BAG3 regulates stability of IL-8 mRNA via interplay between HuR and miR-4312 in PDACs.
BAG3 regulates stability of IL-8 mRNA via interplay between HuR and miR-4312 in PDACs.
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BAG3 通过 PDAC 中 HuR 和 miR-4312 之间的相互作用调节 IL-8 mRNA 的稳定性
DOI：
10.1038/s41419-018-0874-5
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发表时间：
2018-08-28
影响因子：
9
通讯作者：
Wang HQ
中科院分区：
文献类型：
--
作者：
Li C;Jiang JY;Wang JM;Sun J;An MX;Li S;Yan J;Wang HQ
Bcl-2相关的凋亡基因3（BAG 3）在胰腺导管腺癌（PDAC）中高表达，其高表达似乎是PDAC患者的不良预后因素。在这项研究中，我们表明BAG 3敲低通过减少白细胞介素-8（IL-8）的产生显著降低PDAC的迁移和侵袭。BAG 3敲低通过RNA结合蛋白HuR和miR-4312的募集之间的相互作用在转录后水平调节IL-8的表达。HuR与位于IL-8转录物3′-非翻译区（UTR）的顺式元件结合以稳定IL-8转录物，而含有miR-4312的miRNA诱导的沉默复合物（miRISC）被募集到相邻的种子元件以使其不稳定。HuR的结合阻止Argonaute（Ago 2）的募集，克服miR-4312介导的IL-8翻译抑制。BAG 3敲低通过增加其在Ser 202处的磷酸化来减少HuR的细胞质分布，因此损害其募集，同时促进含有miRISC的miR-4312募集到IL-8转录物。此外，我们的数据表明，只有在Ser 387磷酸化的Ago 2与IL-8的转录相互作用。BAG 3敲低增加Ago 2在Ser 387处的磷酸化，从而进一步促进含有miRISC的miR-4312加载至IL-8转录物。综上所述，我们提出BAG 3通过HuR募集稳定IL-8转录物，随后抑制PDAC中含有miRISC的miR-4312的加载，从而促进侵袭。我们的研究结果揭示了一种新的途径，将BAG 3表达与增强的PDAC转移联系起来，从而使BAG 3成为胰腺癌干预的潜在靶点。
Bcl-2 associated athanogene 3 (BAG3) is highly expressed in pancreatic ductal adenocarcinoma (PDAC), and its high expression appears to be a poor prognostic factor for patients with PDAC. In this study, we show that BAG3 knockdown significantly decreases migration and invasion of PDACs via reduction of interleukine-8 (IL-8) production. BAG3 knockdown regulates IL-8 expression at the posttranscriptional levels via interplay between recruitment of RNA-binding protein HuR and miR-4312. HuR binds to the cis-elements located in the 3′-untranslational region (UTR) of the IL-8 transcript to stabilize it, whereas miR-4312-containing miRNA-induced silencing complex (miRISC) is recruited to the adjacent seed element to destabilize it. The binding of HuR prevents the recruitment of Argonaute (Ago2), overriding miR-4312-mediated translation inhibition of IL-8. BAG3 knockdown decreases cytoplasmic distribution of HuR via increasing its phosphorylation at Ser202, therefore compromising its recruitment while promoting recruitment of miR-4312 containing miRISC to IL-8 transcript. Furthermore, our data indicate that only phosphorylated Ago2 at Ser387 interacts with IL-8 transcript. BAG3 knockdown increases phosphorylation of Ago2 at Ser387, thereby further promoting loading of miR-4312 containing miRISC to IL-8 transcript. Taken together, we propose that BAG3 promotes invasion by stabilizing IL-8 transcript via HuR recruitment, and subsequently suppressing the loading of miR-4312 containing miRISC in PDACs. Our results reveal a novel pathway linking BAG3 expression to enhanced PDAC metastasis, thus making BAG3 a potential target for intervention in pancreatic cancer.
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BAG3 直接稳定己糖激酶 2 mRNA 并促进胰腺癌细胞中的有氧糖酵解
DOI：
10.1083/jcb.201701064
发表时间：
2017-12-04
期刊：
The Journal of cell biology
影响因子：
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作者：
An MX;Li S;Yao HB;Li C;Wang JM;Sun J;Li XY;Meng XN;Wang HQ
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Brody JR
影响因子：
11.2
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通讯作者：
Ristimäki, A
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作者：
Galbiati, Valentina;Carne, Alice;Corsini, Emanuela
通讯作者：
Corsini, Emanuela
影响因子：
16.6
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通讯作者：
Gallouzi, Imed-Eddine