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Micropeptide CIP2A-BP encoded by LINC00665 inhibits triple-negative breast cancer progression.
- Source :
-
The EMBO journal [EMBO J] 2020 Jan 02; Vol. 39 (1), pp. e102190. Date of Electronic Publication: 2019 Nov 22. - Publication Year :
- 2020
-
Abstract
- 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.<br /> (© 2019 The Authors.)
- Subjects :
- Adaptor Proteins, Signal Transducing genetics
Adaptor Proteins, Signal Transducing metabolism
Animals
Apoptosis
Autoantigens genetics
Biomarkers, Tumor genetics
Cell Cycle Proteins genetics
Cell Cycle Proteins metabolism
Cell Proliferation
Disease Progression
Female
Humans
Intracellular Signaling Peptides and Proteins genetics
Membrane Proteins genetics
Mice
Mice, Nude
Neoplasm Invasiveness
Peptide Fragments genetics
Phosphatidylinositol 3-Kinases genetics
Phosphatidylinositol 3-Kinases metabolism
Prognosis
Protein Phosphatase 2 genetics
Protein Phosphatase 2 metabolism
Proto-Oncogene Proteins c-akt genetics
Proto-Oncogene Proteins c-akt metabolism
Signal Transduction
Smad4 Protein genetics
Smad4 Protein metabolism
Survival Rate
Transforming Growth Factor beta genetics
Transforming Growth Factor beta metabolism
Triple Negative Breast Neoplasms genetics
Triple Negative Breast Neoplasms metabolism
Triple Negative Breast Neoplasms pathology
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Autoantigens metabolism
Biomarkers, Tumor metabolism
Gene Expression Regulation, Neoplastic
Intracellular Signaling Peptides and Proteins metabolism
Membrane Proteins metabolism
Peptide Fragments metabolism
RNA, Long Noncoding genetics
Triple Negative Breast Neoplasms prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2075
- Volume :
- 39
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The EMBO journal
- Publication Type :
- Academic Journal
- Accession number :
- 31755573
- Full Text :
- https://doi.org/10.15252/embj.2019102190