miRNA-128 suppresses prostate cancer by inhibiting BMI-1 to inhibit tumor-initiating cells.
miRNA-128 suppresses prostate cancer by inhibiting BMI-1 to inhibit tumor-initiating cells.
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DOI：
10.1158/0008-5472.can-14-0404
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发表时间：
2014-08-01
期刊：
影响因子：
11.2
通讯作者：
Tang DG
中科院分区：
文献类型：
--
作者：
Jin M;Zhang T;Liu C;Badeaux MA;Liu B;Liu R;Jeter C;Chen X;Vlassov AV;Tang DG
microRNA-128（miR-128）在前列腺癌（PCa）中相对于正常/良性前列腺组织减少，但因果关系尚不清楚。在这里，我们表明，外源性引入的miR-128抑制多种PCa异种移植模型中的肿瘤再生。癌症干细胞样细胞（CSC）相关特性被阻断，包括全克隆和球体形成以及克隆存活。使用miR-128传感器来基于miR-128表达区分细胞，我们发现miR-128-lo细胞比miR-128-hi细胞具有更高的克隆、克隆形成和致瘤活性。miR-128靶向干细胞调节因子BMI-1、NANOG和TGFBR 1，我们发现这些因子的表达与PCa干/祖细胞群中miR-128的表达呈负相关。特别是，我们将BMI-1定义为PCa细胞中miR-128的直接和功能相关的靶点，这些基因在PCa细胞中被重复表达并表现出相反的生物学功能。我们的研究结果通过限制BMI-1和其他中央干细胞调节因子介导的CSC特性，定义了miR-128在PCa中的肿瘤抑制功能，对PCa基因治疗具有潜在意义。
MicroRNA-128 (miR-128) is reduced in prostate cancer (PCa) relative to normal/benign prostate tissues but causal roles are obscure. Here we show that exogenously introduced miR-128 suppresses tumor regeneration in multiple PCa xenograft models. Cancer stem-like cell (CSC) associated properties were blocked, including holoclone and sphere formation as well as clonogenic survival. Using a miR-128 sensor to distinguish cells on the basis of miR-128 expression, we found that miR-128-lo cells possessed higher clonal, clonogenic and tumorigenic activities than miR-128-hi cells. miR-128 targets the stem cell regulatory factors BMI-1, NANOG, and TGFBR1, the expression of which we found to vary inversely with miR-128 expression in PCa stem/progenitor cell populations. In particular, we defined BMI-1 as a direct and functionally relevant target of miR-128 in PCa cells, where these genes were reciprocally expressed and exhibited opposing biological functions. Our results define a tumor suppressor function for miR-128 in PCa by limiting CSC properties mediated by BMI-1 and other central stem cell regulators, with potential implications for PCa gene therapy.