Loss of SNAIL Regulated miR-128-2 on Chromosome 3p22.3 Targets Multiple Stem Cell Factors to Promote Transformation of Mammary Epithelial Cells
Loss of SNAIL Regulated miR-128-2 on Chromosome 3p22.3 Targets Multiple Stem Cell Factors to Promote Transformation of Mammary Epithelial Cells
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染色体 3p22.3 上 SNAIL 调控的 miR-128-2 的缺失靶向多种干细胞因子，促进乳腺上皮细胞的转化
DOI：
10.1158/0008-5472.can-12-1507
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发表时间：
2012-11-15
期刊：
影响因子：
11.2
通讯作者：
Zhu, Tao
中科院分区：
文献类型：
--
作者：
Qian, PengXu;Banerjee, Arindam;Zhu, Tao
据报道，87%的原发性乳腺癌在染色体3 p处存在不连续的洛缺失。尽管在该区域中鉴定了几个肿瘤抑制基因，但尚未对该区域中的非编码RNA（包括miRNA）进行详细分析。在这项研究中，我们在该区域鉴定了16种异常miRNA，并确定了几种在乳腺癌中经常丢失或扩增的miRNA。miR-128-2是最常见的缺失miRNA。miR-128-2嵌入在染色体3p22.3的ARPP 21基因的内含子中，在乳腺癌中经常与ARPP 21一起沿着下调，其与临床病理特征和生存结局呈负相关。miR-128的强制表达阻碍了乳腺癌细胞的几种致癌特性，而在体外和体内，耗尽miR-128-2表达足以在永生化的非致瘤性乳腺上皮细胞中进行致癌转化和干细胞样行为。miR-128-2沉默部分地通过去抑制一组直接靶点（BMI 1、CSF 1、KLF 4、LIN 28 A、NANOG和SNAIL）来实现转化能力，这些靶点一起作用以刺激PI 3 K/AKT和STAT 3信号传导途径。我们还发现，miR-128-2被SNAIL直接下调，并被TGF-β信号转导抑制，为该网络增加了2个额外的负反馈环。总之，我们已经确定了一个新的TGF-β/SNAIL/miR-128轴，提供了一个新的途径来了解乳腺上皮细胞的致癌转化的基础。Cancer Res; 72（22）; 6036-50. (C)2012年AACR。
A discontinuous pattern of LOH at chromosome 3p has been reported in 87% of primary breast cancers. Despite the identification of several tumor suppressor genes in this region, there has yet to be a detailed analysis of noncoding RNAs including miRNAs in this region. In this study, we identified 16 aberrant miRNAs in this region and determined several that are frequently lost or amplified in breast cancer. miR-128-2 was the most commonly deleted miRNA. Embedded in the intron of the ARPP21 gene at chromosome 3p22.3, miR-128-2 was frequently downregulated along with ARPP21 in breast cancer, where it was negatively associated with clinicopathologic characteristics and survival outcome. Forced expression of miR-128 impeded several oncogenic traits of mammary carcinoma cells, whereas depleting miR-128-2 expression was sufficient for oncogenic transformation and stem cell-like behaviors in immortalized nontumorigenic mammary epithelial cells, both in vitro and in vivo. miR-128-2 silencing enabled transforming capacity partly by derepressing a cohort of direct targets (BMI1, CSF1, KLF4, LIN28A, NANOG, and SNAIL), which together acted to stimulate the PI3K/AKT and STAT3 signaling pathways. We also found that miR-128-2 was directly downregulated by SNAIL and repressed by TGF-beta signaling, adding 2 additional negative feedback loops to this network. In summary, we have identified a novel TGF-beta/SNAIL/miR-128 axis that provides a new avenue to understand the basis for oncogenic transformation of mammary epithelial cells. Cancer Res; 72(22); 6036-50. (C) 2012 AACR.