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妊娠合并乙肝病毒感染患者血清dnmt1、TIM-3与HBV-DNA病毒载量和妊娠结局的关系分析

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现代生物医学进展 2024年第4期24卷 656-660,728页

作者：李倩睿唐娟张永男丁祎张觅孙丽洲南京医科大学第一附属医院产科江苏南京210000 南京市第二医院妇产科江苏南京210037 南京市第二医院检验科江苏南京210037

目的:探讨妊娠合并乙肝病毒(HBV)感染患者血清脱氧核糖核酸甲基转移酶1(dnmt1)、T细胞免疫球蛋白粘蛋白-3(TIM-3)与乙型肝炎病毒-脱氧核糖核酸(HBV-DNA)病毒载量和妊娠结局的关系。方法:选取2021年1月~2022年1月南京医科大学第一附属医... 详细信息

目的:探讨妊娠合并乙肝病毒(HBV)感染患者血清脱氧核糖核酸甲基转移酶1(dnmt1)、T细胞免疫球蛋白粘蛋白-3(TIM-3)与乙型肝炎病毒-脱氧核糖核酸(HBV-DNA)病毒载量和妊娠结局的关系。方法:选取2021年1月~2022年1月南京医科大学第一附属医院收治的186例妊娠合并HBV感染患者为HBV感染组,根据HBV-DNA病毒载量分为阳性组56例和阴性组130例,根据妊娠结局分为结局不良组和结局良好组,另选取同期于南京医科大学第一附属医院进行孕检的150名健康孕妇为对照组。采用酶联免疫吸附法检测血清dnmt1、TIM-3水平。比较HBV感染组与对照组、阳性组与阴性组血清dnmt1、TIM-3水平。采用单因素及多因素Logistic回归分析妊娠合并HBV感染患者妊娠结局不良的影响因素,受试者工作特征(ROC)曲线分析血清dnmt1、TIM-3水平对妊娠合并HBV感染患者妊娠结局不良的预测价值。结果:与对照组比较,HBV感染组血清dnmt1、TIM-3水平升高(Pdnmt1、TIM-3水平升高(P186例妊娠合并HBV感染患者妊娠结局不良发生率为55.38%(103/186)。单因素分析显示,妊娠结局不良与HBV感染孕周、HBV-DNA病毒载量、谷草转氨酶(AST)、谷丙转氨酶(ALT)、dnmt1、TIM-3有关(Pdnmt1>34.94 ng/mL、TIM-3>18.96 pg/mL为妊娠合并HBV感染患者妊娠结局不良的独立危险因素(Pdnmt1、TIM-3水平单独和联合检测预测妊娠合并HBV感染患者妊娠结局不良的曲线下面积分别为0.798、0.791、0.870。结论:妊娠合并HBV感染患者血清dnmt1、TIM-3水平升高与HBV-DNA病毒载量阳性和妊娠结局不良密切相关,血清dnmt1、TIM-3水平联合对妊娠合并HBV感染患者妊娠结局预测价值良好。

关键词：妊娠乙肝病毒感染 dnmt1 TIM-3 HBV-DNA 妊娠结局

Decitabine induces IRF7-mediated immune responses in p53-mutated triple-negative breast cancer:a clinical and translational study

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Frontiers of Medicine 2024年第2期18卷 357-374页

作者： Haoyu Wang Zhengyuan Wang Zheng Wang Xiaoyang Li Yuntong Li Ni Yan Lili Wu Ying Liang Jiale Wu Huaxin Song Qing Qu Jiahui Huang Chunkang Chang Kunwei Shen Xiaosong Chen Min Lu Department of General Surgery Comprehensive Breast Health CenterRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai200025China Shanghai Institute of Hematology State Key Laboratory of Medical GenomicsNational Research Center for Translational Medicine(Shanghai)Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai200025China Department of Hematology Shanghai Institute of HematologyRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai200025China Department of Hematology Shanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghai200025China

p53 is mutated in half of cancer cases.However,no p53-targeting drugs have been approved.Here,we reposition decitabine for triple-negative breast cancer(TNBC),a subtype with frequent p53 mutations and extremely poor prognosis.In a retrospective study on tissue microarrays with 132 TNBC cases,dnmt1 overexpression was associated with p53 mutations(P=0.037)and poor overall survival(OS)(P=0.010).In a prospective DEciTabinE and Carboplatin in TNBC(DETECT)trial(NCT03295552),decitabine with carboplatin produced an objective response rate(ORR)of 42%in 12 patients with stage IV TNBC.Among the 9 trialed patients with available TP53 sequencing results,the 6 patients with p53 mutations had higher ORR(3/6 vs.0/3)and better OS(16.0 vs.4.0 months)than the patients with wild-type p53.In a mechanistic study,isogenic TNBC cell lines harboring DETECT-derived p53 mutations exhibited higher dnmt1 expression and decitabine sensitivity than the cell line with wild-type p53.In the DETECT trial,decitabine induced strong immune responses featuring the striking upregulation of the innate immune player IRF7 in the p53-mutated TNBC cell line(upregulation by 16-fold)and the most responsive patient with TNBC.Our integrative studies reveal the potential of repurposing decitabine for the treatment of p53-mutated TNBC and suggest IRF7 as a potential biomarker for decitabine-based treatments.

关键词： p53 mutation triple-negative breast cancer decitabine dnmt1 IRF7 innate immune response

A SLC31A1-MEK-dnmt1-miR-124 feedback loop contributes to pancreatic cancer progression

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Genes & Diseases 2023年第3期10卷 654-656页

作者： Jing Jin Mingjun Ma Bingru Yan Botao Qiu Shounan Lu Lin Yang Yuzhe Nie Sheng Tai Ze Yu Chun-Bo Teng College of Life Science Northeast Forestry UniversityHarbinHeilongjiang 150040China Department of Minimally Invasive Hepatic Surgery The First Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiang 150007China Department of Hepatic Surgery The Second Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiang 150086China

Although the role of copper (Cu) in promoting KRas- or BRaf-mutation driven cancers via activating MEK1/2 kinases is known, the mechanism by which the copper transporter SLC31A1 (CTR1) is upregulated in pancreatic cancer (PDAC, KRas mutation) is not defined. In this study, we provide evidence that MEK signal maintains a high level of SLC31A1 through silencing the expression of miR-124-3P (miR-124) via a novel MEK-dnmt1-miR-124 feedback loop in PDAC cells. Further, we reveal that miR-124 directly targets suppression of SLC31A1, and miR-124 introduction together with tetrathiomolybdate (TM) treatment hampered pancreatic cancer growth in vitro and in vivo. Our results demonstrate that a SLC31A1-MEK-dnmt1-miR-124 feedback loop is an important pathway to maintain copper absorption and promote pancreatic cancer progression, and we hope to provide a Cu-chelation as an adjuvant treatment strategy, to block the progression in Kras mutant PDAC patients.

关键词： dnmt1 SLC treatment

Matrix stiffness exacerbates the proinflammatory responses of vascular smooth muscle cell through the DDR1-dnmt1 mechanotransduction axis

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Bioactive Materials 2022年第11期7卷 406-424页

作者： Jin Wang Si-an Xie Ning Li Tao Zhang Weijuan Yao Hucheng Zhao Wei Pang Lili Han Jiayu Liu Jing Zhou Department of Physiology and Pathophysiology School of Basic Medical SciencesHemorheology CenterSchool of Basic Medical SciencesPeking UniversityBeijingPR China Key Laboratory of Molecular Cardiovascular Science Ministry of EducationBeijingPR China National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides Beijing Key Laboratory of Cardiovascular Receptors ResearchPeking UniversityBeijingPR China Department of Gastroenterology Beijing Friendship HospitalCapital Medical UniversityNational Clinical Research Center for Digestive DiseaseBeijing Digestive Disease CenterBeijing Key Laboratory for Precancerous Lesion of Digestive DiseaseBeijingPR China Center for Biomechanics and Bioengineering Key Laboratory of Microgravity(National Microgravity Laboratory)And Beijing Key Laboratory of Engineered Construction and MechanobiologyInstitute of MechanicsChinese Academy of SciencesBeijingPR China School of Engineering Sciences University of Chinese Academy of SciencesBeijingPR China Department of Vascular Surgery Peking University People’s HospitalBeijingPR China Institute of Biomechanics and Medical Engineering School of Aerospace EngineeringTsinghua UniversityBeijingPR China

Vascular smooth muscle cell (vSMC) is highly plastic as its phenotype can change in response to mechanical cues inherent to the extracellular matrix (ECM). VSMC may be activated from its quiescent contractile phenotype to a proinflammatory phenotype, whereby the cell secretes chemotactic and inflammatory cytokines, e.g. MCP1 and IL6, to functionally regulate monocyte and macrophage infiltration during the development of various vascular diseases including arteriosclerosis. Here, by culturing vSMCs on polyacrylamide (PA) substrates with variable elastic moduli, we discovered a role of discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase that binds collagens, in mediating the mechanical regulation of vSMC gene expression, phenotype, and proinflammatory responses. We found that ECM stiffness induced DDR1 phosphorylation, oligomerization, and endocytosis to repress the expression of DNA methyltransferase 1 (dnmt1), very likely in a collagen-independent manner. The DDR1-to-dnmt1 signaling was sequentially mediated by the extracellular signal-regulated kinases (ERKs) and p53 pathways. ECM stiffness primed vSMC to a proinflammatory phenotype and this regulation was diminished by DDR1 inhibition. In agreement with the in vitro findings, increased DDR1 phosphorylation was observed in human arterial stiffening. DDR1 inhibition in mouse attenuated the acute injury or adenine diet-induced vascular stiffening and inflammation. Furthermore, mouse vasculature with SMC-specific deletion of dnmt1 exhibited proinflammatory and stiffening phenotypes. Our study demonstrates a role of SMC DDR1 in perceiving the mechanical microenvironments and down-regulating expression of dnmt1 to result in vascular pathologies and has potential implications for optimization of engineering artificial vascular grafts and vascular networks.

关键词： Matrix stiffness Inflammation DDR1 dnmt1 Mechanotransduction

The dnmt1-PAS1-PH20 axis drives breast cancer growth and metastasis

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Signal Transduction and Targeted Therapy 2022年第4期7卷 1311-1321页

作者： Yenan Fu Xi Zhang Xiao Liu Peng Wang Wenhui Chu Wei Zhao Yunling Wang Guangbiao Zhou Yu Yu Hongquan Zhang Program for Cancer and Cell Biology Department of Human AnatomyHistology and EmbryologySchool of Basic Medical SciencesPKU International Cancer InstituteMOE Key Laboratory of Carcinogenesis and Translational Research and State Key Laboratory of Natural and Biomimetic DrugsPeking University Health Science CenterBeijing 100191China Department of Orthopedics Peking University Third HospitalBeijing 100191China Institute for Cardiovascular Research Peking UniversityBeijing 100191China State Key Laboratory of Molecular Oncology National Cancer CenterNational Clinical Research Center for CancerCancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

PH20 is a member of the human hyaluronidase family that degrades hyaluronan in the extracellular matrix and controls tumor progression.Inhibition of DNA methyltransferases(dnmts)leads to elevated hyaluronan levels;however,whether dnmt inhibitors control PH20 remains unclear.Here,we report that the dnmt1 inhibitor,decitabine,suppresses PH20 expression by activating the long non-coding RNA PHACTR2-AS1(PAS1).PAS1 forms a tripartite complex with the RNA-binding protein vigilin and histone methyltransferase SUV39H1.The interaction between PAS1 and vigilin maintains the stability of PAS1.Meanwhile,PAS1 recruits SUV39H1 to trigger the H3K9 methylation of PH20,resulting in its silencing.Functionally,PAS1 inhibits breast cancer growth and metastasis,at least partially,by suppressing PH20.Combination therapy of decitabine and PAS1-30nt-RNA,which directly binds to SUV39H1,effectively blocked breast cancer growth and metastasis in mice.Taken together,dnmt1,PAS1,and PH20 comprise a regulatory axis to control breast cancer growth and metastasis.These findings reveal that the dnmt1-PAS1-PH20 axis is a potential therapeutic target for breast cancer.

关键词： metastasis breast dnmt1

白背飞虱dnmt1基因的结构特点及在雌雄成虫中的差异表达

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中山大学学报（自然科学版）（中英文） 2022年第2期61卷 76-81页

作者：何静怡杨梅林佳梁安文李广宏王方海有害生物控制与资源利用国家重点实验室/中山大学生命科学学院广东广州510275

DNA甲基转移酶1(dnmt1)是基因组DNA甲基化关键酶之一,在生物的生长发育过程中起到重要的调控作用。本研究在白背飞虱(Sogatella furcifera)转录组测序结果中找到一条带有起始密码子ATG和终止密码子TGA的dnmt1基因的cDNA序列,全长为4524 ... 详细信息

DNA甲基转移酶1(dnmt1)是基因组DNA甲基化关键酶之一,在生物的生长发育过程中起到重要的调控作用。本研究在白背飞虱(Sogatella furcifera)转录组测序结果中找到一条带有起始密码子ATG和终止密码子TGA的dnmt1基因的cDNA序列,全长为4524 bp,编码的蛋白质具有dnmt1的典型结构:位于N端的DN⁃MT相关蛋白结合结构域,复制灶靶向序列,富含半胱氨酸的锌指结构域和聚溴同源结构域,以及位于C端的催化结构域。进一步与白背飞虱全基因组序列进行比对,发现白背飞虱dnmt1基因位于白背飞虱第3号染色体上,全长为22567 bp,含有18个外显子和17个内含子。该基因主要在白背飞虱腹部表达,且在雌成虫中的表达量明显高于雄成虫,达4.3倍。本研究将增进对昆虫dnmts的具体结构和生物学功能的认识,并为探索新的防治稻飞虱的方法或途径提供理论基础。

关键词： dnmt1 白背飞虱(Sogatella furcifera) 开放阅读框基因表达

Protein expression trends of dnmt1 in gastrointestinal diseases:From benign to precancerous lesions to cancer

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World Journal of Gastrointestinal Oncology 2019年第12期11卷 1141-1150页

作者： Tian-Miao Ma Li-Ping Sun Nan-Nan Dong Ming-Jun Sun Yuan Yuan Department of Gastroenterology the First Hospital of China Medical UniversityShenyang 110001Liaoning ProvinceChina Tumor Etiology and Screening Department of Cancer Institute and General Surgery the First Hospital of China Medical UniversityShenyang 110001Liaoning ProvinceChina

BACKGROUND In recent years,the incidence of gastrointestinal(GI)cancer in China has increased annually.Early detection and appropriate therapy are considered to be the key to treat GI cancer.dnmt1 takes an active part in the advancement of GI cancer,which will change as the disease progresses.But its expression characteristics in the dynamic variations of GI carcinogenesis are still unclear.AIM To investigate the expression characteristics of dnmt1 in different GI diseases.METHODS We detected the expression of dnmt1 in 650 cases of different GI diseases by immunohistochemistry,including 90 cases of chronic superficial gastritis(CSG),72 cases of atrophic gastritis with intestinal metaplasia(AG/GIM),54 cases of low-grade intraepithelial neoplasia(GLIN),66 cases of high-grade intraepithelial neoplasia(GHIN),71 cases of early gastric cancer(EGC),90 cases of normal intestinal mucosa(NIM),54 cases of intestinal low-grade intraepithelial neoplasia(ILIN),71 cases of intestinal high-grade intraepithelial neoplasia(IHIN),and 82 cases of early colorectal cancer(ECRC).RESULTS In the CSG group,all cases showed weakly positive or negative expression of dnmt1.However,in other four groups(AG/GIM,GLIN,GHIN,and EGC),the positive expression rate gradually increased with the severity of the diseases;the negative or weakly positive cases accounted for 55.56%(40/72),38.89%(21/54),1.52%(1/66),and 1.41%(1/71),respectively.Besides,the moderately positive cases were 44.44%(32/72),57.41%(31/54),80.30%(53/66),and 43.66%(31/71),respectively.The strongly positive cases only existed in the GLIN(3.70%,2/54),GHIN(18.18%,12/66),and EGC(54.93%,39/71)groups.The differences between any two groups were statistically significant(Pdnmt1 were predominant(91.11%,82/90),and the rest were moderately positive cases(8.89%,8/90).In the ILIN,IHIN,and ECRC groups,the rates of cases with weak or negative expression of dnmt1 were 46.30%(25/54),12.68%(9/71),and 4.88%(4/82),respectively;with

关键词： Gastric cancer Colorectal cancer dnmt1 Precancerous lesion Intraepithelial neoplasia

Effects on Biological Behavior of Bladder Carcinoma T24 Cells via Silencing dnmt1 and/or dnmt3b with shRNA In Vitro

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2009年第2期29卷 215-219页

作者：张士龙曾甫清彭世波朱朝辉李恒汪良 Department of Urology Union HospitalTongji Medical CollegeHuazhong University of Science and Technology

In this study, RNA interference technique was employed to silence the expression of dnmt1 and/or dnmt3b in human bladder cancer T24 cells. The expression levels of their mRNA and protein were greatly decreased by up to 75% and 65% respectively after T24 cells were trans- fected with lipofectamine2000 for 72 h, indicating RNA interference is an effective tool in gene knockdown. Proliferation and apoptosis of T24 cells were detected by MTT, and annexin-V-FITC and propidium iodide staining flow cytometry, respectively. It was found that loss of the dnmt1 or dnmt3b expression could inhibit the cell growth and promote the cell apoptosis to some extent. However, combined treatment with shRNA targeting both dnmt1 and dnmt3b mRNA could obviously enhance the above effects. It was concluded that simultaneously silencing both genes could result in strong suppressing effect on tumor proliferation and promoting cell apoptosis than separate use, suggesting combined use of dnmt1 and dnmt3b can achieve a synergistic effect in the CpG island methylation in human bladder tumorigenesis.

关键词： dnmt1 dnmt3b apoptosis proliferation bladder cancer

基于甲基化修饰逆转探讨参术白胡颗粒治疗胃癌作用机制

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中国医院药学杂志 2024年第7期44卷 772-780页

作者：刘盼盼任伟宏张旭冉苗晋鑫李文博韩文彦冯倩冯慧洁荣昊贺娇张振强河南中医药大学第一附属医院检验科河南郑州450000 河南中医药大学第一临床医学院河南郑州450046

目的:预测并验证参术白胡颗粒甲基化调控位点,探讨其治疗胃癌的作用机制。方法:采用NSG裸鼠胃癌模型验证参术白胡颗粒(下称“参术”)的抗肿瘤作用。通过TCMSP、DrugBank、UniProt及PubChem数据库检索参术中的有效化学成分和作用靶点,在G... 详细信息

目的:预测并验证参术白胡颗粒甲基化调控位点,探讨其治疗胃癌的作用机制。方法:采用NSG裸鼠胃癌模型验证参术白胡颗粒(下称“参术”)的抗肿瘤作用。通过TCMSP、DrugBank、UniProt及PubChem数据库检索参术中的有效化学成分和作用靶点,在GeneCards、MalaCards和GEO数据库中获取胃癌差异表达基因,利用Venny 2.1.0将两者取交集获得参术治疗胃癌的潜在靶点。在STRING 11.5数据库构建蛋白相互作用网络图,利用DAVID数据库进行GO功能分析和KEGG通路富集分析,并通过Cytoscape软件构建“药物-成分-靶标-疾病-通路”网络图,从而筛选出参术治疗胃癌的关键通路和核心靶点。通过AutoDockTools 1.1.2软件将有效成分和核心靶点进行分子对接验证,使用Pymol软件进行作图结果可视化。最后采用RT-qPCR、Western blot和免疫组化法验证靶基因。结果:给药12 d后,治疗组模型鼠肿瘤体积和质量均显著小于对照组(P1个胃癌差异基因交集后得到15个靶基因。GO和KEGG分析得到11条通路和两个甲基化修饰的主要基因——dnmt1和EZH2。研究发现治疗组肿瘤组织中dnmt1和EZH2表达显著下降(Pdnmt1和EZH2有对接活性。结论:参术白胡颗粒中金合欢素、木犀草素、槲皮素等7种关键有效活性成分可作用于dnmt1和EZH2核心靶蛋白,逆转DNA/组蛋白甲基化修饰,发挥抑制胃癌生长的药理作用。

关键词：胃癌参术白胡颗粒 dnmt1 EZH2 DNA甲基化组蛋白修饰