Prolyl isomerase Pin1 acts downstream of miR200c to promote cancer stem-like cell traits in breast cancer.
Prolyl isomerase Pin1 acts downstream of miR200c to promote cancer stem-like cell traits in breast cancer.
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DOI：
10.1158/0008-5472.can-13-2785
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发表时间：
2014-07-01
期刊：
影响因子：
11.2
通讯作者：
Lu KP
中科院分区：
文献类型：
--
作者：
Luo ML;Gong C;Chen CH;Lee DY;Hu H;Huang P;Yao Y;Guo W;Reinhardt F;Wulf G;Lieberman J;Zhou XZ;Song E;Lu KP
乳腺癌干细胞样细胞（BCSC）与肿瘤生长、转移、耐药性和复发有关，但在该细胞群的适当亚群中的可药用靶点尚未确定。在这里，我们确定了脯氨酰异构酶Pin 1在驱动BCSC扩增、侵袭性和致瘤性中的基本作用，将其定义为miR-200 c的关键靶点，miR-200 c已知是BSCS中的关键调节剂。Pin 1的过度表达扩大了BCSC的生长和致瘤性，并触发了上皮-间质转化（EMT）。相反，Pin 1的遗传或药理学抑制降低了BCSC的丰度和自我更新活性。此外，miR-200 c抗性Pin 1的适度过表达挽救了miR-200 c表达细胞中的BCSC缺陷。Pin 1基因缺失也降低了正常小鼠乳腺干细胞的丰度和再生能力。在从乳房缩小术组织中新鲜分离的人类细胞中，Pin 1过表达赋予正常乳腺上皮细胞BCSC特征，在这些细胞中扩展管腔和基底/肌上皮谱系。与此相反，Pin 1基因沉默在原发性乳腺癌细胞分离的临床样品中抑制BCSC的扩增，自我更新活性和肿瘤发生在体外和体内。总体而言，我们的工作表明Pin 1是miR-200 c下游的关键调节因子，可驱动BCSC和乳腺致瘤性，突出了根除BCSC的新治疗靶点。
Breast cancer stem-like cells (BCSC) have been implicated in tumor growth, metastasis, drug resistance and relapse but druggable targets in appropriate subsets of this cell population have yet to be identified. Here we identify a fundamental role for the prolyl isomerase Pin1 in driving BCSC expansion, invasiveness and tumorigenicity, defining it as a key target of miR-200c which is known to be a critical regluator in BSCS. Pin1 overexpression expanded the growth and tumorigenicity of BCSC and triggered epithelial-mesenchymal transition (EMT). Conversely, genetic or pharmaacological inhibition of Pin1 reduced the abundance and self-renewal activity of BCSC. Moreover, moderate overexpression of miR-200c-resistant Pin1 rescued the BCSC defect in miR-200c-expressing cells. Genetic deletion of Pin1 also decreased the abundance and repopulating capability of normal mouse mammary stem cells. In human cells freshly isolated from reduction mammoplasty tissues, Pin1 overexpression endowed BCSC traits to normal breast epithelial cells, expanding both luminal and basal/myoepithelial lineages in these cells. In contrast, Pin1 silencing in primary breast cancer cells isolated from clinical samples inhibited the expansion, self-renewal activity and tumorigenesis of BCSC in vitro and in vivo. Overall, our work demonstrated that Pin1 is a pivotal regulator acting downstream of miR-200c to drive BCSC and breast tumorigenicity, highlighting a new therapeutic target to eradicate BCSC.
影响因子：
3.7
作者：
Xu HR;Xu ZF;Sun YL;Han JJ;Li ZJ
通讯作者：
Li ZJ