Stress-response protein RBM3 attenuates the stem-like properties of prostate cancer cells by interfering with CD44 variant splicing.
Stress-response protein RBM3 attenuates the stem-like properties of prostate cancer cells by interfering with CD44 variant splicing.
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DOI：
10.1158/0008-5472.can-12-1343
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发表时间：
2013-05
期刊：
影响因子：
11.2
通讯作者：
Yu Zeng;D. Wodzenski;D. Gao;T. Shiraishi;N. Terada;Youqiang Li;Donald J. Vander Griend;Jun Luo
中科院分区：
文献类型：
--
作者：
Yu Zeng;D. Wodzenski;D. Gao;T. Shiraishi;N. Terada;Youqiang Li;Donald J. Vander Griend;Jun Luo
应激反应途径在癌症中起着重要作用。冷诱导RNA结合蛋白RBM 3在几种类型的癌症中上调，包括前列腺癌，但其致病作用尚未确定。与成人前列腺或CD 133-PrEC相比，RBM 3在人胎儿前列腺或CD 133（+）前列腺上皮细胞（PrEC）中以低基础水平表达，并且RBM 3在软琼脂中培养或暴露于应激的细胞中下调。值得注意的是，在前列腺癌细胞中RBM 3过表达减弱了它们在体外的干细胞样特性以及它们在体内的致瘤潜力。有趣的是，过度表达RBM 3或在32°C下培养细胞抑制了CD 44变体v8-v10的RNA剪接，并增加了标准CD 44（CD 44 s）同种型的表达。相反，沉默RBM 3或在软琼脂中培养细胞（在富集干细胞样细胞的条件下）增加了CD 44 v8-v10与CD 44 s mRNA的比率。机制研究表明，升高CD 44 v8-v10干扰MMP 9介导的CD 44 s切割和抑制细胞周期蛋白D1的表达，而siRNA介导的CD 44 v8-v10沉默损害前列腺癌细胞在软琼脂中形成集落的能力。总之，这些发现表明RBM 3通过抑制CD 44 v8-v10剪接而有助于前列腺癌中的干细胞样特征。我们的工作揭示了RBM 3在将应激调节的RNA剪接与肿瘤发生联系起来方面迄今未被认识的作用，在前列腺癌中具有潜在的预后和治疗意义。
Stress-response pathways play an important role in cancer. The cold-inducible RNA-binding protein RBM3 is upregulated in several types of cancer, including prostate cancer, but its pathogenic contributions are undetermined. RBM3 is expressed at low basal levels in human fetal prostate or in CD133(+) prostate epithelial cells (PrEC), compared with the adult prostate or CD133-PrEC, and RBM3 is downregulated in cells cultured in soft agar or exposed to stress. Notably, RBM3 overexpression in prostate cancer cells attenuated their stem cell-like properties in vitro as well as their tumorigenic potential in vivo. Interestingly, either overexpressing RBM3 or culturing cells at 32°C suppressed RNA splicing of the CD44 variant v8-v10 and increased expression of the standard CD44 (CD44s) isoform. Conversely, silencing RBM3 or culturing cells in soft agar (under conditions that enrich for stem cell-like cells) increased the ratio of CD44v8-v10 to CD44s mRNA. Mechanistic investigations showed that elevating CD44v8-v10 interfered with MMP9-mediated cleavage of CD44s and suppressed expression of cyclin D1, whereas siRNA-mediated silencing of CD44v8-v10 impaired the ability of prostate cancer cells to form colonies in soft agar. Together, these findings suggested that RBM3 contributed to stem cell-like character in prostate cancer by inhibiting CD44v8-v10 splicing. Our work uncovers a hitherto unappreciated role of RBM3 in linking stress-regulated RNA splicing to tumorigenesis, with potential prognostic and therapeutic implications in prostate cancer.