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Inhibition of intestinal tumor formation by deletion of the DNA methyltransferase 3a

机译：通过缺失DNA甲基转移酶3a抑制肠道肿瘤的形成

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摘要

Aberrant de novo methylation of DNA is considered an important mediator of tumorigenesis. To investigate the role of de novo DNA methyltransferase 3a (Dnmt3a) in intestinal tumor development, we analyzed the expression of Dnmt3a in murine colon crypts, murine colon adenomas and human colorectal cancer using RNA fluorescence in situ hybridization (FISH), quantitative PCR and immunostaining. Following conditional deletion of Dnmt3a in the colon of APC((Min/+)) mice, we analyzed tumor numbers, genotype of macroadenomas and laser dissected microadenomas, global and regional DNA methylation and gene expression. Our results showed increased Dnmt3a expression in colon adenomas of APC((Min/+)) mice and human colorectal cancer samples when compared with control tissue. Interestingly, in tumor tissue, RNA FISH analysis showed highest Dnmt3a expression in Lgr5-positive stem/progenitor cells. Deletion of Dnmt3a in APC((Min/+)) mice reduced colon tumor numbers by similar to 40. Remaining adenomas and microadenomas almost exclusively contained the non-recombined Dnmt3a allele; no tumors composed of the inactivated Dnmt3a allele were detected. DNA methylation was reduced at the Oct4, Nanog, Tff2 and Cdkn1c promoters and expression of the tumor-suppressor genes Tff2 and Cdkn1c was increased. In conclusion, our results show that Dnmt3a is predominantly expressed in the stem/progenitor cell compartment of tumors and that deletion of Dnmt3a inhibits the earliest stages of intestinal tumor development.
机译：DNA的异常从头甲基化被认为是肿瘤发生的重要介质。为了研究从头DNA甲基转移酶3a（Dnmt3a）在肠道肿瘤发展中的作用，我们使用RNA荧光原位杂交（FISH）、定量PCR和免疫染色分析了Dnmt3a在小鼠结肠隐窝、小鼠结肠腺瘤和人结直肠癌中的表达。在APC（（Min/+））小鼠结肠中Dnmt3a有条件缺失后，我们分析了肿瘤数量、大腺瘤和激光解剖微腺瘤的基因型、全球和区域DNA甲基化和基因表达。我们的结果显示，与对照组织相比，APC（（（Min/+）） 小鼠和人结直肠癌样本的结肠腺瘤中 Dnmt3a 表达增加。有趣的是，在肿瘤组织中，RNA FISH分析显示Lgr5阳性干细胞/祖细胞中Dnmt3a表达最高。APC（（Min/+））小鼠中Dnmt3a的缺失使结肠肿瘤数量减少了40%。剩余的腺瘤和微腺瘤几乎完全含有未重组的 Dnmt3a 等位基因;未检测到由灭活的 Dnmt3a 等位基因组成的肿瘤。Oct4、Nanog、Tff2 和 Cdkn1c 启动子的 DNA 甲基化减少，肿瘤抑制基因 Tff2 和 Cdkn1c 的表达增加。总之，我们的结果表明，Dnmt3a主要在肿瘤的干细胞/祖细胞区室中表达，并且Dnmt3a的缺失抑制了肠道肿瘤发展的早期阶段。

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  • 来源
    《Oncogene》 |2015年第14期|1822-1830|共9页
  • 作者

    Weis B.; Schmidt J.; Maamar H.Raj A.Lin H.Toth C.Riedmann K.Raddatz G.Seitz H-KHo A. D.Lyko F.Linhart H. G.;

  • 作者单位

    German Canc Res Ctr, Div Epigenet A130, D-69120 Heidelberg, Germany;

    Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA;

    Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USAHeidelberg Univ, Dept Pathol, Natl Ctr Tumor Dis NCT, Tissue Bank, Heidelberg, GermanyHeidelberg Univ, Dept Med, Salem Med Ctr, Alcohol Res Ctr, Heidelberg, GermanyHeidelberg Univ, Dept Hematol Oncol, Med Ctr, Heidelberg, Germany;

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  • 正文语种 英语
  • 中图分类 肿瘤学;
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