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Induction of HLA-G expression in a melanoma cell line OCM-1A following the treatment with 5-aza-2'-deoxycytidine

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Cell Research 2005年第7期15卷 523-531页

作者： Chien Chung CHANG,Soldano FERRONE Department of Immunology Roswell Park Cancer Institute Buffalo.NY 14263 USA Department of Immunology Roswell Park Cancer Institute Buffalo.NY 14263 USA

The non-classical HLA class I antigen HLA-G is an immune modulator which inhibits the functions of T cells, NK cells, and the Dendritic cells (DC). As a result, HLA-G expression in malignant cells may provide them with a mechanism to escape the immune surveillance. In melanoma, HLA-G antigen expression has been found in 30% of surgically removed lesions but in less than 1% of established cell lines. One possible mechanism underlying the differential HLA-G expression in vivo and in vitro is that the HLA-G gene is epigenetically repressed in melanoma cells in vitro. To test this hypothesis, we treated the HLA-G negative melanoma cell line OCM-1A with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-AC) and analyzed whether HLA-G expression can be restored. Our data strongly suggest that HLA-G is silenced as a result of CpG hypermethylation within a 5' regulatory region encompassing 220 bp upstream of the start codon. After treatment, HLA-G mRNA expression was dramatically increased. Western blot and flow cytometry showed that HLA-G protein was induced. Interestingly, HLA-G cell surface expression on the 5-AC treated OCM-1 A cells is much less than that on the HLA-G positive JEG-3 cells while a similar amount of total HLA-G was observed. Possible mechanisms for the difference were analyzed in the study such as cell cold-treatment, peptide loading and antigen processing machinery components (APM) as well as β2 microglobulin (β2-m) expression. Data revealed that the APM component calreticulin might be involved in the lower HLA-G surface expression on OCM-1 A cells. Taken together, our results indicated that DNA methylation is an important epigenetic mechanism by which HLA-G antigen expression is modulated in melanoma cells in vitro. Furthermore, to the first time, we hypothesized that the deficiency of calreticulin might be involved in the low HLA-G surface expression on the 5-AC treated OCM-1 A cells.

关键词： HLA-G methylation 5-aza-2’-deoxycytidine APM.

5-aza-2’-deoxycytidine暴露对新生大鼠精子发生的影响

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环境与职业医学 2009年第2期26卷 136-139页

作者：李克勇肖武生吴庆常秀丽周志俊张杰苏德奇复旦大学公共卫生学院劳动卫生教研室上海200032 新疆医科大学公共卫生学院新疆乌鲁木齐830011

[目的]探讨暴露于DNA甲基化抑制剂5-aza-2’-deoxycytidine(5-aza-CdR)对新生SD大鼠生长发育和成年精子发生的影响。[方法]新生大鼠随机分为3组,每组24只雄鼠。自出生第3天(postnatal day 3,PND 3)开始经口给予5-aza-CdR 25、250μg/kg... 详细信息

[目的]探讨暴露于DNA甲基化抑制剂5-aza-2’-deoxycytidine(5-aza-CdR)对新生SD大鼠生长发育和成年精子发生的影响。[方法]新生大鼠随机分为3组,每组24只雄鼠。自出生第3天(postnatal day 3,PND 3)开始经口给予5-aza-CdR 25、250μg/kg,对照组给予等量的溶剂。连续暴露5d,最后一次暴露结束后24h,处死半数雄鼠(幼鼠)。剩余部分继续喂养至12周龄(成鼠),乙醚麻醉。取睾丸组织做病理学检查、精子头计数等,附睾做精子畸形检查。[结果]随着剂量的增加,幼鼠体重出现下降趋势,与对照组比较差异有统计学意义(P5)。组织病理学发现幼鼠睾丸组织中出现空泡变性。检查发现染毒结束后继续喂养至12周的成鼠睾丸组织无明显形态和组织学变化;但每克睾丸组织精子头计数及每日精子生成量随幼年时暴露剂量增加呈现下降趋势(P5),而精子畸形率随剂量增加呈现上升趋势(P5)。[结论]新生大鼠对DNA甲基化抑制制5-aza-CdR生殖毒性作用敏感,低剂量短时间的暴露即可引起成年期生殖功能的异常。

关键词： 5-aza-2’-deoxycytidine 生长发育精子形成

Gene Expression Profiling of Human Myeloid Leukemic MV4-11 Cells Treated with 5-aza-2’-deoxycytidine

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Journal of Cancer Therapy 2012年第3期3卷 177-182页

作者： Kyu-Tae Kim David Mossman Donald Small Rodney J. Scott Division of Genetics Hunter Area Pathology Service John Hunter Hospital New Lambton Australia School of Biomedical Sciences and Pharmacy Faculty of Health University of Newcastle Callaghan Australia School of Medicine Johns Hopkins University Baltimore USA

The pyrimidine analog, 5-aza-2’-deoxycytidine (5-aza-dC) is a DNA methyltransferase inhibitor that triggers DNA demethylation leading to the reactivation of epigenetically silenced tumor suppressor genes. To understand the shift in gene expression which mediates the beneficial 5-aza-dC effects in leukemia, we have treated human myeloid derived leukemic cells with 5-aza-dC. Target genes were identified first in MV4-11 cells using a genome-wide gene expression profiling assay to detect differences in treated and untreated cells. From this analysis six genes were identified (HOXA4, HOXD4, HOXA8, HOXD12, CD9 and RGS2) as being significantly different expressed after treatment. To validate microarray data, we performed quantitative PCR on these genes from multiple leukemic cells. The results suggest that these genes are epigenetically regulated indicating that dysregulation of HOXA4, HOXD4, HOXA8, HOXD12, CD9 and RGS2 expression may play an important role in establishing the malignant phenotype in AML.

关键词： 5-aza-2’-deoxycytidine Gene Expression Profile HOX CD9 RGS2

Combined treatment with valproic acid and 5-aza-2'-deoxycytidine synergistically inhibits human clear cell renal cell carcinoma growth and migration

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Combined treatment with valproic acid and 5-Aza-2'-deoxycyti...

Study on the Synthesis Process of 5-aza-2'-deoxycytidine by Immobilized Deoxynucleotidyl Transferase

第十二届全国免疫学学术大会

作者： Xi Wenjin Chen Xu Lin Zhifeng Zuo Baile Wang Wei Wu Jieheng Yang Angang Wang Tao Department of Immunology Fourth Military Medical University Fourth Military Medical University Department of Medical Genetics and Developmental Biology Fourth Military Medical University

Background:Histone acetylation and DNA methylation are important mammalian epigenetic modifications that participate in the regulation of gene *** dysregulation of histone deacetylase and DNA methyltransferases are hallmarks of malignancy,they have become promising therapeutic *** this study,we explored the antitumor activity of valproic acid(VPA),a histone deacetylase inhibitor(HDACi) and 5-aza-2’-deoxycytidine(5-aza),an inhibitor of DNA methyltransferases,on renal cell carcinoma(RCC) cell lines 786-0 and ***:To analyze the impact of VPA,5-aza and their combination on ***:The cell proliferation was detected by xCELLigence RTCA DP Instrument,viability by CCK8 assay,cell apoptosis and cell cycle by flow cytometry,and cell migration by wound healing assay,transwell assay and xCELLigence RTCA DP ***:We discovered that VPA and 5-aza could individually induce decreased viability and have an inhibitory effect on the proliferation of 786-0 and 769-P *** anti-growth effect was more pronounced when the cells were treated with both VPA and *** combination of VPA and 5-aza also elicited more apoptosis and produced more cell cycle arrest in the G1 phase for both cell *** the other hand,treatment of RCC cells with VPA,5-aza,or a combination of both resulted in slow wound healing and impaired ***:These findings clearly demonstrated that VPA combined with 5-aza could significantly increase anti-RCC effects by inhibiting cellular proliferation,inducing apoptosis,promoting cell cycle arrest and prohibiting the migration of human RCC cells.

关键词： Valproic acid 5-aza-2’-deoxycytidine Renal cell carcinoma Proliferation Migration

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Study on the Synthesis Process of 5-Aza-2'-deoxycytidine by ...

Silence of HIN-1 expression through methylation of its gene promoter in gastric cancer

河南省化学会2016年学术年会

作者： Li-Juan Guo Tao Li Kai-Yue Zhuo Dong-Kun Wang Gui-Rong Qu Shan-Tao Xing Xi-Ning Yang Xinke college Henan Institute of science and technology Xinxiang tuoxin biochemical CO. Ltd. Henan university of science and technology new academy of sciences

Nucleoside and their derivatives have been comprehensively applied in biology and medicine duo to their particular activities.5-aza-2’-deoxycytidine a kind of 2’-deoxidization cytidine analogues, which has a unique therapeutic mechanism of methylation transferase inhibitor. To inhibit DNA methylation transferase. making it as a more effective drugs in active demethylation of DNA and then prohibits the propagation of the cancer cells. Now it is currently being used in clinical trials for myelodysplastic syndrome, Thus the products can bring the enormous social benefit, so it so it is of medical importance and social significance on the research of production methods of decitabine. Besides, As raw materials mainly used in the production of other drugs which have higher *** synthesis methods of 5-aza-2’-deoxycytidine were included chemical synthesis and biosynthesis, but the chemical synthesis method has many problems. such as, the complicated steps, the low yield and the product of reaction is difficult to separate, under considerable pressure to go green, the probiems have seriously restricted mass ***, how to develop innovative processes has become a serious problem to be soon studied and solved. Study on the Synthesis Process of 5-aza-2’-deoxycytidine by Immobilized Deoxynucleotidyl Transferase. Optimize the synthetic process and in highly efficient way to make5-aza-2’-deoxycytidine which was proposed to make ues of the thymidine and 5-azacytosine as substrate and immobilized the deoxynucleotidyl Transferaseas an enzyme source to synthetic decitabine. To achieve the objectives such as low-cost, high yield,environmental and easier extraction,which indicated that the new technology were suitable for industrial application.

关键词： Immobilized Deoxynucleotidyl Transferase 5-aza-2’-deoxycytidine

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World Journal of Gastroenterology 2011年第4期17卷 526-533页

作者： Yan Gong Ming-Zhou Guo Zhi-Jia Ye Xiu-Li Zhang Yong-Liang Zhao Yun-Sheng Yang Department of Gastroenterology and Hepatology Chinese PLAGeneral Hospital Beijing 100853 China Department of Genetics Yale Medical School TACS320 1 Gilbert Street New Haven CT 06520 United States Department of General Surgery Southwest Hospital Third Military Medical University Chongqing 400038China

AIM: To clarify the role of high in normal-1 (HIN-1) gene promoter methylation during gastric cancer development. METHODS: Gastric cancer cell lines and tissue specimens were analyzed for expression of HIN-1 mRNA and protein using the semi-quantitative reverse transcription polymerase chain reaction and immunohistochemistry. The methylation of the HIN-1 gene promoter was detected in gastric carcinoma cells and tissues using methylation-specific polymerase chain reaction. The 3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium cell viability assay and flow cytometry were used to assess the changes in behaviors of gastric cancer cells with or without 5-aza-2’-deoxycytidine treatment. RESULTS: HIN-1 was not expressed in 4 of 5 gastric cancer cell lines. The demethylation reagent 5-aza-2’-deoxycytidine was able to induce or upregulate HIN-1 expression in gastric cancer cell lines, which is associated with reduction of tumor cell viability. Furthermore, methylation of the HIN-1 gene promoter was shown in 57.8% (26/45) of the primary gastric cancer and 42.1% (17/38) of adjacent tissue samples, but was not shown in normal gastric mucosa (0/10). From the clinicopathological data of the patients, methylation of the HIN-1 gene promoter was found to be associated with tumor differentiation (P = 0.000). CONCLUSION: High methylation of HIN-1 gene promoter results in silence of HIN-1 expression in gastric cancer. 5-aza-2’-deoxycytidine reverses HIN-1 methylation and reduces viability of gastric cancer cells.

关键词： High in normal-1 Gene methylation 5-aza-2’-deoxycytidine Tumor differentiation Gastric cancer

DNA Methyltransferase Inhibitors Induce Cerebral Dopamine Neurotrophic Factor Expression in C6 Glioma Cells

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American Journal of Molecular Biology 2023年第3期13卷 170-182页

作者： Sumeya Z. Mukhtar Lennard P. Niles Department of Psychiatry and Behavioural Neurosciences McMaster University Hamilton Canada

Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) are involved in neuroprotection and mitigating endoplasmic reticulum (ER) stress in the brain and peripheral organs. In earlier work, an increase in histone acetylation, following treatment with an epigenetic modulator, valproic acid, was associated with induction of CDNF and MANF in cultured cells and rat brain. These findings prompted an investigation of the effects of DNA methyltransferase (DNMT) inhibitors, which can alter epigenetic function, on the expression of CDNF and MANF. Rat C6 glioma cells were treated with a micromolar range of DNMT inhibitors: 5-aza-2’-deoxycytidine (DAC or decitabine), 5-azacytidine (aza) or zebularine (ZEB) for 24 h. Subsequently, qPCR analysis was used to examine the mRNA expression of DNMT1, ten-eleven translocation methylcytosine dioxygenase 2 (TET-2), CDNF and MANF. A significant dose-dependent decrease in DNMT1 mRNA levels, together with a significant increase in TET-2 expression, was observed following treatment with aza or DAC. Importantly, DAC, aza and ZEB caused a significant dose-dependent increase in CDNF mRNA levels. In contrast, MANF mRNA expression decreased following treatment with aza, with no significant effects observed with DAC or ZEB. Western analysis revealed no significant changes in CDNF protein levels following treatment with DAC for 24 h. The significant increase in CDNF expression, following treatment with DNMT1 inhibitors, suggests that DNA methylation is involved in the regulation of this neurotrophic factor. Clarification of the epigenetic or other mechanisms underlying the regulation of CDNF may provide novel therapeutic approaches in neurodegenerative and ER stress-related disorders.

关键词： CDNF MANF 5-azacytidine 5-aza-2’-deoxycytidine Zebularine Gene Expression

Effect of 5-aza-CdR on the Apoptosis Induced by 5-FU in Human Colon Cancer Cell Line Caco-2

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Effect of 5-Aza-CdR on the Apoptosis Induced by 5-FU in Huma...

华东六省一市生物化学与分子生物学会2009年学术交流会

作者： liqiao liu~(1)) daya luo~(1)) fusheng wan1~(2)) (1) Department of Biochemistry and Molecular Biology,Nanchang University,Nanchang 330006, China 2)medical school,Nanchang University,Nanchang 330006,China)

＜正＞Objective:To investigate methylation status of promoter of p16 in four different colon cancer cell *** analyse the changes of the growth rate, sensitivity in response to the chemotherapy and apoptosis induced by 5-fluorouracil （5-FU） before and after the treatment with demethylation agent 5-aza-2’-deoxycytidine（5-aza-CdR） on p16 methylated colon cancer cell line Caco-2. These results may provide insight information for understanding the colon carcinogenesis and be helpful in combined therapy in colon ***:In the present study,we examined the expression of p16 methylation state in four different colon cancer cell lines by methylation specific polymerase chain reaction（MSP）, colon cancer cell line Caco-2 was treated with 5-aza-CdR in different concentrations（0.625μmol/L,1.25μmol/L,2.5μmol/L and 5μmol/L） and were investigated for the expression of p16 mRNA by reverse transcriptase-polymerase chain reaction（RT-PCR）.MTT method was used to observe the change of inhibitory rate of Caco-2 to 5-aza-CdR and 5-FU,RT-PCR and western-blotting were used to observe the change of the expression of apoptosis-related gene Bnip3/bax/ bcl-2, flow cytometry was used to observe the changes of the apoptosis rate of Caco-2 and ordinary Giemsa staining with light microscopy and Hoechst 33342 staining with fluorescence microscopy were used to observe specific and typical morphology of apoptosis before and after ***:We examined the expression of p16 mRNA and its methylation status in four different colon cancer cell lines by MSP and found that the promoter region of p16 gene were completely methylation in two cell lines（Caco-2 and RKO） and hemimethylation in two cell lines（SW480 and HCT116）. The expression of p16 mRNA was detected in Caco-2 colon cancer cell lines after 72 hours treatment of 5-aza-CdR（0.625μmol/L,1.25μmol/L,2.5μmol/L and 5μmol/L） in *** promoter region of p16 gene showed partly methylation after the treatment of 5-aza-CdR at 1.25μmol/L,2.

关键词： colon cancer DNA hypermethylation p16 5-aza-2’-deoxycytidine 5-fluorouracil

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不同剂量地西他滨对调节性T细胞的影响

不同剂量地西他滨对调节性T细胞的影响

作者：李庆贺天津医科大学

学位级别：硕士

目的：探讨不同剂量甲基转移酶抑制剂地西他滨(decitabine, aza)通过调节Foxp3基因表达在体内外实验中对CD4+CD25+Treg细胞变化的影响,寻找体内外aza影响CD4+CD25+Treg变化的合适剂量。方法：(1)体外实验部分,利用密度梯度离心法分离纯... 详细信息

目的：探讨不同剂量甲基转移酶抑制剂地西他滨(decitabine, aza)通过调节Foxp3基因表达在体内外实验中对CD4+CD25+Treg细胞变化的影响,寻找体内外aza影响CD4+CD25+Treg变化的合适剂量。方法：(1)体外实验部分,利用密度梯度离心法分离纯化C57BL/6(H-2b)小鼠脾脏单个核细胞,联合使用抗小鼠CD3单克隆抗体、抗小鼠CD28单克隆抗体、IL-2、TGF-β及不同剂量的aza,进行淋巴细胞培养,观察不同剂量的aza对培养体系的影响,以流式细胞技术检测培养体系CD4+CD25+Foxp3+Treg比例,实时荧光定量PCR检测培养体系Foxp3mRNA表达水平。(2)体内实验部分,按不同分组经C57BL/6(H-2b)小鼠阴茎背静脉注射不同剂量的aza,观察不同剂量的aza对小鼠机体的影响,以流式细胞技术检测外周血CD4+CD25+Foxp3+Treg比例,实时荧光定量PCR检测脾脏Foxp3mRNA表达水平。结果：(1)体外实验中发现,①联合使用抗小鼠CD3单克隆抗体、抗小鼠CD28单克隆抗体、IL-2. TGF-β及aza能够使小鼠脾脏淋巴细胞培养体系中初始CD4+CD25-T细胞分化为CD4+CD25+Treg细胞。同时Foxp3mRNA表达水平上升。②不同剂量aza诱导初始CD4+CD25-T细胞分化为CD4+CD25+Foxp3+Treg细胞的数量不同。Foxp3mRNA表达水平也不同。③浓度为5uM aza组淋巴细胞培养体系中CD4+CD25+Foxp3+Treg比例和Foxp3mRNA表达水平与其他浓度组相比升高最明显,且差异有统计学意义(P5)。(2)体内实验结果显示,①aza使经阴茎背静脉注射给药后第7天小鼠外周血CD4+CD25+Treg细胞数量增加,脾脏中Foxp3mRNA表达水平上升。②不同剂量aza对小鼠外周血CD4+CD25+Treg细胞数量和脾脏中Foxp3mRNA表达水平影响不同。③按4ug/g.体重/day剂量给予aza组对小鼠外周血CD4+CD25+Foxp3+Treg比例和脾脏Foxp3mRNA表达水平的影响与其他实验组相比升高最明显,且均有显著性差异(P5)。结论：在本实验中,无论是体内还是体外,甲基转移酶抑制剂5-氮杂-2’-脱氧胞苷(5-aza-2’-deoxycytidine, aza)即地西他滨(Decitabine)均可诱导初始CD4+CD25T细胞分化为CD4+CD25+Treg且Foxp3mRNA表达水平上调,但是不同剂量aza对CD4+CD25+Foxp3+Treg细胞的影响效果不同。在体内,小鼠按4ug/g/d剂量给予aza,在体外,浓度为5uM的aza诱导CD4+CD25+Treg细胞的增殖和分化最明显。

关键词：地西他滨 5-aza-2’-deoxycytidine Foxp3 CD4+CD25+调节性T细胞