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MBD3抑制肝癌干细胞的形成。

MBD3 inhibits formation of liver cancer stem cells.

作者信息

Li Ruizhi, He Qihua, Han Shuo, Zhang Mingzhi, Liu Jinwen, Su Ming, Wei Shiruo, Wang Xuan, Shen Li

机构信息

Stem Cell Research Center, Department of Cell Biology, School of Basic Medical Sciences, Peking University, Haidian District, Beijing, 100191, China.

Beijing DongFang YaMei Gene Science and Technology Research Institute, Beijing, People's Republic of China.

出版信息

Oncotarget. 2017 Jan 24;8(4):6067-6078. doi: 10.18632/oncotarget.13496.

DOI:10.18632/oncotarget.13496
PMID:27894081
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5351613/
Abstract

Liver cancer cells can be reprogrammed into induced cancer stem cells (iCSCs) by exogenous expression of the reprogramming transcription factors Oct4, Sox2, Klf4 and c-Myc (OSKM). The nucleosome remodeling and deacetylase (NuRD) complex is essential for reprogramming somatic cells. In this study, we investigated the function of NuRD in the induction of liver CSCs. We showed that suppression of methyl-CpG binding domain protein 3 (MBD3), a core subunit of the NuRD repressor complex, together with OSKM transduction, induces conversion of liver cancer cells into stem-like cells. Expression of the transcription factor c-JUN is increased in MBD3-depleted iCSCs, and c-JUN activates endogenous pluripotent genes and regulates iCSC-related genes. These results indicate that MBD3/NuRD inhibits the induction of iCSCs, while c-JUN facilitates the generation of CSC-like properties. The iCSC reprogramming approach devised here provides a novel platform for dissection of the disordered signaling in liver CSCs. In addition, our results indicate that c-JUN may serve as a potential target for liver cancer therapy.

摘要

通过重编程转录因子Oct4、Sox2、Klf4和c-Myc（OSKM）的外源表达，肝癌细胞可被重编程为诱导癌干细胞（iCSCs）。核小体重塑和去乙酰化酶（NuRD）复合物对于体细胞重编程至关重要。在本研究中，我们调查了NuRD在肝脏癌干细胞诱导中的功能。我们发现，抑制NuRD阻遏复合物的核心亚基甲基化CpG结合域蛋白3（MBD3），并同时进行OSKM转导，可诱导肝癌细胞转变为干细胞样细胞。在MBD3缺失的iCSCs中，转录因子c-JUN的表达增加，并且c-JUN可激活内源性多能性基因并调节与iCSC相关的基因。这些结果表明，MBD3/NuRD抑制iCSCs的诱导，而c-JUN促进CSC样特性的产生。此处设计的iCSC重编程方法为剖析肝脏癌干细胞中紊乱的信号传导提供了一个新平台。此外，我们的结果表明，c-JUN可能作为肝癌治疗的一个潜在靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1766/5351613/6e47febc332e/oncotarget-08-6067-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1766/5351613/588da082f338/oncotarget-08-6067-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1766/5351613/dac91da1c39b/oncotarget-08-6067-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1766/5351613/5ee9efc2f919/oncotarget-08-6067-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1766/5351613/ae4411c362c4/oncotarget-08-6067-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1766/5351613/a521331ba9e0/oncotarget-08-6067-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1766/5351613/6e47febc332e/oncotarget-08-6067-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1766/5351613/588da082f338/oncotarget-08-6067-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1766/5351613/dac91da1c39b/oncotarget-08-6067-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1766/5351613/5ee9efc2f919/oncotarget-08-6067-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1766/5351613/ae4411c362c4/oncotarget-08-6067-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1766/5351613/a521331ba9e0/oncotarget-08-6067-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1766/5351613/6e47febc332e/oncotarget-08-6067-g006.jpg

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本文引用的文献

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Positive Feedback Loop of OCT4 and c-JUN Expedites Cancer Stemness in Liver Cancer.OCT4 和 c-JUN 的正反馈环加速肝癌中的癌症干细胞特性。
Stem Cells. 2016 Nov;34(11):2613-2624. doi: 10.1002/stem.2447. Epub 2016 Jul 11.
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The oncogene c-Jun impedes somatic cell reprogramming.癌基因 c-Jun 阻碍体细胞核重编程。
Nat Cell Biol. 2015 Jul;17(7):856-67. doi: 10.1038/ncb3193. Epub 2015 Jun 22.
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Zic2 is an enhancer-binding factor required for embryonic stem cell specification.Zic2是胚胎干细胞特化所需的一种增强子结合因子。
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Epigenetic modulator inhibition overcomes temozolomide chemoresistance and antagonizes tumor recurrence of glioblastoma.表观遗传调节剂抑制克服替莫唑胺化疗耐药并拮抗胶质母细胞瘤肿瘤复发。
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