Reduced miR-128 in Breast Tumor-Initiating Cells Induces Chemotherapeutic Resistance via Bmi-1 and ABCC5
Reduced miR-128 in Breast Tumor-Initiating Cells Induces Chemotherapeutic Resistance via Bmi-1 and ABCC5
复制标题
乳腺肿瘤起始细胞中 miR-128 的减少通过 Bmi-1 和 ABCC5 诱导化疗耐药
DOI：
10.1158/1078-0432.ccr-11-0071
复制
发表时间：
2011-11-15
影响因子：
11.5
通讯作者：
Song, Erwei
中科院分区：
文献类型：
--
作者：
Zhu, Yinghua;Yu, Fengyan;Song, Erwei
目的：肿瘤起始细胞对化疗有抗性，但microRNA如何在调节乳腺肿瘤起始细胞（BT-IC）的耐药性中发挥作用需要澄清。实验设计：在BT-IC中进行慢病毒介导的miR-128转导，通过乳腺球培养或CD 44（+）CD 24（-）荧光激活细胞分选富集。细胞凋亡和DNA损伤后测定阿霉素治疗。通过原位杂交检测乳腺癌组织中miR-128的表达，并将其与乳腺肿瘤对新辅助化疗的反应和患者生存率相关。miR-128在从乳腺癌细胞系和原发性乳腺肿瘤富集的化学抗性BT-IC中显著降低（P < 0.01），伴随Bmi-1和ABCC 5的过表达，其被鉴定为miR-128的靶点。miR-128的异位表达降低了BT-IC中Bmi-1和ABCC 5的蛋白水平，在阿霉素存在下，沿着细胞活力降低（P <0.001）和细胞凋亡增加（P < 0.001）以及DNA损伤增加（P < 0.001）。乳腺癌组织中miR-128表达降低与化疗耐药（P < 0.001）和乳腺癌患者生存率低相关（P < 0.05; n = 57）。结论：miR-128表达降低导致Bmi-1和ABCC 5过表达是BT-IC的干细胞样特征，其有助于乳腺癌的化疗耐药。miR-128的异位表达使BT-IC对阿霉素的促凋亡和DNA损伤作用敏感，表明其治疗潜力。临床癌症研究; 17（22）; 7105-15。(C)2011年AACR。
Purpose: Tumor-initiating cells are resistant to chemotherapy, but how microRNAs play a role in regulating drug resistance of breast tumor-initiating cells (BT-IC) needs to be clarified.Experimental Design: Lentivirus-mediated miR-128 transduction was done in BT-ICs, enriched by mammosphere cultures or CD44(+)CD24(-) fluorescence-activated cell sorting. Apoptosis and DNA damage were determined upon treatment with doxorubicin. Expression of miR-128 in breast cancer tissues was examined by in situ hybridization and correlated with breast tumor response to neoadjuvant chemotherapy and patient survival.Results: MiR-128 was significantly reduced in chemoresistant BT-ICs enriched from breast cancer cell lines and primary breast tumors (P < 0.01), accompanied by an overexpression of Bmi-1 and ABCC5, which were identified as targets of miR-128. Ectopic expression of miR-128 reduced the protein levels of Bmi-1 and ABCC5 in BT-ICs, along with decreased cell viability (P < 0.001) and increased apoptosis (P < 0.001) and DNA damage (P < 0.001) in the presence of doxorubicin. Reduced miR-128 expression in breast tumor tissues was associated with chemotherapeutic resistance (P < 0.001) and poor survival of breast cancer patients (P < 0.05; n = 57).Conclusions: Reduction in miR-128 leading to Bmi-1 and ABCC5 overexpression is a stem cell-like feature of BT-ICs, which contributes to chemotherapeutic resistance in breast cancers. Ectopic expression of miR-128 sensitizes BT-ICs to the proapoptotic and DNA-damaging effects of doxorubicin, indicating therapeutic potential. Clin Cancer Res; 17(22); 7105-15. (C) 2011 AACR.