Micropeptide CIP2A-BP encoded by LINC00665 inhibits triple-negative breast cancer progression
Open accessAbstract
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.
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CIP2A supports NF-kB activity in ovarian cancer cells.
“On the other hand, the identified role of CIP2A in supporting NF-kB activity in OvCa cells is consistent with recent results from breast cancer cells (27).”
From Ovarian Cancers with Low CIP2A Tumor Expression Constitute an APR-246–Sensitive Disease Subtype (2022) · cites this paper as [27]
The identified role for CIP2A in supporting NF-kB activity in ovarian cancer cells is consistent with recent results from breast cancer cells.
“On the other hand, the identified role for CIP2A in supporting NF-kB activity in OvCa cells is consistent with recent results from breast cancer cells (28).”
From Ovarian cancers with low CIP2A tumor expression constitute an APR-246 sensitive disease subtype (2021) · cites this paper as [28]
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- [37]37. Sangodkar J, Farrington CC, McClinch K, Galsky MD, Kastrinsky DB, Narla G (2016) All roads lead to PP2A: exploiting the therapeutic potential of this phosphatase. FEBS J 283: 1004 -1024 ª 2019 The Authors The EMBO Journal 39: e102190 | 2020
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Ovarian Cancers with Low CIP2A Tumor Expression Constitute an APR-246–Sensitive Disease Subtype
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Ovarian cancers with low CIP2A tumor expression constitute an APR-246 sensitive disease subtype
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- Authors
- Guo, B., Wu, S., Zhu, X., Zhang, L., Deng, J., Li, F., Wang, Y., Zhang, S., Wu, R., Lu, J., & Zhou, Y.
- Affiliations
- Soochow University (CN)
- Second Affiliated Hospital of Soochow University (CN)
- Corresponding author
- Zhou, Yifeng
- ORCID
- Venue
- The EMBO Journal
- Published
- 2019-11-22
- Volume
- 39
- Issue
- 1
- Pages
- e102190-e102190
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC6939193
- OpenAlex
- W2991491391
- Semantic Scholar
- 676e6ea729e9e4f73a323e4ab8f3dd7481baf837
- Cited by
- 243
- References
- 54
- Citations by year
- 2026: 23 · 2025: 34 · 2024: 54 · 2023: 41 · 2022: 37 · 2021: 34 · 2020: 19 · 2019: 1
- FWCI
- 7.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81772544, 81972649, 81472630)
- Foundation for Distinguished Young Scholar in Jiangsu (BK20160008)
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- National Key R&D Program of China (2016YFC1302100)
- Program for Guangdong Introducing Innovative and Entrepreneurial Teams (2017ZT07S096)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- LINC00665, micropeptides, triple-negative breast cancer, TGF-beta signaling, Smad signaling, 4E-BP1, eIF4E, translational regulation, MMP-2, MMP-9, snails, lung metastasis, prognostic factors, therapeutic target
- MeSH terms
- Animals, Autoantigens, Female, Humans, Membrane Proteins, Mice, Nude, Neoplasm Invasiveness, Peptide Fragments, Prognosis, Tumor Cells, Cultured, Biomarkers, Tumor, Signal Transduction, Gene Expression Regulation, Neoplastic, Survival Rate, Transforming Growth Factor beta, Apoptosis, Disease Progression, Cell Cycle Proteins, Phosphatidylinositol 3-Kinases, Xenograft Model Antitumor Assays, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Cell Proliferation, Proto-Oncogene Proteins c-akt, Mice, Smad4 Protein, Protein Phosphatase 2, RNA, Long Noncoding, Triple Negative Breast Neoplasms
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