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Autophagy in cancer biology and therapy

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Frontiers in Biology 2014年第1期9卷 35-50页

作者： Noor GAMMOH Simon WILKINSON Edinburgh Cancer Research UK centre MRC Institute of Genetics and Molecular Medicine University of Edinburgh Crewe Road SouthUnited Kingdom EH4 2XR

The role of macroautophagy （hereafter autophagy） in cancer biology and response to clinical intervention is complex. It is clear that autophagy is dysregulated in a wide variety of tumor settings, both during tumor initiation and progression, and in response to therapy. However, the pleiotropic mechanistic roles of autophagy in controlling cell behavior make it difficult to predict in a given tumor setting what the role of autophagy, and, by extension, the therapeutic outcome of targeting autophagy, might be. In this review we summarize the evidence in the literature supporting pro- and anti-tumorigenic and -therapeutic roles of autophagy in cancer. This overview encompasses roles of autophagy in nutrient management, cell death, cell senescence, regulation of proteotoxic stress and cellular homeostasis, regulation of tumor-host interactions and participation in changes in metabolism. We also try to understand, where possible, the mechanistic bases of these roles for autophagy. We specifically expand on the emerging role of genetically- engineered mouse models of cancer in shedding light on these issues in vivo. We also consider how any or all of the above functions of autophagy proteins might be targetable by extant or future classes of pharmacologic agents. We conclude by briefly exploring non-canonical roles for subsets of the key autophagy proteins in cellular processes, and how these might impact upon cancer.

关键词： autophagy cancer inflammation metabolism apoptosis homeostasis

A Bama miniature pig model of monoallelic TSC1 mutation for human tuberous sclerosis complex

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Journal of Genetics and Genomics 2020年第12期47卷 735-742页

作者： Xiaoxue Li Tingdong Hu Jiying Liu Bin Fang Xue Geng Qiang Xiong Lining Zhang Yong Jin Xiaorui Liu Lin Li Ying Wang Rongfeng Li Xiaochun Bai Haiyuan Yang Yifan Dai Jiangsu Key Laboratory of Xenotransplantation Nanjing Medical UniversityNanjing 211166China Key Laboratory of Targeted intervention of Cardiovascular Disease Collaborative Innovation Center for Cardiovascular Disease Translational MedicineNanjing Medical UniversityNanjing 211166China Department of Cell Biology Guangdong Provincial Key Laboratory of Bone and Joint Degenerative DiseasesSchool of Basic Medical SciencesSouthern Medical UniversityGuangzhou 510515China State Key Laboratory of Reproductive Medicine Nanjing Medical UniversityNanjing 211166China Shenzhen Xenotransplantation Medical Engineering Research and Development Center Institute of Translational MedicineShenzhen Second People's HospitalFirst Affiliated Hospital of Shenzhen UniversityShenzhen 518035China

Tuberous sclerosis complex(TSC)is a dominant genetic neurocutaneous syndrome characterized by multiple organ *** rodent models bearing a germline mutation in either TSC1 or TSC2 gene have been generated,they do not develop pathogenic lesions matching those seen in patients with TSC because of the significant differences between mice and humans,highlighting the need for an improved large animal model of ***,we successfully generate monoallelic TSC1-modified Bama miniature pigs using the CRISPR/Cas9 system along with somatic cell nuclear transfer(SCNT)*** expression of phosphorylated target ribosomal protein S6 is significantly enhanced in the piglets,indicating that disruption of a TSC1 allele activate the mechanistic target of rapamycin(mTOR)signaling ***,differing from the mouse TSC models reported previously,the TSC1^(+/−)Bama miniature pig developed cardiac rhabdomyoma and subependymal nodules,resembling the major clinical features that occur in patients with *** TSC1^(+/−)Bama miniature pigs could serve as valuable large animal models for further elucidation of the pathogenesis of TSC and the development of therapeutic strategies for TSC disease.

关键词： CRISPR/Cas9 Cardiac rhabdomyosarcoma Subependymal nodules TSC1 Tuberous sclerosis complex

Evaluating role of bone marrow-derived stem cells in dry age-related macular degeneration using multifocal electroretinogram and fundus autofluorescence imaging

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International Journal of Ophthalmology(English edition) 2017年第10期10卷 1552-1558页

作者： Atul Kumar Neha Midha Sujata Mohanty Annu Chohan Tulika Seth Varun Gogia Shikha Gupta Dr.Rajendra Prasad centre for Ophthalmic Sciences All India Institute of Medical Sciences Stem Cell Facility All India Institute of Medical Sciences Department of Hematology All India Institute of Medical Sciences

AIM：To evaluate the role of bone marrow-derived stem cells in the treatment of advanced dry age-related macular degeneration（AMD）using multifocal electroretinogram（mf-ERG）and fundus autofluorescence ***：Thirty patients（60 eyes）with bilateral central geographic atrophy（GA）were *** eye of each patient received autologous bone marrow-derived hematopoietic stem cells（BM-HSCs）（group 1）and the fellow eye with better visual acuity served as control（group2）.The effect of stem cell therapy was determined in terms of visual acuity,amplitude and implicit time in mf-ERG and size of GA on fundus autofluorescence *** tests were performed at presentation and first,third and sixth month follow *** events（if any）were also ***：At 6mo follow-up there was no statistically significant improvement in median log MAR best corrected visual acuity（BCVA）in either ***-ERG revealed significant improvement in amplitude and implicit time in the intervention group.A significant decrease was also noted in greatest linear dimension（GLD）of GA in the eyes receiving stem cells[6.78±2.60 mm at baseline to 6.56±2.59 mm at 6mo（P=0.021）].However,no such improvement was noted in the control ***：Electrophysiological and anatomical improvement in the intervention group sheds light on the therapeutic role of *** studies are required to determine the stage of disease at which the maximal benefit can be achieved and to standardize the dose andfrequency of stem cell injection.

关键词： dry age-related macular degeneration multifocal electroretinogram stem cells fimdus autofluorescence imaging

Specific pupylation as IDEntity reporter(SPIDER)for the identification of protein-biomolecule interactions

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Science China(Life Sciences) 2023年第8期66卷 1869-1887页

作者： He-Wei Jiang Hong Chen Yun-Xiao Zheng Xue-Ning Wang Qingfeng Meng Jin Xie Jiong Zhang ChangSheng Zhang Zhao-Wei Xu Zi-Qing Chen Lei Wang Wei-Sha Kong Kuan Zhou Ming-Liang Ma Hai-Nan Zhang Shu-Juan Guo Jun-Biao Xue Jing-Li Hou Zhe-Yi Liu Wen-Xue Niu Fang-Jun Wang Tao Wang Wei Li Rui-Na Wang Yong-Jun Dang Daniel MCzajkowsky JianFeng Pei Jia-Jia Dong Sheng-Ce Tao Shanghai Center for Systems Biomedicine Key Laboratory of Systems Biomedicine(Ministry of Education)Shanghai Jiao Tong UniversityShanghai 200240China Center for Quantitative Biology Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijing 100871China Inflammation and Immune Mediated Diseases Laboratory of Anhui Province School of PharmacyAnhui Medical UniversityHefei 230032China Key Laboratory of Organofluorine Chemistry Center for Excellence in Molecular SynthesisShanghai Institute of Organic ChemistryUniversity of the Chinese Academy of SciencesChinese Academy of SciencesShanghai 200240China College of Chemistry and Molecular Engineering Peking UniversityBeijing 100871China Key Laboratory of Gastrointestinal Cancer(Fujian Medical University) Ministry of EducationFuzhou 350122China Department of Molecular Biology Princeton UniversityNew Jersey 08540USA Instrumental Analysis Center Shanghai Jiao Tong UniversityShanghai 200240China CAS Key Laboratory of Separation Sciences for Analytical Chemistry Dalian Institute of Chemical PhysicsChinese Academy of SciencesDalian 116023China Institute of Systems Biology Shenzhen Bay LaboratoryPeking University Shenzhen Graduate SchoolShenzhen 518055China Department of Medicinal Chemistry School of PharmacyChina Pharmaceutical UniversityNanjing 211198China Key Laboratory of Metabolism and Molecular Medicine the Ministry of EducationDepartment of Biochemistry and Molecular BiologySchool of Basic Medical SciencesFudan UniversityShanghai 200240China Center for Novel Target and therapeutic intervention Chongqing Medical UniversityChongqing 400016China School of Biomedical Engineering Shanghai Jiao Tong UniversityShanghai 200240China

Protein-biomolecule interactions play pivotal roles in almost all biological *** a biomolecule of interest,the identification of the interacting protein(s)is *** this need,although many assays are available,highly robust and reliable methods are always *** combining a substrate-based proximity labeling activity from the pupylation pathway of Mycobacterium tuberculosis and the streptavidin(SA)-biotin system,we developed the Specific Pupylation as IDEntity Reporter(SPIDER)method for identifying protein-biomolecule *** SPIDER,we validated the interactions between the known binding proteins of protein,DNA,RNA,and small *** successfully applied SPIDER to construct the global protein interactome for m^(6)A and m RNA,identified a variety of uncharacterized m^(6)A binding proteins,and validated SRSF7 as a potential m^(6)A *** globally identified the binding proteins for lenalidomide and Cob ***,we identified SARS-CoV-2-specific receptors on the cell ***,SPIDER is powerful and highly accessible for the study of proteinbiomolecule interactions.

关键词： proximity labeling protein-biomolecule interaction proteomics pupylation

HBx induced AFP receptor expressed to activate PI3K/AKT signal to promote expression of Src in liver cells and hepatoma cells

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HBx induced AFP receptor expressed to activate PI3K/AKT sign...

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

第七届生命科学联合学术大会

作者： Mingyue Zhu Junli Guo Wei Li Hua Xia Yan Lu Xu Dong Yi Chen Xieju Xie Shigan Fu Mengsen Li Hainan Provincial Key Laboratory of Carcinogenesis and intervention Hainan Medical College Key Laboratory of Molecular Biology Hainan Medical College Department of Pathophysiology Hainan Medical College Department of Physiology Hainan Medical College Institution of Tumor Hainan Medical College

Background Hepatitis B virus(HBV)-X protein(HBx)is a transactivator of host several cellular genes including alpha-fetoprotein(AFP)and AFP receptor(AFPR)which contributes to HBV-associated tumor *** expression of AFP/AFPR are correlated with hepatocellular carcinoma(HCC)-initial *** the role of AFP and AFR in promoting occurrence of HBV-related HCC were still *** A total of 71 clinical patients’liver specimens,normal human liver cells L-02 and HCC cell lines,PLC/PRF/5 were selected for analyzing the effects of HBx on expression of AFP,AFPR and *** expression of goal proteins were detected by Immunohistochemical stained and Western blotting;HBx-expressed vectors were constructed and transfected into L-02 cells,laser confocal microscopy was applied to observe expression and location of AFP,AFPR and Src in the normal liver cells and HCC cells,soft agar colony formation assay was used to observe colonies formed of the *** We confirmed HBx gives preference to promote the expression of AFP and AFPR;HBx priors to up-regulate the expression of AFPR and AFP in L-02 cells and in normal liver specimens;AFPR signal been able to stimulate Src *** results also indicated that phosphatidylinositol 3-kinase(PI3K)inhibitors Ly294002 and GDC0941 effectively suppress AFPR mediated up-regulation expression of Src in AFPR positive HCC *** HBx priors to drive the expression of AFP and AFPR to promote expression of Src in normal liver cells and hepatoma cells;AFP and AFPR maybe play pivotal role in HBV-related hepatocarcinogenesis;Targeting AFPR is an available therapeutic strategy of HCC.

关键词： Hepatitis B virus-x(HBx) Alpha fetoprotein(AFP)/AFP receptor PI3K/AKT signal Hepatoma cells

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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

High-frequency terahertz waves disrupt Alzheimer’s β-amyloid fibril formation

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eLight 2023年第1期3卷 85-93页

作者： Wenyu Peng Zhi Zhu Jing Lou Kun Chen Yuanming Wu Chao Chang Department of Biochemistry and Molecular Biology Shaanxi Provincial Key Laboratory of Clinic GeneticsSchool of Basic MedicineAir Force Medical UniversityXi’an 710032China Innovation Laboratory of Terahertz Biophysics National Innovation Institute of Defense TechnologyBeijing 100071China Key Laboratory of Optical Technology and Instrument for Medicine Ministry of EducationCollege of Optical-Electrical and Computer EngineeringUniversity of Shanghai for Science and TechnologyShanghai 200093China Department of Anatomy Histology and Embryology and K.K.Leung Brain Research CentreSchool of Basic MedicineAir Force Medical UniversityXi’an 710032China School of Physics Peking UniversityBeijing 100871China

The accumulation and deposition of amyloid can cause a variety of neurodegenerative diseases,including Alzheimer’s and Parkinson’s *** degradation or clearance of this accumulation is currently the most widely accepted therapeutic strategy for intervention in these *** study on amyloid-β(Aβ)oligomers in vitro revealed that high-frequency terahertz(THz)waves at a specific frequency of 34.88 THz could serve as a physical,efficient,non-thermal denaturation technique to delay the fibrotic process by 80%,as monitored by a thioflavine T(ThT)binding assay and Fourier transform infrared(FTIR)***,THz waves of this frequency have been shown to have no side effects on normal cells,as confirmed by cell viability and mitochondrial membrane potential ***,molecular dynamic(MD)simulations revealed that the THz waves could resonate with Aβ fibrils,disrupting the dense conformation by breaking the β-sheet structure and promoting the formation of abundant coil and bend *** study uses the amyloid of Aβ as an example,and the results will further guide interventions for the accumulation of other amyloids,which may provide new ideas for the remission of related diseases.

关键词： amyloid Alzheimer Aβ

Radiation-induced tumor immune microenvironments and potential targets for combination therapy

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Signal Transduction and Targeted Therapy 2023年第6期8卷 2773-2794页

作者： Siyu Guo Yihan Yao Yang Tang Zengfeng Xin Dang Wu Chao Ni Jian Huang Qichun Wei Ting Zhang Department of Radiation Oncology Second Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouChina Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province Second Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouChina Cancer Institute(Key Laboratory of Cancer Prevention and intervention National Ministry of Education)Second Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouChina Cancer Center Zhejiang UniversityHangzhouChina Department of Orthopedic Surgery Second Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouChina Department of Breast Surgery Second Affiliated HospitalZhejiang University School of MedicineZhejiang UniversityHangzhouChina

As one of the four major means of cancer treatment including surgery,radiotherapy(RT),chemotherapy,immunotherapy,RT can be applied to various cancers as both a radical cancer treatment and an adjuvant treatment before or after *** RT is an important modality for cancer treatment,the consequential changes caused by RT in the tumor microenvironment(TME)have not yet been fully ***-induced damage to cancer cells leads to different outcomes,such as survival,senescence,or *** RT,alterations in signaling pathways result in changes in the local immune ***,some immune cells are immunosuppressive or transform into immunosuppressive phenotypes under specific conditions,leading to the development of *** who are radioresistant respond poorly to RT and may experience cancer *** that the emergence of radioresistance is inevitable,new radiosensitization treatments are urgently *** this review,we discuss the changes in irradiated cancer cells and immune cells in the TME under different RT regimens and describe existing and potential molecules that could be targeted to improve the therapeutic effects of ***,this review highlights the possibilities of synergistic therapy by building on existing research.

关键词： microenvironment alterations surgery

Acute ST-segment myocardial infarction—Evolution of treatment strategies

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World Journal of Cardiovascular Diseases 2013年第9期3卷 551-560页

作者： Dennis T. L. Wong Rishi Puri Peter J. Psaltis Stephen G. Worthley Matthew I. Worthley Department of Medicine University of Adelaide Adelaide Australia Cardiovascular Research Centre Royal Adelaide Hospital Adelaide Australia Department of Medicine University of Adelaide Adelaide Australia MonashHeart Monash Medical Centre Clayton Australia

The commonest cause of acute myocardial infarction involves the rupture or erosion of vulnerable atherosclerotic plaques followed by aggregation of platelets and subsequent thrombus formation, leading to partial or complete epicardial coronary arterial occlusion. Over the last 25 years, advancement in therapeutic options for acute myocardial infarction has resulted in substantial improvement in morbidity and mortality. As a result, the absolute risk reduction of in-hospital deaths for patients presenting with STEMI has been on the decline in the last decade. The focus of the treatment for acute myocardial infarction involves achieving epicardial and microvascular patency, prevention of recurrent ischaemic events while balancing the risk of bleeding. This involves antiplatelet and antithrombotic therapies or fibrinolytic agents when timely performance of primary percutaneous coronary intervention is not possible. We review the evolution of treatment strategies for STEMI that has contributed to the improvement in patient outcome.

关键词： Myocardial Infarction STEMI PCI Coronary Artery intervention