Micropeptide CIP 2A‐ BP encoded by LINC 00665 inhibits triple‐negative breast cancer progression

Abstract

TGF-b signaling pathway plays a key role in breast cancer metastasis. Recent studies suggest that TGF-b 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-b in breast cancer cell lines. Using TNBC cell lines, we showed that TGF-b-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 B56c subunit, thus releasing PP2A activity, which inhibits PI3K/AKT/NFjB 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.

The Challenges and Opportunities of LncRNAs in Ovarian Cancer Research and Clinical Use

“…According to the evidence provided about the molecular mechanisms of some of these reviewed lncRNAs, they could be druggable targets for small interfering RNAs or antisense oligonucleotides, but this therapy is not yet possible in clinical practice owing to delivery problems, which could be solved by ongoing nanotechnological approaches. Additionally, in a recently opened research line, lncRNAs were regarded as true coding RNAs producing small peptides of less than 100 amino acids, which could be the real effectors of the lncRNAs in the cells and could have profound implications for cancer physiology [193]. These lncRNAs and their derived peptides, which are also putative therapeutic targets to be tested in the next years, can be consulted in the database SmProt [175].…”

The lncRNA Toolkit: Databases and In Silico Tools for lncRNA Analysis

“…Recent studies revealed that some transcripts previously classified as lncRNAs encode micropeptides [ 55 , 56 , 57 ]. Micropeptides are polypeptides with a length of <150 amino acids (aa), transcribed from short ORFs (sORFs) [ 58 ].…”

Circular HER2 RNA positive triple negative breast cancer is sensitive to Pertuzumab

“…To date, functional peptides or proteins generated from unconventional regions, including long intergenic non-coding RNAs (LincRNAs), 5′ un-translational region (5'UTR) and circRNAs, have been adequately demonstrated [11][12][13]. We previously reported that open reading frame (ORF) in circRNAs driven by internal ribosomal entry site (IRES) translates functional proteins during glioblastoma tumorigenesis [14,15].…”