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.
Keywords: TNBC; CIP2A-BP; PI3K/AKT/NFκB pathways; invasion and metastasis.
© 2019 The Authors.
Conflict of interest statement
The authors declare that they have no conflict of interest.
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- 81772544/National Natural Science Foundation of China (NSF)
- 81972649/National Natural Science Foundation of China (NSF)
- 81472630/National Natural Science Foundation of China (NSF)
- BK20160008/Foundation for Distinguished Young Scholar in Jiangsu
- Priority Academic Program Development of Jiangsu Higher Education Institutions