Micropeptide YG-6 encoded by exosomal LINC01123 derived from highly migratory ovarian cancer cells promotes tumor progression

Intercellular crosstalk plays a pivotal role in tumor progression and metastasis. Exosomes can package long non-coding RNAs (lncRNAs) to mediate extracellular communication. Although exosome research in various cancers has made remarkable progress, it remains unclear in ovarian cancer (OC) whether the cellular communication between OC cells with different metastatic potentials influences progression via exosomal-lncRNA. Besides, lncRNA can encode functional micropeptides, yet the association between OC and micropeptides encoded by exosomal-derived lncRNA has not been reported. OC cell-derived exosomes were characterized using transmission electron microscopy, nanoparticle tracking analysis, and WB. Exosomal lncRNA sequencing results of highly migratory OC cells (HMOs) and low migratory OC cells (LMOs) were analyzed, and LINC01123 was selected for further study. The effect of exosome LINC01123 on the function of LMOs was detected by the co-culture experiment. Bioinformatics prediction, mass spectrometry (MS), WB, and a series of functional experiments showed that LINC01123 encodes a small 59 aa peptide, named YG-6 (LINC01123 Yield peptide Gaining metastasis function: ORF no.6). Immunofluorescence, qPCR, WB, immunohistochemistry, and MS analysis were used to detect the endogenous expression of YG-6 in OC cells and tissues. The function of YG-6 in OC was investigated by detecting cell migration ability and observing tumor metastasis in nude mice. Mechanistically, the relationship between the YG-6 and ACTC1 in OC was verified by Co-Immunoprecipitation, WB, MS, immunofluorescence, and functional experiment. LINC01123 was significantly up-regulated in exosomes derived from HMOs and was readily internalized by LMOs, promoting their malignant behavior. Interestingly, LINC01123 encodes a small peptide composed of 59 amino acids, named YG-6, which exhibits endogenous high expression in OC cells and tissues. Functional experiments demonstrated that LINC01123 promotes tumor progression by encoding the peptide YG-6, rather than via an RNA-dependent mechanism. Furthermore, we identified ACTC1 as a binding protein of YG-6, which can synergistically activate the focal adhesion signaling pathway together with YG-6, thereby promoting the migration and adhesion of LMOs. Our findings not only demonstrate the YG-6 peptide encoded by LINC01123 as a potential prognostic biomarker for OC but also uncover a new mechanism of OC progression driven by YG-6 peptides.