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Micropeptide CIP2A-BP encoded by LINC00665 inhibits triple-negative breast cancer progression.
The EMBO Journal ( IF 9.4 ) Pub Date : 2019-11-22 , DOI: 10.15252/embj.2019102190
Binbin Guo 1 , Siqi Wu 1 , Xun Zhu 2 , Liyuan Zhang 3 , Jieqiong Deng 1 , Fang Li 1 , Yirong Wang 1 , Shenghua Zhang 1 , Rui Wu 1 , Jiachun Lu 4 , Yifeng Zhou 1
Affiliation  

TGF-β signaling pathway plays a key role in breast cancer metastasis. Recent studies suggest that TGF-β regulates tumor progression and invasion not only via transcriptional regulation, but also via translational regulation. Using both bioinformatics and experimental tools, we identified a micropeptide CIP2A-BP encoded by LINC00665, whose translation was downregulated by TGF-β in breast cancer cell lines. Using TNBC cell lines, we showed that TGF-β-activated Smad signaling pathway induced the expression of translation inhibitory protein 4E-BP1, which inhibited eukaryote translation initiation factor elF4E, leading to reduced translation of CIP2A-BP from LINC00665. CIP2A-BP directly binds tumor oncogene CIP2A to replace PP2A's B56γ subunit, thus releasing PP2A activity, which inhibits PI3K/AKT/NFκB pathway, resulting in decreased expression levels of MMP-2, MMP-9, and Snail. Downregulation of CIP2A-BP in TNBC patients was significantly associated with metastasis and poor overall survival. In the MMTV-PyMT model, either introducing CIP2A-BP gene or direct injection of CIP2A-BP micropeptide significantly reduced lung metastases and improved overall survival. In conclusion, we provide evidence that CIP2A-BP is both a prognostic marker and a novel therapeutic target for TNBC.

中文翻译:


LINC00665 编码的微肽 CIP2A-BP 可抑制三阴性乳腺癌进展。



TGF-β信号通路在乳腺癌转移中发挥关键作用。最近的研究表明,TGF-β不仅通过转录调节,而且还通过翻译调节来调节肿瘤进展和侵袭。利用生物信息学和实验工具,我们鉴定了 LINC00665 编码的微肽 CIP2A-BP,其翻译在乳腺癌细胞系中被 TGF-β 下调。使用TNBC细胞系,我们发现TGF-β激活的Smad信号通路诱导翻译抑制蛋白4E-BP1的表达,其抑制真核生物翻译起始因子elF4E,导致LINC00665的CIP2A-BP翻译减少。 CIP2A-BP直接结合肿瘤癌基因CIP2A,取代PP2A的B56γ亚基,从而释放PP2A活性,抑制PI3K/AKT/NFκB通路,导致MMP-2、MMP-9和Snail表达水平降低。 TNBC 患者中 CIP2A-BP 的下调与转移和较差的总生存率显着相关。在MMTV-PyMT模型中,引入CIP2A-BP基因或直接注射CIP2A-BP微肽均显着减少了肺转移并提高了总体生存率。总之,我们提供的证据表明 CIP2A-BP 既是 TNBC 的预后标志物,也是新的治疗靶点。
更新日期:2020-01-02
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