Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.
Carcinogenesis. 2013 Mar;34(3):713-22. doi: 10.1093/carcin/bgs383. Epub 2012 Dec 17.
MicroRNAs (miRNAs or miR) have been integrated into tumorigenic programs as either oncogenes or tumor suppressor genes. The miR-124 was reported to be attenuated in several tumors, such as glioma, medulloblastoma and hepatocellular carcinoma. However, its role in cancer remains greatly elusive. In this study, we show that the miR-124 expression is significantly suppressed in human breast cancer specimens, which is reversely correlated to histological grade of the cancer. More intriguingly, ectopic expression of miR-124 in aggressive breast cancer cell lines MDA-MB-231 and BT-549 strongly inhibits cell motility and invasive capacity, as well as the epithelial-mesenchymal transition process. Also, lentivirus-delivered miR-124 endows MDA-MB-231 cells with the ability to suppress cell colony formation in vitro and pulmonary metastasis in vivo. Further studies have identified the E-cadherin transcription repressor Slug as a direct target gene of miR-124; its downregulation by miR-124 increases the expression of E-cadherin, a hallmark of epithelial cells and a repressor of cell invasion and metastasis. Moreover, knockdown of Slug notably impairs the motility of MDA-MB-231 cells, whereas re-expression of Slug abrogates the reduction of motility and invasion ability induced by miR-124 in MDA-MB-231 cells. These findings highlight an important role for miR-124 in the regulation of invasive and metastatic potential of breast cancer and suggest a potential application of miR-124 in cancer treatment.
微小 RNA（miRNA 或 miR）已被整合到肿瘤发生程序中，作为癌基因或肿瘤抑制基因。据报道，miR-124 在几种肿瘤中表达减弱，如神经胶质瘤、髓母细胞瘤和肝癌。然而，其在癌症中的作用仍然很大程度上难以捉摸。在这项研究中，我们表明 miR-124 的表达在人乳腺癌标本中显著受到抑制，与癌症的组织学分级呈负相关。更有趣的是，在侵袭性乳腺癌细胞系 MDA-MB-231 和 BT-549 中异位表达 miR-124 强烈抑制细胞迁移和侵袭能力，以及上皮-间充质转化过程。此外，慢病毒递送的 miR-124 赋予 MDA-MB-231 细胞体外抑制细胞集落形成和体内肺转移的能力。进一步的研究表明，E-钙粘蛋白转录抑制因子 Slug 是 miR-124 的直接靶基因；miR-124 下调 Slug 增加了 E-钙粘蛋白的表达，E-钙粘蛋白是上皮细胞的标志，也是细胞侵袭和转移的抑制剂。此外，Slug 的敲低显著损害了 MDA-MB-231 细胞的迁移能力，而 Slug 的重新表达则消除了 miR-124 在 MDA-MB-231 细胞中诱导的迁移和侵袭能力的降低。这些发现强调了 miR-124 在调节乳腺癌侵袭和转移潜能中的重要作用，并表明 miR-124 在癌症治疗中的潜在应用。
