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Alpha5 nicotine acetylcholine receptor subunit promotes intrahepatic cholangiocarcinoma metastasis

Signal Transduction and Targeted Therapy 2024年第4期9卷 1690-1705页

作者： Yan Fu keyu Shen Hao Wang Shun Wang Xufeng Wang Le Zhu Yan Zheng Tiantian Zou Hongfei Ci Qiongzhu Dong Lun-Xiu Qin Hepatobiliary Surgery Department of General SurgeryHuashan Hospital&Cancer Metastasis InstituteFudan University200040 ShanghaiChina Center of interventional Radiology and Vascular Surgery Department of RadiologyZhongda HospitalMedical SchoolSoutheast University87 Dingjiaqiao Road210009 NanjingChina institutes of Biomedical Sciences Fudan University200032 ShanghaiChina key laboratory of whole-period monitoring and precise intervention of digestive cancer Shanghai Municipal Health CommissionMinhang HospitalFudan UniversityShanghaiChina

Neurotransmitter-initiated signaling pathway were reported to play an important role in regulating the malignant phenotype of tumor *** cells could exhibit a"neural addiction"property and build up local nerve networks to achieve an enhanced neurotransmitter-initiated signaling through nerve growth factor-mediated *** the dysregulated nervous systems might represent a novel strategy for cancer ***,whether intrahepatic cholangiocarcinoma(ICC)could build its own nerve networks and the role of neurotransmitters in the progression ICC remains largely *** staining and Enzyme-linked immunosorbent assay suggested that IcC cells and the infiltrated nerves could generate a tumor microenvironment rich in acetylcholine that promotes IcC metastasis by inducing epithelial-mesenchymal transition(EMT).Acetylcholine promoted iCC metastasis through interacting with its receptor,alpha 5 nicotine acetylcholine receptor subunits(CHRNA5).Furthermore,acetylcholine/CHRNA5 axis activated GSK3β/β-catenin signaling pathway partially through the influx of Ca^(2+)-mediated activation of Ca/calmodulin-dependent protein kinases(CAMKll).In addition,acetylcholine signaling activation also expanded nerve infiltration through increasing the expression of Brain-Derived Neurotrophic Factor(BDNF),which formed a feedforward acetylcholine-BDNF axis to promote ICC ***93,a small-molecule inhibitor of CAMKIll,significantly inhibited the migration and enhanced the sensitivity to gemcitabine of ICC *** all,Acetylcholine/CHRNA5 axis increased the expression ofβ-catenin to promote the metastasis and resistance to gemcitabine of ICC via CAMKIl/GSK3βsignaling,and the CAMKIl inhibitor KN93 may be an effective therapeutic strategy for combating ICC metastasis.

关键词： GSK3β metastasis Alpha

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Detection and surveillance of circulating tumor cells in osteosarcoma for predicting therapy response and prognosis

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cancer Biology & Medicine 2022年第9期19卷 1397-1409页

作者： Haoran Mu Dongqing Zuo Jie Chen Zhigang Liu Zhuo Wang Liu Yang Qihui Shi Yingqi Hua Shanghai Bone Tumor Institute and Department of Orthopedics Shanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai 200080China key laboratory of Systems Biomedicine(Ministry of Education) Shanghai Center for Systems BiomedicineShanghai Jiao Tong UniversityShanghai 200240China Shanghai key laboratory of Medical Epigenetics and the International Co-laboratory of Medical Epigenetics and Metabolism(MOST) Institutes of Biomedical SciencesFudan UniversityShanghai 200032China key laboratory of whole-period monitoring and precise intervention of digestive cancer(SMHC)and Institute of Fudan-Minhang Academic Health System Minhang HospitalFudan UniversityShanghai 201199China Shanghai Engineering Research Center of Biomedical Analysis Reagents Shanghai 201203China

Objective:Osteosarcoma(OS)is an aggressive,highly metastatic,relatively drug-resistant bone tumor with poor long-term survival *** presence and persistence of circulating tumor cells(CTCs)in the peripheral blood are believed to be associated with treatment inefficiency and distant metastases.A blood-based CTC test is thus greatly needed for monitoring disease progression and predicting clinical ***,traditional methods cannot detect CTCs from tumors of mesenchymal origin such as OS,and research on CTC detection in mesenchymal tumors has been hindered for ***:In this study,we developed a CTC test based on hexokinase 2,a metabolic function-associated marker,for the detection and surveillance of OS CTCs,and subsequently explored its clinical *** patients with OS were enrolled as the training cohort for serial CTC *** CTC counting,in combination with therapy evaluation and post-treatment follow-up,was used to establish a model for predicting post-chemotherapy evaluation and disease-free survival,and the model was further validated with a cohort of 8 patients with ***:Two dynamic CTC number patterns were identified,and the resulting predictive model exhibited 92%consistency with the clinical *** model suggested that a single CTC test has similar predictive power to serial CTC *** the validation cohort,the single CTC test exhibited 100%and 87.5%consistency with therapy response and disease-free survival,***:Our non-invasive test for detection and surveillance of CTCs enables accurate prediction of therapy efficiency and prognosis,and may be clinically valuable for avoiding inefficient therapy and prolonging survival.

关键词： Circulating tumor cells osteosarcoma hexokinase 2 single-cell sequencing mesenchymal tumor

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The molecular biology of pancreatic adenocarcinoma:translational challenges and clinical perspectives

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Signal Transduction and Targeted Therapy 2021年第8期6卷 2348-2370页

作者： Shun Wang Yan Zheng Feng Yang Le Zhu Xiao-Qiang Zhu Zhe-Fang Wang Xiao-Lin Wu Cheng-Hui Zhou Jia-Yan Yan Bei-Yuan Hu Bo Kong De-Liang Fu Christiane Bruns Yue Zhao Lun-Xiu Qin Qiong-Zhu Dong Department of General Surgery Huashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina Department of Pancreatic Surgery Pancreatic Disease InstituteHuashan HospitalFudan UniversityShanghaiChina School of Biomedical Sciences Li Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina General Visceral and Cancer SurgeryUniversity Hospital of CologneCologneGermany Department of Biliary-Pancreatic Surgery Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina Department of Surgery Klinikum rechts der IsarSchool of MedicineTechnical University of Munich(TUM)MunichGermany key laboratory of whole-period monitoring and precise intervention of digestive cancer Shanghai Municipal Health Commission(SMHC)ShanghaiChina

Pancreatic cancer is an increasingly common cause of cancer mortality with a tight correspondence between disease mortality and ***,it is usually diagnosed at an advanced stage with a very dismal *** to the high heterogeneity,metabolic reprogramming,and dense stromal environment associated with pancreatic cancer,patients benefit little from current conventional *** insight into the biology and genetics of pancreatic cancer has supported its molecular classification,thus expanding clinical therapeutic *** this review,we summarize how the biological features of pancreatic cancer and its metabolic reprogramming as well as the tumor microenvironment regulate its development and *** further discuss potential biomarkers for pancreatic cancer diagnosis,prediction,and surveillance based on novel liquid *** also outline recent advances in defining pancreatic cancer subtypes and subtype-specific therapeutic responses and current preclinical therapeutic ***,we discuss prospects and challenges in the clinical development of pancreatic cancer therapeutics.

关键词： clinical mortality diagnosis

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A Novel mRNA Signature Related to Immunity to Predict Survival and Immunotherapy Response in Hepatocellular Carcinoma

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Journal of Clinical and Translational Hepatology 2022年第5期10卷 925-938页

作者： Chenhao Zhou Jialei Weng Yuan Gao Chunxiao Liu Xiaoqiang Zhu Qiang Zhou Chia-Wei Li Jialei Sun Manar Atyah Yong Yi Qinghai Ye Yi Shi Qiongzhu Dong Yingbin Liu Mien-Chie Hung Ning Ren Department of Liver Surgery Liver Cancer InstituteZhongshan Hospitaland Key Laboratory of Carcinogenesis and Cancer Invasion(Ministry of Education)Fudan UniversityShanghaiChina Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer CenterHoustonTXUSA Department of Biliary-Pancreatic Surgery Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina School of Biomedical Sciences Li Ka Shing Faculty of MedicineThe University of Hong KongPok Fu LamHong Kong SARChina Biomedical Research Center Zhongshan HospitalFudan UniversityShanghaiChina Institute of Fudan Minhang Academic Health System and Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer(SMHC)Minhang Hospital&AHSFudan UniversityShanghaiChina Institutes of Biomedical Sciences Fudan UniversityShanghaiChina Graduate Institute of Biomedical Sciences and Center for Molecular Medicine China Medical UniversityTaichung

Background and Aims:Hepatocellular carcinoma(HCC)is the most common primary liver cancer and the incidence and mortality rates are *** the limited treatments of HCC and promising application of immunotherapy for cancer,we aimed to identify an immune-related prognostic signature that can predict overall survival(OS)rates and immunotherapy response in ***:The initial signature development was conducted using a training dataset from the cancer Genome Atlas followed by independent internal and external validations from that resource and the Gene Expression Omnibus.A signature based nomogram was generated using multivariate Cox regression *** associations of signature score with tumor immune phenotype and response to immunotherapy were analyzed using single-sample gene set enrichment analysis and tumor immune dysfunction and exclusion algorithm.A cohort from Zhongshan Hospital was employed to verify the pre dictive robustness of the signature regarding prognostic risk and immunotherapy ***:The prognostic signature,IGS_(HCC),consisting of 22 immune-related genes,had independent prognostic ability,with training and validation ***,IGS_(HCC)stratified HCC patients with different outcomes in *** prognostic accuracy of IGS_(HCC)was better than three reported prognostic *** IGS_(HCC)-based nomogram had high accuracy and significant clinical benefits in predicting 3-and 5-year ***_(HCC)reflected distinct immunosuppressive phenotypes in low-and high-score *** with low IGS_(HCC)scores were more likely than those with high scores to benefit from ***:IGS_(HCC)predicted HCC prognosis and response to immunotherapy,and contributed to individualized clinical management.

关键词： Hepatocellular carcinoma Gene signature Immune microenvironment Prognosis Immunotherapy

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