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.

越来越多的研究表明，microRNA-21（miR-21）在人类大肠癌（CRC）的发展中起着重要作用。我们最近的工作还表明，针对miR-21的反义寡核苷酸（ASO）可以损害CRC细胞的体外生长。但是，miR-21在针对CRC的基因治疗中的潜在作用仍有待充分阐明。在这里，我们使用人CRC的异种移植模型进一步观察了ASO抗miR-21对CRC体内生长和转移的影响。我们发现ASOs可以有效抑制CRC在体内的生长和转移，并伴随miR-21表达下调和AKT和ERK途径的转导减少。在机械上，整体基因表达分析表明，DUSP8（miR-21的新靶标）的表达在肿瘤块中被上调。此外，DUSP8的过表达可以显着抑制体外CRC细胞的增殖和迁移。最后，DUSP8的下调可以消除针对miR-21的ASO对CRC细胞增殖和迁移以及AKT和ERK信号传导途径的改变的影响。总之，这些数据表明，针对miRNA的ASO是治疗人CRC的诱人且潜在的疗法，有待进一步开发。