Department of Biomedical Science, Ontario Veterinary College, University of Guelph, 50 Stone Road East, Guelph, Ontario, Canada N1G2W1.
Exp Cell Res. 2018 Aug 1;369(1):17-26. doi: 10.1016/j.yexcr.2018.04.024. Epub 2018 Apr 25.
The miR-200 family of microRNAs consisting of miR-141, miR-200a, miR-200b, miR-200c and miR-429 are emerging as important regulators of breast cancer progression. This family of microRNAs maintain mammary epithelial identity and downregulation of miR-200 expression has been associated with epithelial-to-mesenchymal transition in mammary tumors. Therefore, re-expression of one or more miR-200 family members in mammary tumor cells with mesenchymal characteristics may restore an epithelial phenotype including growth and metastasis suppression. To test this hypothesis, the miR-200b/200a/429 cluster was re-expressed in a murine claudin-low cell line, RJ423. Re-expression of the miR-200b/200a/429 cluster in RJ423 cells significantly suppressed the expression of Vim, Snai1, Twist1, Twist2 and Zeb1, reverted RJ423 cells to a more epithelial morphology and significantly inhibited proliferation in vitro. Moreover, the miR-200b/200a/429 cluster prevented lung metastasis in an experimental metastasis model and although tumor initiation was not prevented, re-expression of the miR-200b/200a/429 cluster induced a dormancy-like state where mammary tumors failed to grow beyond ~150 mm or grew extremely slowly following intra-mammary injection. These dormant tumors contained elevated levels of collagen and were highly vascularized. Therefore, re-expression of the miR-200b/200a/429 cluster in the claudin-low mammary tumor cell line, RJ423, is sufficient to alter cell morphology, impair metastasis and induce tumor dormancy.
miR-200 家族由 miR-141、miR-200a、miR-200b、miR-200c 和 miR-429 组成，它们作为乳腺癌进展的重要调节因子而崭露头角。这个 miRNA 家族维持着乳腺上皮细胞的特性，miR-200 表达的下调与乳腺肿瘤中的上皮间质转化有关。因此，在具有间质特征的乳腺肿瘤细胞中重新表达一个或多个 miR-200 家族成员可能会恢复上皮表型，包括生长和转移抑制。为了验证这一假说，我们在小鼠 Claudin-low 细胞系 RJ423 中重新表达了 miR-200b/200a/429 簇。在 RJ423 细胞中重新表达 miR-200b/200a/429 簇显著抑制了 Vim、Snai1、Twist1、Twist2 和 Zeb1 的表达，使 RJ423 细胞的形态更具上皮特征，并显著抑制了体外增殖。此外，miR-200b/200a/429 簇在实验性转移模型中阻止了肺转移，尽管肿瘤起始没有被阻止，但 miR-200b/200a/429 簇的重新表达诱导了一种休眠样状态，其中乳腺肿瘤在乳腺内注射后无法生长超过 150mm 或生长极其缓慢。这些休眠肿瘤中胶原水平升高，血管化程度高。因此，在 Claudin-low 乳腺肿瘤细胞系 RJ423 中重新表达 miR-200b/200a/429 簇足以改变细胞形态、损害转移并诱导肿瘤休眠。
