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Diverse functions of sox9 in liver development and homeostasis and hepatobiliary diseases

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Genes & Diseases 2024年第4期11卷 170-187页

作者： Taiyu Shang Tianyi Jiang Xiaowen Cui Yufei Pan Xiaofan Feng Liwei Dong Hongyang Wang School of Life Sciences Institute of Metabolism and Integrative BiologyFudan UniversityShanghai 200438China National Center for liver cancer The Naval Medical UniversityShanghai 201805China International Cooperation laboratory on Signal Transduction Eastern Hepatobiliary Surgery InstituteThe Second Military Medical UniversityShanghai 200438China laboratory of signaling regulation and targeting therapy of liver cancer Second Military Medical University&Ministryof EducationShanghai 200438China

The liver is the central organ for digestion and detoxification and has unique metabolic and regenerative *** hepatobiliary system originates from the foregut endoderm,in which cells undergo multiple events of cell proliferation,migration,and differentiation to form the liver parenchyma and ductal system under the hierarchical regulation of transcription *** on liver development and diseases have revealed that SRY-related high-mobility group box 9(SOx9)plays an important role in liver embryogenesis and the progression of hepatobiliary ***9 is not only a master regulator of cell fate determination and tissue morphogenesis,but also regulates various biological features of cancer,including cancer stemness,invasion,and drug resistance,making Sox9 a potential biomarker for tumor prognosis and *** review systematically summarizes the latest findings of sox9 in hepatobiliary development,homeostasis,and *** also highlight the value of sox9 as a novel biomarker and potential target for the clinical treatment of major liverdiseases.

关键词： Biliary system cancer Homeostasis liver diseases SOX9

Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma

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cancer Communications 2024年第2期44卷 226-250页

作者： Weiren Liu Huqiang Wang Qianfu Zhao Chenyang Tao Weifeng Qu Yushan Hou Run Huang Zimei Sun Guiqi Zhu Xifei Jiang Yuan Fang Jun Gao Xiaoling Wu Zhixiang Yang Rongyu Ping Jiafeng Chen Rui Yang Tianhao Chu Jian Zhou Jia Fan Zheng Tang Dong Yang Yinghong Shi Department of liver Surgery and Transplantation Liver Cancer InstituteZhongshan HospitalFudan UniversityKey Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationShanghaiP.R.China Research Unit of liver cancer Recurrence and Metastasis Chinese Academy of Medical SciencesBeijingP.R.China State key laboratory of Medical Proteomics Beijing Proteome Research CenterNational Center for Protein Sciences(Beijing)Beijing Institute of LifeomicsBeijingP.R.China

Background:Intrahepatic cholangiocarcinoma(iCCA)is a highly heteroge-neous and lethal hepatobiliary tumor with few therapeutic *** metabolic reprogramming of tumor cells plays an essential role in the develop-ment of tumors,while the metabolic molecular classification of iCCA is largely ***,we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients,hoping to provide a novel perspective to understand and treat ***:We performed integrated multiomics analysis in 116 iCCA samples,including whole-exome sequencing,bulk RNA-sequencing and proteome *** on the non-negative matrix factorization method and the protein abundance of metabolic genes in human genome-scale metabolic models,the metabolic subtype of iCCA was *** and prognostic gene analy-ses were used to compare overall survival(OS)differences between metabolic *** proliferation analysis,5-ethynyl-2’-deoxyuridine(EdU)assay,colony formation assay,RNA-sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinaseα(DGKA)in iCCA ***:Three metabolic subtypes(S1-S3)with subtype-specific biomarkers of iCCA were *** metabolic subtypes presented with distinct prog-noses,metabolic features,immune microenvironments,and genetic *** S2 subtype with the worst survival showed the activation of some special metabolic processes,immune-suppressed microenvironment and Kirsten ratsar-coma viral oncogene homolog(KRAS)/AT-rich interactive domain 1A(ARID1A)*** the S2 subtype-specific upregulated proteins,DGKA was further identified as a potential drug target for iCCA,which promoted cell proliferation by enhancing phosphatidic acid(PA)metabolism and activating mitogen-activated protein kinase(MAPK)***:Viamultiomics analyses,we identified three metabolic subtypes of iCCA,revealing

关键词： diacylglycerol kinaseα intrahepatic cholangiocarcinoma MAPK signaling metabolic classifi-cation multiomics analysis phosphatidic acid metabolism

Synergistic induction of mitotic pyroptosis and tumor remission by inhibiting proteasome and WEE family kinases

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Signal Transduction and Targeted therapy 2024年第8期9卷 3467-3482页

作者： Zhan-Li Chen Chen Xie Wei Zeng Rui-Qi Huang Jin-E Yang Jin-Yu Liu Ya-Jing Chen Shi-Mei Zhuang MOE key laboratory of Gene Function and regulation Guangdong Province Key Laboratory of Pharmaceutical Functional GenesSchool of Life SciencesState Key Laboratory of Oncology in Southern ChinaSun Yat-sen UniversityGuangzhouPR China key laboratory of liver Disease of Guangdong Province The Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510630PR China

Mitotic catastrophe(MC),which occurs under dysregulated mitosis,represents a fascinating tactic to specifically eradicate tumor *** pyroptosis can be a death form of MC remains ***-mediated protein degradation is crucial for ***(BTZ),which inhibits the 20S catalytic particle of proteasome,is approved to treat multiple myeloma and mantle cell lymphoma,but not solid tumors due to primary *** date,whether and how proteasome inhibitor affected the fates of cells in M-phase remains ***,we show that BTZ treatment,or silencing of PSMC5,a subunit of 19S regulatory particle of proteasome,causes G2-and M-phase arrest,multi-polar spindle formation,and consequent caspase-3/GSDME-mediated pyroptosis in M-phase(designated as mitotic pyroptosis).Further investigations reveal that inhibitor of WEE1/PKMYT1(PD0166285),but not inhibitor of ATR,CHK1 or CHK2,abrogates the BTZ-induced G2-phase arrest,thus exacerbates the BTZ-induced mitotic arrest and *** BTZ and PD0166285 treatment(named BP-Combo)selectively kills various types of solid tumor cells,and significantly lessens the IC50 of both BTZ and PD0166285 compared to BTZ or PD0166285 *** using various mouse models show that BP-Combo has much stronger inhibition on tumor growth and metastasis than BTZ or PD0166285 monotreatment,and no obvious toxicity is observed in BP-Combo-treated *** findings disclose the effect of proteasome inhibitors in inducing pyroptosis in M-phase,characterize pyroptosis as a new death form of mitotic catastrophe,and identify dual inhibition of proteasome and WEE family kinases as a promising anti-cancer strategy to selectively kill solid tumor cells.

关键词： proteasome inhibiting catastrophe

The Functional Redundancy of Neddylation E2s and E3s in Modulating the Fitness of Regulatory T Cells

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Research 2024年第2期2023卷 373-387页

作者： Di Wu Yi Sun cancer Institute(key laboratory of cancer Prevention and Intervention China National Ministry of Education)of the Second Affiliated Hospital and Institute of Translational MedicineZhejiang University School of MedicineHangzhou 310029China cancer Center of Zhejiang University Hangzhou 310029China Zhejang Provincial Clinical Research Center for cancer Zhejang ProvinceChina key laboratory of Molecular Biology in Medical Sciences Zhejang ProvinceChina Research Center for Life Science and Human Health Binjiang Institute of Zhejiang UniversityHangzhou 310053China

Neddylation is necessary for activation of Cullin-RING ligases(CRLs),which degrade various immune regulatory *** recent study showed that while depletion of neddylation E2-E3 pair Ube2f-Sag in regulatory T(T_(reg))cells had no obvious phenotype,the same depletion of either Ube2m or Rbx1 caused inflammation disorders with different *** these E2s or E3s compensate each other in functional regulations of T_(reg)cells is,however,previously *** this report,we generated Foxp3^(Cre);Ube2m^(fl/fl);Ube2f^(fl/fl)or Foxp3^(Cre);Rbx1^(fl/fl);Sag^(fl/fl)double-null mice by simultaneous deletion of both neddylation E2s or E3s in T_(reg)cells,***,Ube2m&Ube2f double-null mice developed much severe autoimmune phenotypes than did Ube2m-null mice,indicating that Ube2m markedly compensates Ube2f in T_(reg)*** minor worsened autoimmune phenotypes seen at the very early stage in Rbx1&Sag double-null than Rbx1-null mice is likely due to already severe phenotypes of the later,indicating a minor compensation of Rbx1 for *** RNA profiling-based analyses revealed that up-and down-regulations of few signaling pathways in T_(reg)cells are associated with the severity of autoimmune ***,severer inflammation phenotypes seen in mice with double E3-null than with double E2-null T_(reg)cells indicate a neddylation-independent mechanism of 2 E3s,also known to serve as the RING component of CRLs in regulation of T_(reg)cell fitness.

关键词： Foxp3 inflammation markedly

PCK1 attenuates tumor stemness via activating the Hippo signaling pathway in hepatocellular carcinoma

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Genes & Diseases 2024年第4期11卷 340-352页

作者： Rui Liu Yi Liu Wenlu Zhang Guiji Zhang Zhirong Zhang Luyi Huang Ni Tang Kai Wang key laboratory of Molecular Biology for Infectious Diseases(ministry of education) Institute for Viral HepatitisDepartment of Infectious DiseasesThe Second Affiliated HospitalChongqing Medical UniversityChongqing 400016China Department of Clinical laboratory Sichuan Clinical Research Center for CancerSichuan Cancer Hospital&InstituteSichuan Cancer CenterAffiliated Cancer Hospital of University of Electronic Science and Technology of ChinaChengduSichuan 610041China

liver cancer stem cells were found to rely on glycolysis as the preferred metabolic *** carboxylase 1(PCK1),a gluconeogenic metabolic enzyme,is down-regulated in hepatocellular carcinoma and is closely related to poor *** onco-genesis and progression of tumors are closely related to cancer stem *** is not completely clear whether the PCK1 deficiency increases the stemness of hepatoma cells and promotes the oncogenesis of hepatocellular ***,the results showed that PCK1 inhibited the self-renewal property of hepatoma cells,reduced the mRNA level of cancer stem cell markers,and inhibited ***,PCK1 increased the sensitivity of hepatocellular carci-noma cells to ***,we found that PCK1 activated the Hippo pathway by enhancing the phosphorylation of YAP and inhibiting its nuclear *** reduced the stemness of hepatoma cells and promoted the pro-apoptotic effect of ***,combined treatment with verteporfin and sorafenib may be a potential anti-tumor strat-egy in hepatocellular carcinoma.

关键词： cancer stem cells Chemoresistance Gluconeogenesis Hepatocellular carcinoma YAP

Ononin inhibits triple-negative breast cancer lung metastasis by targeting the EGFR-mediated PI3K/Akt/mTOR pathway

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Science China(Life Sciences) 2024年第9期67卷 1849-1866页

作者： Kumar Ganesan Cong Xu Jianming Wu Bing Du Qingqing Liu Yue Sui Cailu Song Jinhui Zhang Hailin Tang Jianping Chen School of Chinese Medicine LKS Faculty of MedicineThe University of Hong KongHong Kong 999077China School of Pharmacy Southwest Medical UniversityEducation Ministry Key Laboratory of Medical ElectrophysiologySichuan Key Medical Laboratory of New Drug Discovery and Druggability EvaluationLuzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia MedicaSouthwest Medical UniversityLuzhou 646000China College of Food Science South China Agricultural UniversityGuangzhou 510642China State key laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer CenterGuangzhou 510080China

The spreading of cancer cells from the primary tumor site to other parts of the body,known as metastasis,is the leading cause of cancer recurrence and mortality in patients with triple-negative breast cancer(TNBC).Overexpression of epidermal growth factor receptor(EGFR)is observed in approximately 70%of TNBC *** is crucial for promoting tumor metastasis and associated with poor ***,it is vital to identify effective therapeutic strategies targeting EGFR ***,an isoflavonoid found in various plants,such as clover and soybeans,has been shown to have anticancer properties in several *** the present study,we aimed to investigate the effects of ononin on TNBC lung metastasis and the associated molecular *** used various assays,including cell viability,colony formation,Transwell,wound healing,ELISA,Western blotting,and staining techniques,to achieve this *** results demonstrated that ononin effectively suppressed cellular proliferation and induced apoptosis,as evidenced by the cell viability assay,colony formation assay,and expression of apoptosis markers,and reduced the metastatic capabilities of TNBC *** effects were achieved through the direct suppression of cell adhesion,invasiveness and ***,in TNBC xenograft lung metastatic models,ononin treatment significantly reduced tumor growth and lung ***,ononin reversed the epithelial-mesenchymal transition(EMT)by downregulating the expression of EMT markers and matrix metalloproteinases,as confirmed by Western blot ***,ononin treatment reduced EGFR phosphorylation and suppressed the PI3K,Akt,and m TOR signaling pathways,which was further confirmed using EGFR agonists or ***,ononin treatment did not exert any toxic effects on liver or kidney *** conclusion,our findings suggest that ononin is a safe and potentially therapeutic treatment for TNBC metastasis that targets the EGFRm

关键词： ononin TNBC breast cancer lung metastasis EGFR PI3k/Akt EMT therapeutic effect

The role of reactive oxygen species in gastric cancer

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cancer Biology & Medicine 2024年第9期21卷 740-753页

作者： Yuqi Wang Jingli Xu Zhenjie Fu Ruolan Zhang Weiwei Zhu Qianyu Zhao Ping Wang Can Hu Xiangdong Cheng College of Pharmaceutical Sciences Zhejiang University of TechnologyHangzhou 310014China Department of Gastric Surgery Zhejiang Cancer HospitalHangzhou 310022China key laboratory of Prevention Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang ProvinceHangzhou 310022China Zhejiang Provincial Research Center for Upper Gastrointestinal Tract cancer Zhejiang Cancer HospitalHangzhou 310022China

Gastric cancer(GC)ranks fifth in cancer incidence and fourth in cancer-related mortality *** oxygen species(ROS)are highly oxidative oxygen-derived products that have crucial roles in cell signaling regulation and maintaining internal *** are closely associated with the occurrence,development,and treatment of *** review summarizes recent findings on the sources of ROS and the bidirectional regulatory effects on GC and discusses various treatment modalities for GC that are related to ROS *** addition,the regulation of ROS by natural small molecule compounds with the highest potential for development and applications in anti-GC research is *** aim of the review is to accelerate the clinical application of modulating ROS levels as a therapeutic strategy for GC.

关键词： Gastric cancer reactive oxygen species ROSantitumor therapy natural products pharmacology

Long term ingestion of dietary ALEs induces metabolic disorders in mice by inducing gut dysbiosis and inhibiting AMPK/SIRT1 pathway

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Food Science and Human Wellness 2024年

作者： Yaya Wang Tianchang Zhang Linqing Nie Yan Zhang Junping Wang Shuo Wang State key laboratory of Food Nutrition and Safety， key laboratory of Food Nutrition and Safety， ministry of education of China， School of Food Science and Engineering， Tianjin University of Science and Technology Tianjin key laboratory of Food Science and Health， School of Medicine， Nankai University

Advanced lipoxidation end products (ALEs) are formed by modifying proteins with lipid oxidation products. ALEs formed in the body have been linked to diabetes and hepatic disease. However， it is not known whether ALEs formed in heat-processed foods can induce metabolic diseases. Our results indicate that dietary ALEs induce lipid accumulation in the liver of mice at an early stage and continuous feeding of ALEs induces inflammation， oxidative stress and hepatic insulin resistance. The core reason for these adverse reactions is the damage to the intestinal barrier caused by ALEs. Due to the damage to the intestinal barrier， there is an increase in lipopolysaccharides (LPS) in the liver that induces hepatic lipid accumulation by modulating hepatic lipid metabolism. Furthermore， ALEs plays a major role in the regulation of metabolic diseases by directly or indirectly inhibiting AMPK/SIRT1 signaling through LPS.

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Protein neddylation and its role in health and diseases

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Signal Transduction and Targeted therapy 2024年第5期9卷 1869-1904页

作者： Shizhen Zhang Qing Yu Zhijian Li Yongchao Zhao Yi Sun Department of Breast Surgery the Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310029China cancer Institute(key laboratory of cancer Prevention and Intervention China National Ministry of Education)the Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310029China Institute of Translational Medicine Zhejiang University School of MedicineHangzhou 310029China Department of Thyroid Surgery Zhejiang Cancer HospitalInstitute of Basic Medicine and Cancer(IBMC)Chinese Academy of SciencesHangzhou 310022China key laboratory of Head&Neck cancer Translational Research of Zhejiang Province Hangzhou 310022China Department of Hepatobiliary and Pancreatic Surgery Zhejiang University School of MedicineHangzhou 310029China Zhejiang Provincial key laboratory of Pancreatic Disease The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310029China Zhejiang University cancer Center Hangzhou 310029China Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang Hangzhou 310024China Research Center for Life Science and Human Health Binjiang Institute of Zhejiang UniversityHangzhou 310053China

NEDD8(Neural precursor cell expressed developmentally downregulated protein 8)is an ubiquitin-like protein that is covalently attached to a lysine residue of a protein substrate through a process known as neddylation,catalyzed by the enzyme cascade,namely NEDD8 activating enzyme(E1),NEDD8 conjugating enzyme(E2),and NEDD8 ligase(E3).The substrates of neddylation are categorized into cullins and non-cullin *** of cullins activates CRLs(cullin RING ligases),the largest family of E3 ligases,whereas neddylation of non-cullin substrates alters their stability and activity,as well as subcellular ***,the neddylation pathway and/or many neddylation substrates are abnormally activated or over-expressed in various human diseases,such as metabolic disorders,liver dysfunction,neurodegenerative disorders,and cancers,among ***,targeting neddylation becomes an attractive strategy for the treatment of these *** this review,we first provide a general introduction on the neddylation cascade,its biochemical process and regulation,and the crystal structures of neddylation enzymes in complex with cullin substrates;then discuss how neddylation governs various key biological processes via the modification of cullins and non-cullin *** further review the literature data on dysregulated neddylation in several human diseases,particularly cancer,followed by an outline of current efforts in the discovery of small molecule inhibitors of neddylation as a promising therapeutic ***,few perspectives were proposed for extensive future investigations.

关键词： NEDD8 attached attractive