Zhang Hongyao, Li Ning, Zhang Jiahui, Jin Fengjiao, Shan Meihua, Qin Junfang, Wang Yue
a Medical School of Nankai University , Tianjin , China.
Cancer Biol Ther. 2016 Jun 2;17(6):614-24. doi: 10.1080/15384047.2016.1177678. Epub 2016 Apr 15.
In this study, we investigate the effect of miR-34a expression and biological characteristics of breast cancer stem cells (BCSCs). The mammospheres were formed from murine breast cancer cell line 4T1 and regarded as murine BCSCs. Identification of stemness molecules and cloning experiments validate the biological characteristics of BCSCs we have established. We showed that miR-34a, as a tumor suppressor, could separately reduce the stemness of BCSCs and activate the cytotoxic susceptibility of BCSCs to natural killer (NK) cells in vitro via down regulating the expression of Notch1 signaling molecules. Moreover, miR-34a could completely restrain established mice breast tumor xenografts in vivo in the NOD/SCID mice that have functional NK cells at a normal level, whereas it was less effective in NOD/SCID/ CD122/IL-2Rβ mice that do not have functional NK cells. We conclude that miR-34a is a crucial, dual tumor suppressor and BCSCs-targeting immunotherapeutic agent and has shown efficacy in the treatment of murine breast cancer. The results also suggest that impaired NK cells could contribute to the resistance to therapies.
在本研究中，我们探究了miR-34a对乳腺癌干细胞（BCSCs）表达及生物学特性的影响。小鼠乳腺癌细胞系4T1形成的乳腺球被视为小鼠BCSCs。干性分子的鉴定和克隆实验验证了我们所建立的BCSCs的生物学特性。我们发现，作为一种肿瘤抑制因子，miR-34a可通过下调Notch1信号分子的表达，分别降低BCSCs的干性，并在体外激活BCSCs对自然杀伤（NK）细胞的细胞毒性敏感性。此外，在体内，miR-34a能够完全抑制在NOD/SCID小鼠中建立的小鼠乳腺肿瘤异种移植瘤，这些小鼠具有正常水平的功能性NK细胞，而在没有功能性NK细胞的NOD/SCID/CD122/IL-2Rβ小鼠中效果较差。我们得出结论，miR-34a是一种关键的双重肿瘤抑制因子和靶向BCSCs的免疫治疗药物，并且已在小鼠乳腺癌治疗中显示出疗效。结果还表明，NK细胞功能受损可能导致对治疗产生抗性。
