germinal center kinases immune regulation signal transduction

Structural and biochemical studies of RIG-I antiviral signaling

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Protein & Cell 2013年第2期4卷 142-154页

作者： Miao Feng Zhanyu Ding Liang Xu Liangliang Kong Wenjia Wang Shi Jiao Zhubing Shi Mark IGreene Yao Cong zhaocai zhou State Key Laboratory of Cell Biology Institute of Biochemistry and Cell BiologyShanghai Institutes for Biological SciencesChinese Academy of SciencesShanghai 200031China State Key Laboratory of Molecular Biology Institute of Biochemistry and Cell BiologyShanghai Institutes for Biological SciencesChinese Academy of SciencesShanghai 200031China Department of Pathology and Laboratory Medicine University of PennsylvaniaPA 19104USA

Retinoic acid-inducible gene I(RIG-I)is an important pattern recognition receptor that detects viral RNA and triggers the production of type-I interferons through the downstream adaptor MAVS(also called IPS-1,CARDIF,or VISA).A series of structural studies have elaborated some of the mechanisms of dsRNA recognition and activation of *** studies have proposed that K63-linked ubiquitination of,or unanchored K63-linked polyubiquitin binding to RIG-I positively regulates MAVS-mediated antiviral *** phos-phorylation of RIG-I appears to play an inhibitory role in controlling RIG-I antiviral signal *** we performed a combined structural and biochemical study to further define the regulatory features of RIG-I *** and dsRNA binding triggered dimeriza-tion of RIG-I with conformational rearrangements of the tandem CARD *** length RIG-I appeared to form a complex with dsRNA in a 2:2 molar ***-pared with the previously reported crystal structures of RIG-I in inactive state,our electron microscopic struc-ture of full length RIG-I in complex with blunt-ended dsRNA,for the first time,revealed an exposed active conformation of the CARD ***,we found that purified recombinant RIG-I proteins could bind to the CARD domain of MAVS independently of dsRNA,while S8E and T170E phosphorylation-mimick-ing mutants of RIG-I were defective in binding E3 ligase TRIM25,unanchored K63-linked polyubiquitin,and MAVS regardless of *** findings suggested that phosphorylation of RIG inhibited downstream signaling by impairing RIG-I binding with polyubiquitin and its interaction with MAVS.

关键词： RIG-I MAVS antiviral signaling polyubiq-uitin phosphorylation

Squalene epoxidase promotes colorectal cancer cell proliferation through accumulating calcitriol and activating CYP24A1-mediatedMAPK signaling

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Cancer Communications 2021年第8期41卷 726-746页

作者： Luwei He Huaguang Li Chenyu Pan Yutong Hua Jiayin Peng zhaocai zhou Yun Zhao Moubin Lin Center for Clinical Research and Translational Medicine Yangpu HospitalTongji University School of MedicineShanghai 200090P.R.China Institute of Gastrointestinal Surgery and Translational Medicine Tongji University School of MedicineShanghai 200090P.R.China Department of General Surgery Yangpu HospitalTongji University School of MedicineShanghai 200090P.R.China The State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell ScienceShanghai Institute of Biochemistry and Cell BiologyUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200031P.R.China State Key Laboratory of Genetic Engineering School of Life SciencesZhongshan HospitalFudan UniversityShanghai 200438P.R.China School of Life Science and Technology ShanghaiTech UniversityShanghai 201210P.R.China

Background:Colorectal cancer(CRC)is one of the most malignant tumorswith high incidence,yet its molecular mechanism is not fully understood,hindering the development of targeted *** abnormalities are a hallmark of *** dysregulated metabolic features has become an important direction for modern anticancer *** this study,we aimed to identify a new metabolic enzyme that promotes proliferation of CRC and to examine the related molecular ***:We performed RNA sequencing and tissue microarray analyses of human CRC samples to identify new genes involved in *** epoxidase(SQLE)was identified to be highly upregulated in CRC *** regulatory function of SQLE in CRC progression and the therapeutic effect of SQLE inhibitors were determined by measuring CRC cell viability,colony and organoid formation,intracellular cholesterol concentration and xenograft tumor *** of SQLE functionwas explored by combining transcriptome and untargeted metabolomics *** blotting and realtime PCR were used to assess MAPK signaling activation by ***:SQLE-related control of cholesterol biosynthesis was highly upregulated in CRC patients and associated with poor *** promoted CRC growth in vitro and in *** of SQLE reduced the levels of calcitriol(active form of vitamin D3)and CYP24A1,followed by an increase in intracellular Ca2+***,MAPK signaling was suppressed,resulting in the inhibition of CRC cell ***,terbinafine,an SQLE inhibitor,suppressed CRC cell proliferation and organoid and xenograft tumor ***:Our findings demonstrate that SQLE promotes CRC through the accumulation of calcitriol and stimulation of CYP24A1-mediated MAPK signaling,highlighting SQLE as a potential therapeutic target for CRC treatment.

关键词： calcitriol cell proliferation cholesterol biosynthesis colorectal cancer CYP24A1 MAPK signaling squalene epoxidase terbinafine

Improving hard metal implant and soft tissue integration by modulating the“inflammatory-fibrous complex”response

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Bioactive Materials 2023年第2期20卷 42-52页

作者： Peina Huang Jieyun Xu Lv Xie Guangqi Gao Shoucheng Chen Zhuohong Gong Xiaomei Lao Zhengjie Shan Jiamin Shi zhaocai zhou Zhuofan Chen Yang Cao Yan Wang Zetao Chen Hospital of Stomatology Guanghua School of StomatologySun Yat-sen University and Guangdong Provincial Key Laboratory of StomatologyNo.56Lingyuan West RoadYuexiu DistrictGuangzhou510055China

Soft tissue integration is one major difficulty in the wide applications of metal materials in soft tissue-related *** inevitable inflammatory response and subsequent fibrous reaction toward the metal implant is one key response for metal implant-soft tissue *** is of great importance to modulate this inflammatory-fibrous response,which is mainly mediated by the multidirectional interaction between fibroblasts and *** this study,macrophages are induced to generate M1 and M2 macrophage immune *** cytokine profiles have been proven to have potentially multi-regulatory effects on *** multi-reparative effects of soft tissue cells(human gingival fibroblasts)cultured on metal material(titanium alloy disks)in M1 and M2 immune microenvironments are then *** in the M1 immune microenvironment tend to aggravate the inflammatory response in a pro-inflammatory positive feedback loop,while M2 immune microenvironment enhances multiple functions of fibroblasts in soft tissue integration,including soft tissue regeneration,cell adhesion on materials,and contraction to immobilize soft *** by the close interaction between macrophages and fibroblasts,we propose the concept of an“inflammatory-fibrous complex”to disclose possible methods of precisely and effectively modulating inflammatory and fibrous responses,thus advancing the development of metal soft tissue materials.

关键词： Inflammation Soft tissue Macrophage Fibroblast Metal material

MST4 kinase regulates immune thrombocytopenia by phosphorylating STAT1-mediated M1 polarization of macrophages

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Cellular & Molecular Immunology 2023年第12期20卷 1413-1427页

作者： Jingjing Cao Lili Ji Yanxia Zhan Xia Shao Pengcheng Xu Boting Wu Pu Chen Luya Cheng Xibing Zhuang Yang Ou Fanli Hua Lihua Sun Feng Li Hao Chen zhaocai zhou Yunfeng Cheng Department of Hematology Zhongshan HospitalFudan UniversityShanghai200032China Center for Tumor Diagnosis&Therapy Jinshan HospitalFudan UniversityShanghai201508China Department of Transfusion Medicine Zhongshan HospitalFudan UniversityShanghai200032China Department of Laboratory Medicine Zhongshan HospitalFudan UniversityShanghai200032China Department of Hematology Zhongshan Hospital Qingpu BranchFudan UniversityShanghai201700China Department of Thoracic Surgery Zhongshan-Xuhui HospitalFudan UniversityShanghai200031China State Key Laboratory of Genetic Engineering Zhongshan HospitalSchool of Life SciencesFudan UniversityShanghai200438China Institute of Clinical Science Zhongshan HospitalFudan UniversityShanghai200032China

Primary immune thrombocytopenia(ITP)is an autoimmune hemorrhagic disorder in which macrophages play a critical *** sterile-20-like kinase 4(MST4),a member of the germinal-center kinase STE20 family,has been demonstrated to be a regulator of *** MST4 participates in the macrophage-dependent inflammation of ITP remains *** expression and function of MST4 in macrophages of ITP patients and THP-1 cells,and of a macrophage-specific Mst4−/−(Mst4ΔM/ΔM)ITP mouse model were *** phagocytic assays,RNA sequencing(RNA-seq)analysis,immunofluorescence analysis,coimmunoprecipitation(co-IP),mass spectrometry(MS),bioinformatics analysis,and phosphoproteomics analysis were performed to reveal the underlying *** expression levels of the MST4 gene were elevated in the expanded M1-like macrophages of ITP patients,and this elevated expression of MST4 was restored to basal levels in patients with remission after high-dose dexamethasone *** expression of the MST4 gene was significantly elevated in THP-1-derived M1 *** of MST4 decreased the expression of M1 macrophage markers and cytokines,and impaired phagocytosis,which could be increased by overexpression of *** a passive ITP mouse model,macrophage-specific depletion of Mst4 reduced the numbers of M1 macrophages in the spleen and peritoneal lavage fluid,attenuated the expression of M1 cytokines,and promoted the predominance of FcγRIIb in splenic macrophages,which resulted in amelioration of *** of MST4 directly inhibited STAT1 phosphorylation,which is essential for M1 polarization of *** study elucidates a critical role for MST4 kinase in the pathology of ITP and identifies MST4 kinase as a potential therapeutic target for refractory ITP.

关键词： Primary immune thrombocytopenia Mammalian sterile-20-like kinase 4(MST4) Macrophages M1 polarization Signal transducer and activator of transcription-1(STAT1)

MST4 inhibits inflammatory responses by directly phosphorylating TRAF6

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MST4 inhibits inflammatory responses by directly phosphoryla...