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IRE1α regulates the PTHrP-IHH feedback loop to orchestrate chondrocyte hypertrophy and cartilage mineralization

Genes & Diseases 2024年第1期11卷 464-478页

作者： Mengtian Fan Nana Geng Xingyue Li Danyang Yin Yuyou Yang Rong Jiang Cheng Chen Naibo Feng Li Liang Xiaoli Li Fengtao Luo Huabing Qi Qiaoyan Tan Yangli Xie Fengjin Guo Laboratory of Developmental Biology Department of Cell Biology and GeneticsSchool of Basic Medical ScienceChongqing Medical UniversityChongqing 400016China Laboratory of Stem Cells and Tissue Engineering School of Basic Medical ScienceChongqing Medical UniversityChongqing 400016China Department of Orthopedics The 1st Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of wound Repair and Rehabilitation Medicine State Key Laboratory of TraumaBurns and Combined InjuryTrauma CenterResearch Institute of SurgeryDaping HospitalArmy Medical UniversityChongqing 400042China

Cartilage development is controlled by the highly synergistic proliferation and differentiation of growth plate chondrocytes,in which the Indian hedgehog(IHH)and parathyroid hormone-related protein-parathyroid hormone-1 receptor(PTHrP-PTH1R)feedback loop is crucial.The inositol-requiring enzyme 1a/X-box-binding protein-1 spliced(IRE1α/XBP1s)branch of the unfolded protein response(UPR)is essential for normal cartilage development.However,the precise role of ER stress effector IRE1α,encoded by endoplasmic reticulum to nucleus signaling 1(ERN1),in skeletal development remains unknown.Herein,we reported that loss of IRE1α accelerates chondrocyte hypertrophy and promotes endochondral bone growth.ERN1 acts as a negative regulator of chondrocyte proliferation and differentiation in postnatal growth plates.Its deficiency interrupted PTHrP/PTH1R and IHH homeostasis leading to impaired chondrocyte hypertrophy and differentiation.XBP1s,produced by p-IRE1α-mediated splicing,binds and up-regulates PTH1R and IHH,which coordinate cartilage development.Meanwhile,ER stress cannot be activated normally in ERN1-deficient chondrocytes.In conclusion,ERN1 deficiency accelerates chondrocyte hypertrophy and cartilage mineralization by impairing the homeostasis of the IHH and PTHrP/PTH1R feedback loop and ER stress.ERN1 may have a potential role as a new target for cartilage growth and maturation.

关键词： Cartilage development ER stress ERN1 IHH PTHrP/PTH1R

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Discovering deaminases using AlphaFold2:a strategy to search for tool proteins for gene editing

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Signal Transduction and Targeted Therapy 2024年第3期9卷 822-824页

作者： Yongye Huang Jianxin Jiang Min Wu Key Laboratory of Bioresource Research and Development of Liaoning Province College of Life and Health SciencesNortheastern UniversityShenyang 110169China wound trauma medical center State Key Laboratory of TraumaBurns and Combined InjuryDaping HospitalArmy Medical UniversityChongqing 400042China Wenzhou Traditional Chinese Medicine Hospital of Zhejiang Chinese medical University WenzhouZhejiang 325000China Wenzhou Institute University of Chinese Academy of SciencesWenzhou 325000China The Joint Research center Affiliated Xiangshan Hospital of Wenzhou Medical UniversityNingboChina

A recent study by Huang et al.published in Cell reported the application of AlphaFold2 to forecast the structures of deaminase proteins and cluster them based on structural similarity,creating a truncated Sdd that can be used as a cytosine base editor(CBE)to be integrated into a single adeno-associated virus(AAV)1 This ground-breaking study aided by the artificial intelligence system would largely broaden the utility of tool proteins for gene editing.

关键词： CBE Alpha editor

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Risk factors and predictive model of cerebral edema after road traffic accidents-related traumatic brain injury

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Chinese Journal of traumatology 2024年第3期27卷 153-162页

作者： Di-You Chen Peng-Fei Wu Xi-Yan Zhu Wen-Bing Zhao Shi-Feng Shao Jing-Ru Xie Dan-Feng Yuan Liang Zhang Kui Li Shu-Nan Wang Hui Zhao Institute for Traffc Medicine aping HospitalArmy Medical UniverstyChongqing400042China Department of Radiology Daping HospitalArmy Medical UniversityChongqing400042China Chongqing Key Laboratory of Traffic Injury and Vehicle Ergonomics Chongqing400042China wound trauma medical center State Key Laboratory of TraumnaBurns and Combined lnjuryInstitute of Surgery ResearchDaping HospialArmy Medical UniversityChongqing.400042China

Purpose:Cerebral edema(CE)is the main secondary injury following traumatic brain injury(TBI)caused by road traffic accidents(RTAs).It is challenging to be predicted timely.In this study,we aimed to develop a prediction model for CE by identifying its risk factors and comparing the timing of edema occurrence in TBI patients with varying levels of injuries.Methods:This case-control study included 218 patients with TBI caused by RTAs.The cohort was divided into CE and non-CE groups,according to CT results within 7 days.Demographic data,imaging data,and clinical data were collected and analyzed.Quantitative variables that follow normal distribution were presented as mean±standard deviation,those that do not follow normal distribution were presented as median(Q1,Q3).Categorical variables were expressed as percentages.The Chi-square test and logistic regression analysis were used to identify risk factors for CE.Logistic curve fitting was performed to predict the time to secondary CE in TBI patients with different levels of injuries.The efficacy of the model was evaluated using the receiver operator characteristic curve.Results:According to the study,almost half(47.3%)of the patients were found to have CE.The risk factors associated with CE were bilateral frontal lobe contusion,unilateral frontal lobe contusion,cerebral contusion,subarachnoid hemorrhage,and abbreviated injury scale(AIS).The odds ratio values for these factors were 7.27(95%confidence interval(CI):2.08-25.42,p=0.002),2.85(95%CI:1.11-7.31,p=0.030),2.62(95%CI:1.12-6.13,p=0.027),2.44(95%CI:1.25-4.76,p=0.009),and 1.5(95%CI:1.10-2.04,p=0.009),respectively.We also observed that patients with mild/moderate TBI(AIS≤3)had a 50%probability of developing CE 19.7 h after injury(χ^(2)=13.82,adjusted R2=0.51),while patients with severe TBI(AIS>3)developed CE after 12.5 h(χ^(2)=18.48,adjusted R2=0.54).Finally,we conducted a receiver operator characteristic curve analysis of CE time,which showed an area under the curve of 0.744 and 0.672 for severe and mild/moderate TBI,

关键词： Road traffic accident traumatic brain injury Cerebral edema Risk factors Time window

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Bromocriptine protects perilesional spinal cord neurons from lipotoxicity after spinal cord injury

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Neural Regeneration Research 2024年第5期19卷 1142-1149页

作者： Ying Peng Zhuoxuan Li Zhiyang Zhang Yinglun Chen Renyuan Wang Nixi Xu Yuanwu Cao Chang Jiang Zixian Chen Haodong Lin trauma center Shanghai General HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Department of Orthopedics Zhongshan HospitalFudan UniversityShanghaiChina Department of Rehabilitation Medicine Shanghai Geriatric Medical CenterShanghaiChina

Recent studies have revealed that lipid droplets accumulate in neurons after brain injury and evoke lipotoxicity,damaging the neurons.However,how lipids are metabolized by spinal cord neurons after spinal cord injury remains unclear.Herein,we investigated lipid metabolism by spinal cord neurons after spinal cord injury and identified lipid-lowering compounds to treat spinal cord injury.We found that lipid droplets accumulated in perilesional spinal cord neurons after spinal cord injury in mice.Lipid droplet accumulation could be induced by myelin debris in HT22 cells.Myelin debris degradation by phospholipase led to massive free fatty acid production,which increased lipid droplet synthesis,β-oxidation,and oxidative phosphorylation.Excessive oxidative phosphorylation increased reactive oxygen species generation,which led to increased lipid peroxidation and HT22 cell apoptosis.Bromocriptine was identified as a lipid-lowering compound that inhibited phosphorylation of cytosolic phospholipase A2 by reducing the phosphorylation of extracellular signal-regulated kinases 1/2 in the mitogen-activated protein kinase pathway,thereby inhibiting myelin debris degradation by cytosolic phospholipase A2 and alleviating lipid droplet accumulation in myelin debris-treated HT22 cells.Motor function,lipid droplet accumulation in spinal cord neurons and neuronal survival were all improved in bromocriptine-treated mice after spinal cord injury.The results suggest that bromocriptine can protect neurons from lipotoxic damage after spinal cord injury via the extracellular signal-regulated kinases 1/2-cytosolic phospholipase A2 pathway.

关键词： bromocriptine central nervous system cytosolic phospholipase A2 high-content screening lipid droplet lipid metabolism lipotoxicity mitogen-activated protein kinase spinal cord injury spinal cord neurons

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Piezo1 expression in chondrocytes controls endochondral ossification and osteoarthritis development

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Bone Research 2024年第1期12卷 199-214页

作者： Laura J.Brylka Assil-Ramin Alimy Miriam E.A.Tschaffon-Müller Shan Jiang Tobias Malte Ballhause Anke Baranowsky Simon von Kroge Julian Delsmann Eva Pawlus Kian Eghbalian Klaus Püschel Astrid Schoppa Melanie Haffner-Luntzer David J.Beech Frank Timo Beil Michael Amling Johannes Keller Anita Ignatius Timur A.Yorgan Tim Rolvien Thorsten Schinke Department of Osteology and Biomechanics University Medical Center Hamburg-Eppendorf20246 HamburgGermany Department of trauma and Orthopedic Surgery University Medical Center Hamburg-Eppendorf20246 HamburgGermany Institute of Orthopedic Research and Biomechanics University Medical Center UlmBadenWürttemberg89081 UlmGermany Department Legal Medicine University Medical Center Hamburg-Eppendorf20246 HamburgGermany Leeds Institute of Cardiovascular and Metabolic Medicine School of MedicineUniversity of LeedsLS29JT LeedsUK

Piezo proteins are mechanically activated ion channels,which are required for mechanosensing functions in a variety of cell types.While we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for boneanabolic processes,there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in cartilage.Here we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis(OA)development.Mice with chondrocyte-specific inactivation of Piezo1(Piezo1^(Col2a1Cre)),but not of Piezo2,developed a near absence of trabecular bone below the chondrogenic growth plate postnatally.Moreover,all Piezo1^(Col2a1Cre) animals displayed multiple fractures of rib bones at 7 days of age,which were located close to the growth plates.While skeletal growth was only mildly affected in these mice,OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of age.Likewise,when OA was induced by anterior cruciate ligament transection,only the chondrocyte inactivation of Piezo1,not of Piezo2,resulted in attenuated articular cartilage degeneration.Importantly,osteophyte formation and maturation were also reduced in Piezo1^(Col2a1Cre) mice.We further observed increased Piezo1 protein abundance in cartilaginous zones of human osteophytes.Finally,we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in chondrocytes.Collectively,our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes,but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA.

关键词： Piezo1 markedly ossification

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Evaluation of erastin synergized cisplatin anti-nasopharyngeal carcinoma effect with a glutathione-activated near-infrared fluorescent probe

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Chinese Chemical Letters 2024年第2期35卷 311-316页

作者： Rong He Dandan Tang Ningge Xu Heng Liu Kun Dou Xuejun Zhou Fabiao Yu Department of Otolaryngology Head and Neck SurgeryThe First Affiliated Hospital of Hainan Medical UniversityHaikou 570102China Key Laboratory of Hainan trauma and Disaster Rescue Key Laboratory of Emergency and TraumaMinistry of EducationEngineering Research Center for Hainan Bio-Smart Materials and Bio-Medical DevicesCollege of Emergency and TraumaHainan Medical UniversityHaikou 571199China Sichuan Provincial General Hospital of Judicial Police Chengdu 610225China

Nasopharyngeal carcinoma(NPC),a malignant tumor originating from the nasopharynx,is one of the common malignant tumors of the head and neck.There are significant geographical differences in the incidence of nasopharyngeal carcinoma,with a high incidence in China and Southeast Asian countries.Herein,we designed and synthesized a novel near-infrared fluorescent(NIRF)probe to detect glutathione(GSH)in cellular and tumor environments using semi-naphthofluorescein(SNAFL)as the fluorescent molecular backbone and 2-fluoro-4-nitrobenzenesulfonate as the recognition moiety.Upon reaction with GSH,SNAFL-GSH emitted a fluorescence signal,and its emission wavelength at 650 nm was remarkably enhanced.The results of selectivity experiments indicated that SNAFL-GSH was able to discriminate GSH from Cys,Hcy,and H_(2) S.Moreover,SNAFL-GSH could image both endogenous and exogenous GSH and distinguish normal and cancer cells by fluorescence signal difference.At the cellular level,cisplatin(DDP)-induced ferroptosis and inhibition of proliferation of various NPC cell lines(CNE2,CNE1,5-8F cells)by erastin combined with DDP were visualized with the help of SNAFL-GSH.In a mouse tumor xenograft model,we successfully employed SNAFL-GSH for the evaluation of the efficacy of erastin combined with DDP in the treatment of NPC.More importantly,the probe could image cancerous tissue sections from NPC patients with an imaging depth of approximately 80µm.It was foreseen that SNAFL-GSH offered great potential for application in the diagnosis and evaluation of the therapeutic efficacy of NPC,and these results would also provide new ideas for the clinical treatment of NPC.

关键词： Glutathione NIRF probe Ferroptosis Anti-tumor therapy evaluation Bioimaging

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In vivo imaging of the neuronal response to spinal cord injury:a narrative review

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Neural Regeneration Research 2024年第4期19卷 811-817页

作者： Junhao Deng Chang Sun Ying Zheng Jianpeng Gao Xiang Cui Yu Wang Licheng Zhang Peifu Tang Department of Orthopedics The Fourth Medical Center of Chinese PLA General Hospital National Clinical Research center for Orthopedics Sports Medicine and Rehabilitation School of Life Sciences Tsinghua University Department of Orthopedics Air Force Medical CenterPLA medical School of Chinese PLA Institute of Orthopedics The First Medical CenterChinese PLA General Hospital Key Lab of Regenerative Medicine in Orthopedics Key Laboratory of Musculoskeletal Trauma and War Injuries PLA

Deciphering the neuronal response to injury in the spinal cord is essential for exploring treatment strategies for spinal cord injury(SCI).However,this subject has been neglected in part because appropriate tools are lacking.Emerging in vivo imaging and labeling methods offer great potential for observing dynamic neural processes in the central nervous system in conditions of health and disease.This review first discusses in vivo imaging of the mouse spinal cord with a focus on the latest imaging techniques,and then analyzes the dynamic biological response of spinal cord sensory and motor neurons to SCI.We then summarize and compare the techniques behind these studies and clarify the advantages of in vivo imaging compared with traditional neuroscience examinations.Finally,we identify the challenges and possible solutions for spinal cord neuron imaging.

关键词： anterior horn neurons calcium imaging central nervous system dorsal horn neurons dorsal root ganglion in vivo imaging neuronal response spinal cord injury spinal cord two-photon microscopy

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Total body water percentage and 3rd space water are novel risk factors for training-related lower extremity muscle injuries in young males

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Chinese Journal of traumatology 2024年第3期27卷 168-172页

作者： Liang Chen Ke-Xing Jin Jing Yang Jun-Jjie Ouyang Han-Gang Chen Si-Ru Zhou Xiao-Qing Luo Mi Liu Liang Kuang Yang-Li Xie Yan Hu Lin Chen Zhen-Hong Ni Xiao-Lan Du Department of Orthopedic Daping HospitalArmy Medical UniversityChongqing400042China Department of Rehabilitation Medicine Daping HospitalArmy Medical UntiversityChongqing400042China Department of wound Repair and Rehabilitation Medicine Center of Bone Metabolism and RepairLaboratory for Prevention and Rehabilitation of Training InjuriesState Key Laboratory of Trouma and Chemical Poisoning.Trauma CenterResearch Instiute of SurgeryDaping HospitalArmy Medical UniversityChongqing.400042China War Trouma medical center Daping HospitalArmy Medical UniversilyChongqing400042.China Department of Military Basic Training and Arny Management Army Health Service Training BaseArmy Medical UniversityChongqing400042China Department of Army Occupational Disease Laboratory for Prevention and Rehabilitation of Training lnjuriesState Key Laboratory of Trauma and Chemical PoisoningResearch Institute of SurgeryDaping HospitalArmy Medical UniversiryChongqing400042.China

Purpose:To identify the risk factors for training-related lower extremity muscle injuries in young males by a non-invasive method of body composition analysis.Methods:A total of 282 healthy young male volunteers aged 18-20 years participated in this cohort study.Injury location,degree,and injury rate were adjusted by a questionnaire based on the overuse injury assessment methods used in epidemiological studies of sports injuries.The occurrence of training injuries is monitored and diagnosed by physicians and treated accordingly.The body composition was measured using the BodyStat QuadScan 4000 multifrequency Bio-impedance system at 5,50,100 and 200 kHz to obtain 4 impedance values.The Shapiro-Wilk test was used to check whether the data conformed to a normal distribution.Data of normal distribution were shown as mean±SD and analyzed by t-test,while those of non-normal distribution were shown as median(Q1,Q3)and analyzed by Wilcoxon rank sum test.The receiver operator characteristic curve and logistic regression analysis were performed to investigate risk factors for developing training-related lower extremity injuries and accuracy.Results:Among the 282 subjects,78(27.7%)developed training injuries.Lower extremity training injuries revealed the highest incidence,accounting for 23.4%(66 cases).These patients showed higher percentages of lean body mass(p=0.001),total body water(TBW,p=0.006),extracellular water(p=0.020)and intracellular water(p=0.010)as well as a larger ratio of basal metabolic rate/total weight(p=0.006),compared with those without lower extremity muscle injuries.On the contrary,the percentage of body fat(p=0.001)and body fat mass index(p=0.002)were lower.Logistic regression analysis showed that TBW percentage>65.35%(p=0.050,odds ratio=3.114)and 3rd space water>0.95%(p=0.045,odds ratio=2.342)were independent risk factors for lower extremity muscle injuries.Conclusion:TBW percentage and 3rd space water measured with bio-impedance method are potential risk factors for predicting the incidence of lower

关键词： Body composition Training injuries Lower extremity Bio-impedance

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Prevalence of Anemia in Patients with Diabetes Mellitus:A Systematic Review and Meta-Analysis

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Biomedical and Environmental Sciences 2024年第1期37卷 96-107页

作者： Monireh Faghir-Ganji Narjes Abdolmohammadi Maryam Nikbina Alireza Amanollahi Alireza Ansari-Moghaddam Rozhan Khezri Hamidreza Baradaran Student Research Committee Iran University of Medical SciencesTehranIran Department of Epidemiology School of Public HealthIran University of Medical SciencesTehranIran Department of Epidemiology School of Public HealthTehran University of Medical SciencesTehranIran Department of Midwifery Shoushtar Faculty of Medical SciencesShoushtarIran Department of Epidemiology School of Public Health and SafetyShahid Beheshti University of Medical SciencesTehranIran trauma and Injury Research center Iran University of Medical SciencesTehranIran Health Promotion Research center Zahedan University of Medical SciencesZahedanIran Endocrine Research center Institute of Endocrinology and MetabolismIran University of Medical SciencesTehranIran

Objective Anemia is a common public health concern in patients with type 2 diabetes worldwide.This study aimed to identify the prevalence of anemia among patients with diabetes.Methods Electronic databases,including PubMed,Scopus,Web of Sciences,and Google Scholar,were searched systematically for studies published between 2010 and 2021.After removing duplicates and inappropriate reports,the remaining manuscripts were reviewed and appraised using theNewcastleOttawa Scale(NOS)tool.A random-effects model was used to calculate the pooled estimates of the extracted data using Stata version 17.Heterogeneity of the studies was assessed using the Q statistic.Results A total of 51 articles containing information on 26,485 patients with diabetes were included in this study.The articles were mainly from Asia(58.82%)and Africa(35.29%).The overall prevalence of anemia was 35.45%(95%CI:30.30–40.76),with no evidence of heterogeneity by sex.Among the two continents with the highest number of studies,the prevalence of anemia in patients with diabetes was significantly higher in Asia[40.02;95%CI:32.72–47.54]compared to Africa[28.46;95%CI:21.90–35.50](P for heterogeneity=0.029).Moreover,there has been an increasing trend in the prevalence of anemia in patients with diabetes over time,from[15.28;95%CI:9.83–22.21]in 2012 to[40.70;95%CI:10.21–75.93]in 2022.Conclusion Globally,approximately 4 in 10 patients with diabetes suffer from anemia.Therefore,routine anemia screening and control programs every 3 months might be useful in improving the quality of life of these patients.

关键词： Prevalence Diabetic foot Anemia Diabetes mellitus

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Loss of GATA6-mediated up-regulation of UTX promotes pancreatic tumorigenesis and progression

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Genes & Diseases 2024年第2期11卷 921-934页

作者： Hui-Qing Zhang Fanyang Kong Xiangyu Kong Tingting Jiang Muyuan Ma Shaojiang Zheng Junli Guo Keping Xie The Third Department of medical Oncology Jiangxi Cancer HospitalNanchangJiangxi 330006China Departments of Gastroenterology Changhai HospitalSecond Military Medical UniversityShanghai 200433China center for Pancreatic Cancer Research The South China University of Technology School of MedicineGuangzhouGuangdong 510006China Hainan Clinical medical Research center of the First Affiliated Hospital Hainan Women and Children's Medical CenterHainan Medical UniversityHaikouHainan 570102China Key Laboratory of Tropical Cardiovascular Diseases Research of Hainan Province Key Laboratory of Emergency and Trauma of Ministry of EducationHainan Medical UniversityHaikouHainan 571199China

Ubiquitously transcribed tetratricopeptide repeat on chromosome X(UTX),also known as lysine(K)-specific demethylase 6A(KDM6A),functions as a tumor suppressor gene or oncogene depending on the tumor type and context.However,its tumor-suppressive mechanisms remain largely unknown.Here,we investigated the clinical significance and biological effects of UTX expression in pancreatic ductal adenocarcinoma(PDA)and determined the potential mechanisms of its dysregulation.UTX expression and its association with clinicopathologic characteristics of PDA patients were analyzed using immunohistochemistry.UTX mRNA and protein expression and their regulation in PDA cell lines were measured using quantitative polymerase chain reaction and Western blot analyses.The biological functions of UTX in PDA cell growth,migration,and invasion were determined using gain-and loss-of-function assays with both in vitro and in vivo animal models.UTX expression was reduced in human PDA cell lines and specimens.Low UTX expression was associated with poor differentiation and prognosis in PDA.Forced UTX expression inhibited PDA proliferation,migration,and invasion in vitro and PDA growth and metastasis in vivo,whereas knockdown of UTX expression did the opposite.Mechanistically,UTX expression was trans-activated by GATA6 activation.GATA6-mediated PDA progression could be blocked,at least partially,by silencing UTX expression.In conclusion,loss of GATA6-mediated UTX expression was evident in human PDA and restored UTX expression suppressed PDA growth and metastasis.Thus,UTX is a tumor suppressor in PDA and may serve as a prognostic biomarker and therapeutic target.

关键词： Growth Invasion Metastasis Pancreatic cancer UTX

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