PTEN expression is upregulated by a RNA-binding protein RBM38 via enhancing its mRNA stability in breast cancer.
PTEN expression is upregulated by a RNA-binding protein RBM38 via enhancing its mRNA stability in breast cancer.
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RNA 结合蛋白 RBM38 通过增强乳腺癌中 mRNA 的稳定性来上调 PTEN 表达
DOI：
10.1186/s13046-017-0620-3
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发表时间：
2017-10-19
期刊：
影响因子：
--
通讯作者：
Ding Q
中科院分区：
文献类型：
--
作者：
Zhou XJ;Wu J;Shi L;Li XX;Zhu L;Sun X;Qian JY;Wang Y;Wei JF;Ding Q
研究背景PTEN（phosphatase and tensin homolog gene on chromosome 10）是一种重要的肿瘤抑制基因，是磷脂酰肌醇-3-激酶（phosphatidylinositol-3-kinase，PI 3 K）/AKT信号通路的重要调控因子，参与细胞的生存、转移和更新。PTEN的表达与乳腺癌的表型、预后及药物选择密切相关。它主要受转录和转录后修饰的调控。RNA结合基序蛋白38（RBM 38）是一种RNA结合蛋白（RBP），是P53家族的一个靶蛋白，在细胞加工调控中起着重要作用，尤其是在转录后调控和基因转录中。方法采用免疫组化、慢病毒转染、Western blotting、qRT-PCR和ELISA等方法研究RBM 38对乳腺癌组织中PTEN表达的调控作用。采用RNA免疫沉淀、RNA电泳迁移率改变和双荧光素酶报告基因分析来鉴定RBM 38与PTEN转录本的直接结合位点。结果在乳腺癌组织和乳腺癌细胞中，PTEN的表达与RBM 38的表达呈正相关。此外，RBM 38通过与PTEN转录本3′-非翻译区（3′-UTR）的多个富含Au/U的元件（战神）结合，稳定了PTEN转录本，增强了PTEN的表达。另外，特异性抑制剂和小干扰RNA（siRNA）抑制了RBM 38对细胞增殖的抑制作用，提示RBM 38可能通过增强PTEN的表达而发挥抑癌作用。结论本研究揭示了一种新的PTEN调控机制，即RBM 38通过稳定PTEN的转录稳定性，这又减轻了RBM 38介导的生长抑制。
BackgroundPTEN (phosphatase and tensin homolog gene on chromosome 10), a well-characterized tumor suppressor, is a key regulator of the phosphatidylinositol-3-kinase (PI3K)/AKT pathway involved in cell survival, metastasis and cell renewal. PTEN expression is closely related to the phenotype, prognosis and drug selection in breast cancer. It is mainly regulated by transcriptional and post-transcriptional modifications. RNA binding motif protein 38 (RBM38), an RNA-binding protein (RBP) and a target of P53 family, plays a crucial role in the regulation of cellular processing, especially in post-transcription regulation and gene transcription. In this study, we investigated a new post-transcription regulation mechanism of PTEN expression by RBM38 in breast cancer.MethodsImmunohistochemistry, lentivirus transfections, Western blotting analysis, qRT-PCR and ELISA were used to conduct the relation between RBM38 and PTEN. RNA immunoprecipitation, RNA electrophoretic mobility shift and dual-luciferase reporter assays were employed to identify the direct binding sites of RBM38 with PTEN transcript. Colony formation assay was conducted to confirm the function of PTEN in RBM38-induced growth suppression.ResultsPTEN expression was positively associated with the expression of RBM38 in breast cancer tissues and breast cancer cells. Moreover, RBM38 stabilized PTEN transcript to enhance PTEN expression via binding to multiple AU/U- rich elements (AREs) in 3′-untranslated region (3′-UTR) of PTEN transcript. Additionally, specific inhibitors of PTEN activity and small interfering (siRNA) of PTEN expression inhibited RBM38-mediated suppression of proliferation, which implied that RBM38 acted as a tumor suppressor partly by enhancing PTEN expression.ConclusionThe present study revealed a new PTEN regulating mechanism that PTEN was positively regulated by RBM38 via stabilizing its transcript stability, which in turn alleviated RBM38-mediated growth suppression.
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