Regulation of alternative splicing of Bcl-x by BC200 contributes to breast cancer pathogenesis.
Regulation of alternative splicing of Bcl-x by BC200 contributes to breast cancer pathogenesis.
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DOI：
10.1038/cddis.2016.168
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发表时间：
2016-06-09
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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BC 200是一种长链非编码RNA（lncRNA），其参与蛋白质合成的调节，然而BC 200的失调是否有助于人类疾病的发病机制仍然是难以捉摸的。在这项研究中，我们发现BC 200在乳腺癌中上调;在乳腺肿瘤标本中，雌激素受体（ER）阳性的BC 200水平高于ER阴性的肿瘤。进一步的实验表明，雌激素信号传导的激活诱导BC 200的表达。为了确定ER调节的BC 200表达的意义，我们通过CRISPR/Cas9敲除（KO）BC 200。BC 200 KO通过表达促凋亡Bcl-xS同种型在体外和体内抑制肿瘤细胞生长。从机制上讲，BC 200含有与Bcl-x前体mRNA互补的17个核苷酸序列，这可能有助于其与Bcl-x前体mRNA的结合和异质核核糖核蛋白（hnRNP）A2/B1（一种已知的剪接因子）的募集。因此，hnRNP A2/B1干扰Bcl-x前mRNA与Bcl-xS促进因子Sam 68的结合，导致Bcl-xS表达的阻断。总之，这些结果表明，BC 200在乳腺癌中发挥致癌作用。因此，BC 200可以作为一个预后标志物和可能的目标，减弱失调的细胞增殖雌激素依赖性乳腺癌。
BC200 is a long non-coding RNA (lncRNA) that has been implicated in the regulation of protein synthesis, yet whether dysregulation of BC200 contributes to the pathogenesis of human diseases remains elusive. In this study, we show that BC200 is upregulated in breast cancer; among breast tumor specimens there is a higher level of BC200 in estrogen receptor (ER) positive than in ER-negative tumors. Further experiments show that activation of estrogen signaling induces expression of BC200. To determine the significance of ER-regulated BC200 expression, we knockout (KO) BC200 by CRISPR/Cas9. BC200 KO suppresses tumor cell growth in vitro and in vivo by expression of the pro-apoptotic Bcl-xS isoform. Mechanistically, BC200 contains a 17-nucleotide sequence complementary to Bcl-x pre-mRNA, which may facilitate its binding to Bcl-x pre-mRNA and recruitment of heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1, a known splicing factor. Consequently, hnRNP A2/B1 interferes with association of Bcl-x pre-mRNA with the Bcl-xS-promoting factor Sam68, leading to a blockade of Bcl-xS expression. Together, these results suggest that BC200 plays an oncogenic role in breast cancer. Thus, BC200 may serve as a prognostic marker and possible target for attenuating deregulated cell proliferation in estrogen-dependent breast cancer.
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