The EMBO journal, 2020-01, Vol.39 (1), p.e102190-n/a
2020
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- Autor(en) / Beteiligte
- Titel
- 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
- London: Nature Publishing Group UK
- 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. Graphical Abstract Long non‐coding RNA‐translated micropeptide CIP2A‐BP impairs oncogenic CIP2A‐PI3K‐AKT signaling but is controlled by TGF‐β in the malignant state.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0261-4189eISSN: 1460-2075DOI: 10.15252/embj.2019102190Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6939193
- Format
- –
- Schlagworte
- 1-Phosphatidylinositol 3-kinase, Adaptor Proteins, Signal Transducing - genetics, Adaptor Proteins, Signal Transducing - metabolism, AKT protein, Animals, Apoptosis, Autoantigens - genetics, Autoantigens - metabolism, Bioinformatics, Biomarkers, Tumor - genetics, Biomarkers, Tumor - metabolism, Biotechnology, Breast cancer, Cell Cycle Proteins - genetics, Cell Cycle Proteins - metabolism, Cell Proliferation, CIP2A‐BP, Disease Progression, EMBO03, EMBO32, EMBO36, Female, Gene Expression Regulation, Neoplastic, Gene regulation, Humans, Intracellular Signaling Peptides and Proteins - genetics, Intracellular Signaling Peptides and Proteins - metabolism, invasion and metastasis, Membrane Proteins - genetics, Membrane Proteins - metabolism, Metastases, Metastasis, Mice, Mice, Nude, Neoplasm Invasiveness, NF-κB protein, Non-coding RNA, Peptide Fragments - genetics, Peptide Fragments - metabolism, Peptides, Phosphatidylinositol 3-Kinases - genetics, Phosphatidylinositol 3-Kinases - metabolism, PI3K/AKT/NFκB pathways, Prognosis, Protein Phosphatase 2 - genetics, Protein Phosphatase 2 - metabolism, Proto-Oncogene Proteins c-akt - genetics, Proto-Oncogene Proteins c-akt - metabolism, RNA, Long Noncoding - genetics, Signal Transduction, Signaling, Smad protein, Smad4 protein, Smad4 Protein - genetics, Smad4 Protein - metabolism, Survival, Survival Rate, Therapeutic applications, TNBC, Transcription, Transforming Growth Factor beta - genetics, Transforming Growth Factor beta - metabolism, Transforming growth factor-b, Translation, Triple Negative Breast Neoplasms - genetics, Triple Negative Breast Neoplasms - metabolism, Triple Negative Breast Neoplasms - pathology, Triple Negative Breast Neoplasms - prevention & control, Tumor cell lines, Tumor Cells, Cultured, Tumor suppressor genes, Tumors, Xenograft Model Antitumor Assays