Y-box binding protein-1 induces the expression of CD44 and CD49f leading to enhanced self-renewal, mammosphere growth, and drug resistance.
Y-box binding protein-1 induces the expression of CD44 and CD49f leading to enhanced self-renewal, mammosphere growth, and drug resistance.
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DOI：
10.1158/0008-5472.can-09-3155
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发表时间：
2010-04-01
期刊：
影响因子：
11.2
通讯作者：
Dunn SE
中科院分区：
文献类型：
--
作者：
To K;Fotovati A;Reipas KM;Law JH;Hu K;Wang J;Astanehe A;Davies AH;Lee L;Stratford AL;Raouf A;Johnson P;Berquin IM;Royer HD;Eaves CJ;Dunn SE
Y-box binding protein-1（YB-1）是一种致癌的转录/翻译因子，在>40%的乳腺癌中表达，与预后不良、疾病复发和耐药性相关。我们怀疑这是否与YB-1诱导与癌症干细胞相关的基因（如CD 44和CD 49 f）表达的能力有关。在此，我们报告，YB-1结合的CD 44和CD 49 f启动子转录上调其表达。野生型YB-1或活化的P-YB-1 S102的引入刺激了MDA-MB-231和SUM 149乳腺癌细胞系中CD 44和CD 49 f的产生。YB-1转染的细胞也比对照细胞更多地与CD 44配体透明质酸结合。类似地，YB-1在永生化乳腺上皮细胞中被诱导并上调CD 44。相反，沉默YB-1降低了SUM 149细胞中的CD 44表达以及报告基因活性。在小鼠中，乳腺中YB-1的表达诱导CD 44和CD 49 f相关增生。此外，激活的突变体YB-1 S102 D增强了自我更新、原发性和继发性乳腺球生长以及软琼脂集落生长，这些通过CD 44或CD 49 f的丢失是可逆的。我们接下来讨论了该系统对治疗反应性的影响。在这里，我们表明，紫杉醇诱导P-YB-1 S102的表达，激活的YB-1的核定位，和CD 44的表达。野生型YB-1的过表达在紫杉醇存在下促进乳腺球生长。重要的是，靶向YB-1使CD 44 High/CD 24 Low细胞对紫杉醇敏感。总之，YB-1通过诱导CD 44和CD 49 f促进癌细胞生长和耐药性。
Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor expressed in >40% of breast cancers, where it is associated with poor prognosis, disease recurrence, and drug resistance. We questioned whether this may be linked to YB-1’s ability to induce the expression of genes linked to cancer stem cells such as CD44 and CD49f. Herein, we report that YB-1 binds the CD44 and CD49f promoters to transcriptionally up-regulate their expressions. The introduction of wild-type YB-1 or activated P-YB-1S102 stimulated the production of CD44 and CD49f in MDA-MB-231 and SUM 149 breast cancer cell lines. YB-1-transfected cells also bound to the CD44 ligand hyaluronan more than the control cells. Similarly, YB-1 was induced in immortalized breast epithelial cells and up-regulated CD44. Conversely, silencing YB-1 decreased CD44 expression as well as reporter activity in SUM 149 cells. In mice, expression of YB-1 in the mammary gland induces CD44 and CD49f with associated hyperplasia. Further, activated mutant YB-1S102D enhances self-renewal, primary and secondary mammosphere growth, and soft agar colony growth, which were reversible via loss of CD44 or CD49f. We next addressed the consequence of this system on therapeutic responsiveness. Here we show that paclitaxel induces P-YB-1S102 expression, nuclear localization of activated YB-1, and CD44 expression. The over-expression of wild-type YB-1 promotes mammosphere growth in the presence of paclitaxel. Importantly, targeting YB-1 sensitized the CD44High/CD24Low cells to paclitaxel. In conclusion, YB-1 promotes cancer cell growth and drug resistance through its induction of CD44 and CD49f.