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Micropeptide CIP2A‐BP encoded by LINC00665 inhibits triple‐negative breast cancer progression
Ist Teil von
The EMBO journal, 2020-01, Vol.39 (1), p.e102190-n/a
Ort / Verlag
England: Blackwell Publishing Ltd
Erscheinungsjahr
2020
Quelle
Wiley-Blackwell Journals
Beschreibungen/Notizen
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.
Synopsis
The role of signaling peptides translated from long non‐coding RNAs (lncRNA) in breast cancer remains unclear. Here, the micropeptide CIP2A‐BP is shown to act as tumor suppressor controlled by TGF‐β, providing an additional rheostat for cancer invasion and metastasis.
LINC00665 encodes the micropeptide CIP2A‐BP in human breast cancer cells.
CIP2A‐BP translation is decreased by TGF‐β/Smad4 through 4E‐BP1.
CIP2A‐BP inhibits cancer cell invasion in vivo and correlates with better patient survival.
CIP2A‐BP competes with PP2A for CIP2A binding facilitating inhibition of oncogenic PI3K/AKT/NFκB signaling.
Long non‐coding RNA‐translated micropeptide CIP2A‐BP impairs oncogenic CIP2A‐PI3K‐AKT signaling but is controlled by TGF‐β in the malignant state.