Department of Surgery, Chuncheon Sacred Heart Hospital, College of Medicine, Hallym University, Chuncheon, South Korea.
Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China.
Cancer Sci. 2018 May;109(5):1404-1413. doi: 10.1111/cas.13588. Epub 2018 Apr 29.
Metastasis and chemoresistance remain major challenges in the clinical treatment of breast cancer. Recent studies show that dysregulated microRNAs (miRNAs) play an important role in metastasis and chemoresistance development in breast cancer. Herein, we identified downregulated expression of miR-708-3p in breast cancers. In particular, miR-708-3p expression was significantly decreased in specimens from breast cancer patients with metastasis compared to that in specimens from patients with no metastasis. Consistent with clinical data, our in vitro data show that miR-708-3p was more significantly decreased in invasive breast cancer cell lines. In addition, our data show that inhibition of miR-708-3p significantly stimulated breast cancer cell metastasis and induced chemoresistance both in vitro and in vivo. In contrast, overexpression of miR-708-3p dramatically inhibited breast cancer cell metastasis and enhanced the sensitivity of breast cancer cells to chemotherapy both in vitro and in vivo. Furthermore, we identified that miR-708-3p inhibits breast cancer cell epithelial-to-mesenchymal transition (EMT) by directly targeting EMT activators, including ZEB1, CDH2 and vimentin. Taken together, our findings suggest that miR-708-3p acts as a cancer suppressor miRNA and carries out its anticancer function by inhibiting EMT in breast cancer. In addition, our findings suggest that restoration of miR-708-3p may be a novel strategy for inhibiting breast cancer metastasis and overcoming the chemoresistance of breast cancer cells.
转移和化疗耐药仍然是乳腺癌临床治疗的主要挑战。最近的研究表明，失调的 microRNAs（miRNAs）在乳腺癌转移和化疗耐药发展中起重要作用。在此，我们发现 miR-708-3p 在乳腺癌中表达下调。特别是，miR-708-3p 在有转移的乳腺癌患者标本中的表达明显低于无转移的患者标本。与临床数据一致，我们的体外数据显示，侵袭性乳腺癌细胞系中 miR-708-3p 的表达降低更为显著。此外，我们的数据表明，抑制 miR-708-3p 可显著刺激乳腺癌细胞转移，并在体外和体内诱导化疗耐药。相反，过表达 miR-708-3p 可显著抑制乳腺癌细胞转移，并增强乳腺癌细胞对化疗的敏感性，无论是在体外还是体内。此外，我们确定 miR-708-3p 通过直接靶向 EMT 激活因子 ZEB1、CDH2 和波形蛋白来抑制乳腺癌细胞上皮-间质转化（EMT）。总之，我们的研究结果表明，miR-708-3p 作为一种癌症抑制性 miRNA，通过抑制乳腺癌中的 EMT 发挥其抗癌功能。此外，我们的研究结果表明，恢复 miR-708-3p 的表达可能是抑制乳腺癌转移和克服乳腺癌细胞化疗耐药的一种新策略。
