Antisense Oligonucleotides against miR-21 Inhibit the Growth and Metastasis of Colorectal Carcinoma via the DUSP8 Pathway.
Antisense Oligonucleotides against miR-21 Inhibit the Growth and Metastasis of Colorectal Carcinoma via the DUSP8 Pathway.
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DOI：
10.1016/j.omtn.2018.09.004
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发表时间：
2018-12-07
期刊：
影响因子：
--
通讯作者：
Xu L
中科院分区：
文献类型：
--
作者：
Ding T;Cui P;Zhou Y;Chen C;Zhao J;Wang H;Guo M;He Z;Xu L
越来越多的研究表明microRNA-21（miR-21）在人类结直肠癌（CRC）的发生发展中起重要作用。我们最近的工作也表明，针对miR-21的反义寡核苷酸（ASO）可以在体外损害CRC细胞的生长。然而，miR-21在CRC基因治疗中的潜在作用仍有待充分阐明。在此，我们使用人CRC的异种移植模型进一步观察针对miR-21的ASO对CRC的体内生长和转移的影响。我们发现ASO在体内能有效抑制CRC的生长和转移，同时下调miR-21的表达，减少AKT和ERK通路的转导。在机制上，全局基因表达分析显示，miR-21的新靶点DUSP 8的表达在肿瘤块中上调。此外，DUSP 8的过表达在体外可显著抑制结直肠癌细胞的增殖和迁移。最后，DUSP 8的下调可以消除针对miR-21的ASO对CRC细胞增殖和迁移的影响，以及AKT和ERK信号通路的改变。总之，这些数据表明，针对miRNA的ASO是用于治疗人CRC的有吸引力的和潜在的治疗剂，并且值得进一步开发。
Accumulating research has documented that microRNA-21 (miR-21) plays an important role in the development of human colorectal carcinoma (CRC). Our recent work also showed that antisense oligonucleotides (ASOs) against miR-21 can impair the growth of CRC cells in vitro. However, the potential role of miR-21 in gene therapy against CRC remains to be fully elucidated. Here, we further observed the effect of ASOs against miR-21 on the growth and metastasis of CRC in vivo using a xenograft model of human CRC. We found that ASOs could effectively inhibit the growth and metastasis of CRC in vivo, accompanied by downregulated expression of miR-21 and reduced transduction of the AKT and ERK pathway. Mechanically, global gene expression analysis showed that the expression of DUSP8, a novel target of miR-21, was upregulated in tumor mass. Furthermore, overexpression of DUSP8 could remarkably suppress the proliferation and migration of CRC cells in vitro. Finally, downregulation of DUSP8 could abrogate the effects of ASOs against miR-21 on the proliferation and migration of CRC cells, as well as altered transduction of the AKT and ERK signaling pathway. Together, these data suggest that ASOs against miRNAs are an attractive and potential therapeutic for the treatment of human CRC and warrant further development.
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影响因子：
3.8
作者：
Li C;Zhao L;Chen Y;He T;Chen X;Mao J;Li C;Lyu J;Meng QH
通讯作者：
Meng QH
影响因子：
41.2
作者：
Conde J;Oliva N;Zhang Y;Artzi N
通讯作者：
Artzi N
影响因子：
6.4
作者：
Nedaeinia, R.;Sharifi, M.;Salehi, R.
通讯作者：
Salehi, R.
影响因子：
5.7
作者：
Carrasco, Rosa A.;Stamm, Nancy B.;Patel, Bharvin K. R.
通讯作者：
Patel, Bharvin K. R.
DOI：
10.1016/j.omtn.2016.12.005
发表时间：
2017-03-17
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
Lei L;Chen C;Zhao J;Wang H;Guo M;Zhou Y;Luo J;Zhang J;Xu L
通讯作者：
Xu L