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5-Fluorouracil dose escalation generated desensitized colorectal cancer cells with reduced expression of protein methyltransferases and no epithelial-to-mesenchymal transition potential

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Oncology Research 2024年第6期32卷 1047-1061页

作者： KIMBERLY FENECH ISAAC MICALLEF BYRON BARON Centre for molecular Medicine and Biobanking University of MaltaMsidaMSD 2080Malta Department of tumor genetics and Biology Graduate School of Medical SciencesFaculty of Life SciencesKumamoto UniversityKumamoto860-8556Japan

Background:Colorectal cancer(CRC)is one of the most frequently diagnosed cancers.In many cases,the poor prognosis of advanced CRC is associated with resistance to treatment with chemotherapeutic drugs such as 5-Fluorouracil(5-FU).The epithelial-to-mesenchymal transition(EMT)and dysregulation in protein methylation are two mechanisms associated with chemoresistance in many cancers.This study looked into the effect of 5-FU dose escalation on EMT and protein methylation in CRC.Materials and Methods:HCT-116,Caco-2,and DLD-1 CRC cell lines were exposed to dose escalation treatment of 5-FU.The motility and invasive potentials of the cells before and after treatment with 5-FU were investigated through wound healing and invasion assays.This was followed by aWestern blot which analyzed the protein expressions of the epithelial marker E-cadherin,mesenchymal marker vimentin,and the EMT transcription factor(EMTTF),the snail family transcriptional repressor 1(Snail)in the parental and desensitized cells.Western blotting was also conducted to study the protein expressions of the protein methyltransferases(PMTs),Euchromatic histone lysine methyltransferase 2(EHMT2/G9A),protein arginine methyltransferase(PRMT5),and SET domain containing 7/9(SETD7/9)along with the global lysine and arginine methylation profiles.Results:The dose escalation method generated 5-FU desensitized CRC cells with distinct morphological features and increased tolerance to high doses of 5-FU.The 5-FU desensitized cells experienced a decrease in migration and invasion when compared to the parental cells.This was reflected in the observed reduction in E-cadherin,vimentin,and Snail in the desensitized cell lines.Additionally,the protein expressions of EHMT2/G9A,PRMT5,and SETD7/9 also decreased in the desensitized cells and global protein lysine and arginine methylation became dysregulated with 5-FU treatment.Conclusion:This study showed that continuous,dose-escalation treatment of 5-FU in CRC cells generated 5-FU desensitized cancer cells that seemed to be les

关键词： Chemoresistance Epithelial-to-mesenchymal transition Protein methylation Protein methyltransferases

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DNA methylation in poultry:a review

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Journal of Animal Science and Biotechnology 2024年第2期15卷 509-518页

作者： Xing Ju Zhijun Wang Danfeng Cai Semiu Folaniyi Bello Qinghua Nie State Key laboratory for Conservation and Utilization of Subtropical Agro‑Bioresources Lingnan Guangdong Laboratory of AgricultureCollege of Animal ScienceSouth China Agricultural UniversityGuangzhouGuangdong 510642China Guangdong Provincial Key lab of Agro‑Animal Genomics and molecular Breeding and Key lab of Chicken genetics Breeding and ReproductionMinistry of AgricultureGuangzhouGuangdong 510642China College of Animal Science and Technology Zhejiang Agriculture and Forestry University666 Wusu RoadLin’an 311300China

As an important epigenetic modification,DNA methylation is involved in many biological processes such as animal cell differentiation,embryonic development,genomic imprinting and sex chromosome inactivation.As DNA methylation sequencing becomes more sophisticated,it becomes possible to use it to solve more zoological problems.This paper reviews the characteristics of DNA methylation,with emphasis on the research and application of DNA methylation in poultry.

关键词： CpG islands Differentially methylated genes Differentially methylated regions DNA methylation Poultry

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molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer:Unravelling challenges and future directions

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World Journal of Gastroenterology 2024年第13期30卷 1815-1835页

作者： Samantha Sharma Naresh Singh Anita Ahmed Turk Isabella Wan Akshay Guttikonda Julia Lily Dong Xinna Zhang Mateusz Opyrchal Department of Medical and molecular genetics Indiana University School of MedicineIndianapolisIN 46202United States Division of Hematology/Oncology Department of MedicineIndiana University School of MedicineIndianapolisIN 46202United States Melvin and Bren Simon Comprehensive Cancer Center Indiana University School of MedicineIndianapolisIN 46202United States

Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely curable.Over the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint inhibitors.Therapies aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor immunity.These therapies thus have shown promising results in many clinical trials alone or in combination.The efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical trials.Clinical trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC.Unfortunately,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients.To this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response.This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC.The underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.

关键词： Colorectal cancer Immune checkpoint inhibitors Clinical trials Immunotherapy Microsatellite instability Microsatellite stability DNA mismatch repair

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TRAIL and Celastrol Combinational Treatment Suppresses Proliferation, Migration, and Invasion of Human Glioblastoma Cells via Targeting Wnt/β-catenin Signaling Pathway

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Chinese Journal of Integrative Medicine 2024年第4期30卷 322-329页

作者： QIN Jing-jing NIU Meng-da CHA Zhe GENG Qing-hua LI Yu-lin REN Chun-guang David P.Molloy YU Hua-rong Research Center of Neuroscience School of Basic Medical SciencesChongqing Medical UniversityChongqing(400016)China laboratory of Developmental Biology Department of Cell Biology and GeneticsSchool of Basic Medical SciencesChongqing Medical UniversityChongqing(400016)China Department of Biochemistry and molecular Biology School of Basic Medical SciencesChongqing Medical UniversityChongqing(400016)China

Objective To investigate the mechanistic basis for the anti-proliferation and anti-invasion effect of tumor necrosis factor-related apoptosis-induced ligand(TRAIL)and celastrol combination treatment(TCCT)in glioblastoma cells.Methods Cell counting kit-8 was used to detect the effects of different concentrations of celastrol(0-16µmol/L)and TRAIL(0-500 ng/mL)on the cell viability of glioblastoma cells.U87 cells were randomly divided into 4 groups,namely control,TRAIL(TRAIL 100 ng/mL),Cel(celastrol 0.5µmol/L)and TCCT(TRAIL 100 ng/mL+celastrol 0.5µmol/L).Cell proliferation,migration,and invasion were detected by colony formation,wound healing,and Transwell assays,respectively.Quantitative reverse transcription polymerase chain reaction and Western blotting were performed to assess the levels of epithelial-mesenchymal transition(EMT)markers(zona occludens,N-cadherin,vimentin,zinc finger E-box-binding homeobox,Slug,and β-catenin).Wnt pathway was activated by lithium chloride(LiCl,20 mol/L)and the mechanism for action of TCCT was explored.Results Celastrol and TRAIL synergistically inhibited the proliferation,migration,invasion,and EMT of U87 cells(P<0.01).TCCT up-regulated the expression of GSK-3β and down-regulated the expression of β-catenin and its associated proteins(P<0.05 or P<0.01),including c-Myc,Cyclin-D1,and matrix metalloproteinase(MMP)-2.In addition,LiCl,an activator of the Wnt signaling pathway,restored the inhibitory effects of TCCT on the expression of β-catenin and its downstream genes,as well as the migration and invasion of glioblastoma cells(P<0.05 or P<0.01).Conclusions Celastrol and TRAIL can synergistically suppress glioblastoma cell migration,invasion,and EMT,potentially through inhibition of Wnt/β-catenin pathway.This underlies a novel mechanism of action for TCCT as an effective therapy for glioblastoma.

关键词： celastrol Chinese medicine tumor necrosis factor-related apoptosis-induced ligand glioblastoma β-catenin Tripterygium wilfordii

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Nutrient restriction-activated Fra-2 promotes tumor progression via IGF1R in miR-15a downmodulated pancreatic ductal adenocarcinoma

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Signal Transduction and Targeted Therapy 2024年第3期9卷 1132-1146页

作者： Gian Luca Rampioni Vinciguerra Marina Capece Luca Reggiani Bonetti Giovanni Nigita Federica Calore Sydney Rentsch Paolo Magistri Roberto Ballarin Fabrizio Di Benedetto Rosario Distefano Roberto Cirombella Andrea Vecchione Barbara Belletti Gustavo Baldassarre Francesca Lovat Carlo M.Croce Department of Cancer Biology and genetics and Comprehensive Cancer Center The Ohio State UniversityColumbus 43210 OHUSA Department of Clinical and molecular Medicine Faculty of Medicine and PsychologySant’Andrea HospitalUniversity of Rome“Sapienza”Rome 00189Italy Department of Diagnostic Clinic and Public Health MedicineUniversity of Modena and Reggio EmiliaModena 41100Italy Hepato-pancreato-biliary Surgery and Liver Transplantation Unit University of Modena and Reggio EmiliaModena 41100Italy Division of molecular Oncology Centro di Riferimento Oncologico di Aviano(CRO)Istituto di Ricovero e Cura a Carattere Scientifico(IRCCS)National Cancer InstituteAviano 33081Italy

Pancreatic ductal adenocarcinoma(PDAC)is a lethal disease,characterized by an intense desmoplastic reaction that compresses blood vessels and limits nutrient supplies.PDAC aggressiveness largely relies on its extraordinary capability to thrive and progress in a challenging tumor microenvironment.Dysregulation of the onco-suppressor miR-15a has been extensively documented in PDAC.Here,we identified the transcription factor Fos-related antigen-2(Fra-2)as a miR-15a target mediating the adaptive mechanism of PDAC to nutrient deprivation.We report that the IGF1 signaling pathway was enhanced in nutrient deprived PDAC cells and that Fra-2 and IGF1R were significantly overexpressed in miR-15a downmodulated PDAC patients.Mechanistically,we discovered that miR-15a repressed IGF1R expression via Fra-2 targeting.In miR-15a-low context,IGF1R hyperactivated mTOR,modulated the autophagic flux and sustained PDAC growth in nutrient deprivation.In a genetic mouse model,Mir15aKO PDAC showed Fra-2 and Igf1r upregulation and mTOR activation in response to diet restriction.Consistently,nutrient restriction improved the efficacy of IGF1R inhibition in a Fra-2 dependent manner.Overall,our results point to a crucial role of Fra-2 in the cellular stress response due to nutrient restriction typical of pancreatic cancer and support IGF1R as a promising and vulnerable target in miR-15a downmodulated PDAC.

关键词： IGF1R Fra miR

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PCDH17 restricts dendritic spine morphogenesis by regulating ROCK2-dependent control of the actin cytoskeleton,modulating emotional behavior

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Zoological Research 2024年第3期45卷 535-550页

作者： Laidong Yu Fangfang Zeng Mengshu Fan Kexuan Zhang Jingjing Duan Yalu Tan Panlin Liao Jin Wen Chenyu Wang Meilin Wang Jialong Yuan Xinxin Pang Yan Huang Yangzhou Zhang Jia-Da Li Zhuohua Zhang Zhonghua Hu Hunan Key laboratory of molecular Precision Medicine Department of Critical Care MedicineXiangya HospitalCentral South UniversityChangshaHunan 410008China Center for Medical genetics and Hunan Key laboratory of Medical genetics School of Life SciencesCentral South UniversityChangshaHunan 410008China National Clinical Research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangshaHunan 410008China Hunan Provincial Clinical Research Center for Critical Care Medicine Xiangya HospitalCentral South UniversityChangshaHunan 410008China Hunan Key laboratory of Animal Models for Human Diseases School of Life SciencesCentral South UniversityChangshaHunan 410008China MOE Key lab of Rare Pediatric Diseases School of Life SciencesCentral South UniversityChangshaHunan 410008China Department of Neurosciences University of South China Medical SchoolHengyangHunan 421001China

Proper regulation of synapse formation and elimination is critical for establishing mature neuronal circuits and maintaining brain function.Synaptic abnormalities,such as defects in the density and morphology of postsynaptic dendritic spines,underlie the pathology of various neuropsychiatric disorders.Protocadherin 17(PCDH17)is associated with major mood disorders,including bipolar disorder and depression.However,the molecular mechanisms by which PCDH17 regulates spine number,morphology,and behavior remain elusive.In this study,we found that PCDH17 functions at postsynaptic sites,restricting the number and size of dendritic spines in excitatory neurons.Selective overexpression of PCDH17 in the ventral hippocampal CA1 results in spine loss and anxiety-and depression-like behaviors in mice.Mechanistically,PCDH17 interacts with actin-relevant proteins and regulates actin filament(F-actin)organization.Specifically,PCDH17 binds to ROCK2,increasing its expression and subsequently enhancing the activity of downstream targets such as LIMK1 and the phosphorylation of cofilin serine-3(Ser3).Inhibition of ROCK2 activity with belumosudil(KD025)ameliorates the defective F-actin organization and spine structure induced by PCDH17 overexpression,suggesting that ROCK2 mediates the effects of PCDH17 on F-actin content and spine development.Hence,these findings reveal a novel mechanism by which PCDH17 regulates synapse development and behavior,providing pathological insights into the neurobiological basis of mood disorders.

关键词： Synapse development Dendritic spine Mood disorder Actin cytoskeleton Animal behavior

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Extracellular vesicles as tools and targets in therapy for diseases

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Signal Transduction and Targeted Therapy 2024年第3期9卷 872-912页

作者： Mudasir A.Kumar Sadaf K.Baba Hana Q.Sadida Sara Al.Marzooqi Jayakumar Jerobin Faisal H.Altemani Naseh Algehainy Mohammad A.Alanazi Abdul-Badi Abou-Samra Rakesh Kumar Ammira S.Al-Shabeeb Akil Muzafar A.Macha Rashid Mir Ajaz A.Bhat Watson-Crick Centre for molecular Medicine Islamic University of Science and TechnologyAwantiporaKashmir 192122India Department of Human genetics-Precision Medicine in Diabetes Obesity and Cancer ProgramSidra MedicineDohaQatar Qatar Metabolic Institute Academic Health SystemHamad Medical CorporationDohaQatar Department of Medical laboratory Technology Prince Fahad Bin Sultan Chair for Biomedical ResearchFaculty of Applied Medical SciencesUniversity of TabukTabukSaudi Arabia School of Biotechnology Shri Mata Vaishno Devi UniversityKatraIndia

Extracellular vesicles(EVs)are nano-sized,membranous structures secreted into the extracellular space.They exhibit diverse sizes,contents,and surface markers and are ubiquitously released from cells under normal and pathological conditions.Human serum is a rich source of these EVs,though their isolation from serum proteins and non-EV lipid particles poses challenges.These vesicles transport various cellular components such as proteins,mRNAs,miRNAs,DNA,and lipids across distances,influencing numerous physiological and pathological events,including those within the tumor microenvironment(TME).Their pivotal roles in cellular communication make EVs promising candidates for therapeutic agents,drug delivery systems,and disease biomarkers.Especially in cancer diagnostics,EV detection can pave the way for early identification and offers potential as diagnostic biomarkers.Moreover,various EV subtypes are emerging as targeted drug delivery tools,highlighting their potential clinical significance.The need for non-invasive biomarkers to monitor biological processes for diagnostic and therapeutic purposes remains unfulfilled.Tapping into the unique composition of EVs could unlock advanced diagnostic and therapeutic avenues in the future.In this review,we discuss in detail the roles of EVs across various conditions,including cancers(encompassing head and neck,lung,gastric,breast,and hepatocellular carcinoma),neurodegenerative disorders,diabetes,viral infections,autoimmune and renal diseases,emphasizing the potential advancements in molecular diagnostics and drug delivery.

关键词： diseases sized sizes

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T8590C polymorphism of CYP4A11 is a risk factor for hypertension： a meta-analysis

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Chinese Medical Journal 2014年第12期127卷 2382-2385页

作者： Jiang Yuan Hou Jing Zhang Qiang Tang Wenru Luo Ying lab of molecular genetics of aging and tumor Faculty of Life Science and Technology Kunming University of Science and TechnologyKunmingYunnan 650500China lab of molecular genetics of aging and tumor Medical Faculty Kunming University of Science and TechnologyKunmingYunnan 650500China

Background T8590C polymorphism of CYP4A11 has been associated with hypertension,though with conflicting results.The aim of this study was to quantitatively summarize the evidence for CYP4A 11 T8590C polymorphism and hypertension risk.Methods Electronic search of PubMed and the Chinese Biomedicine database was conducted to select studies.Casecontrol studies containing available genotype frequencies of T8590C were chosen,and odds ratio （OR） with 95％ confidence interval （CI） was used to assess the strength of this association.Results Seven case-control studies,including 3 295 cases and 3 192 controls,were identified.The meta-analysis,stratified by ethnicity,showed that individuals with the C allele carriers （CC＋CT） had increased risk of hypertension in over all （OR=1.184,95％ CI：1.063-1.319,P=0.002） and in others （OR=1.217,95％ CI：1.045-1.419,P=0.012）.The results among Asians did not suggest an association （OR=1.152,95％ CI：0.990-1.342,P=0.068）.A symmetric funnel plot,the Egger＇s test （P=0.863）,and the Begg test （P=0.393） were all suggestive of the lack of publication bias.Conclusions This meta-analysis suggests the CYP4A11 T8590C polymorphism may be a risk factor for hypertension.Future well-designed large studies might be necessary to validate this association in different populations incorporated with environmental factors in the susceptibility of hypertension.

关键词： CYP 4A11 meta-analysis hypertension

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PICOTEES:a privacy-preserving online service of phenotype exploration for genetic-diagnostic variants from Chinese children cohorts

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Journal of genetics and Genomics 2024年第2期51卷 243-251页

作者： Xinran Dong Yulan Lu Lanting Guo Chuan Li Qi Ni Bingbing Wu Huijun Wang Lin Yang Songyang Wu Qi Sun Hao Zheng Wenhao Zhou Shuang Wang Center for molecular Medicine Children's Hospital of Fudan UniversityShanghai 201102China Key laboratory of Birth Defects Children's Hospital of Fudan UniversityShanghai 201102China Department of Bioinformatics Hangzhou Nuowei Information Technology Co.LtdHangzhouZhejiang 310000China The Third Research Institute of the Ministry of Public Security Shanghai 200031China Xiamen Campus of Children's Hospital of Fudan University XiamenFujian 361006China Institutes for Systems genetics West China HospitalChengduSichuan 610041China Shanghai Putuo People's Hospital Tongji UniversityShanghai 200060China

The growth in biomedical data resources has raised potential privacy concerns and risks of genetic information leakage. For instance, exome sequencing aids clinical decisions by comparing data through web services, but it requires significant trust between users and providers. To alleviate privacy concerns, the most commonly used strategy is to anonymize sensitive data. Unfortunately, studies have shown that anonymization is insufficient to protect against reidentification attacks. Recently, privacy-preserving technologies have been applied to preserve application utility while protecting the privacy of biomedical data. We present the PICOTEES framework, a privacy-preserving online service of phenotype exploration for genetic-diagnostic variants (https://***:3000/). PICOTEES enables privacy-preserving queries of the phenotype spectrum for a single variant by utilizing trusted execution environment technology, which can protect the privacy of the user's query information, backend models, and data, as well as the final results. We demonstrate the utility and performance of PICOTEES by exploring a bioinformatics dataset. The dataset is from a cohort containing 20,909 genetic testing patients with 3,152,508 variants from the Children's Hospital of Fudan University in China, dominated by the Chinese Han population (>99.9%). Our query results yield a large number of unreported diagnostic variants and previously reported pathogenicity.

关键词： Privacy protecti on Rare diseases in children Genetic testing Web system Trusted executi on envir onment

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A Study of Radiation-Induced Telomere Instability Using Multiplex Ligation-Dependent Probe Amplification (MLPA)

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Advances in Biological Chemistry 2024年第3期14卷 73-85页

作者： Alan Chant Ahmad Chaudary Christina M. Kraemer-Chant Department of Microbiology and molecular genetics University of Vermont Burlington VT USA Department of Public and Allied Health Bowling Green State University Bowling Green OH USA Department of Chemistry Saint Michaels College Colchester VT USA

The integrity of the chromosomes for two WIL2-derived lymphoblastoid cell lines (TK6 and WTK1) in the presence and absence of ionizing radiation was analyzed by Multiplex Ligation-Dependent Probe Amplification (MLPA). The TK6 cell line has the native p53 tumor-suppressor gene, whereas WTK1 cells contain a p53 mutation. Each cell line was isolated pre- and post-irradiation (2 and 3 Gy) and analyzed by MLPA. The impact of irradiation on these two cell lines was investigated using probes that target specific regions on chromosomes associated with subtelomeric regions. Results indicate that WTK1 and TK6 are impacted differently after irradiation, and that each cell line presents its own unique MLPA profile. The most notable differences are the appearance of a number of probes in the post-irradiated MLPA profile that are not present in the controls, and two unique probe signals only seen in WTK1 cells. These results build on our previous studies that indicate how different human cell lines can be affected by radiation in significantly different ways depending on the presence or absence of wild type p53.

关键词： Ionizing Radiation Multiplex Ligation-Dependent Probe Amplification (MLPA) p53 tumor Suppressor Telomere Instability

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