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Oncopeptide MBOP Encoded by LINC01234 Promotes Colorectal Cancer through MAPK Signaling Pathway

Chunyuan Tang,Ying Zhou,Wen Sun,Haihong Hu,Yuxi Liu,Lu Chen,Fengting Ou,Su Zeng,Nengming Lin,Lushan Yu

Simple SummaryColorectal cancer (CRC) claimed more than 900,000 lives globally in 2020. Therefore, its pathogenetic landscape calls for in-depth investigation. Recently, more attention has been paid to oncogenesis driven by noncoding RNAs and even peptides encoded by noncoding RNAs. Here, we report aLINC01234-encoded peptide named MEK1-binding oncopeptide (MBOP), which exists endogenously and is highly expressed in CRC. Through in vivo and in vitro migration and proliferation assays, we demonstrated the oncogenic role of MBOP. In addition, we performed immunoprecipitation assays to identify the interacting proteins and pathways, and MBOP was found to interact with MEK1 and activate the MEK1/pERK/MMP2/MMP9 signaling pathway. Moreover, the ubiquitin–protease-system-mediated degradation of MBOP was elucidated, where the E3 ubiquitin-protein transferase MAEA and RMND5A play vital roles. In conclusion, oncopeptide MBOP plays a substantial role in the tumorigenesis of CRC, and it could be a candidate prognostic biomarker for clinical treatment.AbstractColorectal cancer (CRC) ranks third in incidence rate and second in mortality rate of malignancy worldwide, and the diagnosis and therapeutics of it remain to be further studied. With the emergence of noncoding RNAs (ncRNAs) and potential peptides derived from ncRNAs across various biological processes, we here aimed to identify a ncRNA-derived peptide possible for revealing the oncogenesis of CRC. Through combined predictive analysis of the coding potential of a batch of long noncoding RNAs (lncRNAs), the existence of an 85 amino-acid-peptide, named MEK1-binding oncopeptide (MBOP) and encoded fromLINC01234was confirmed. Mass spectrometry and Western blot assays indicated the overexpression of MBOP in CRC tissues and cell lines compared to adjacent noncancerous tissues and the normal colonic epithelial cell line. In vivo and in vitro migration and proliferation assays defined MBOP as an oncogenic peptide. Immunoprecipitation trials showed that MEK1 was the key interacting protein of MBOP, and MBOP promoted the MEK1/pERK/MMP2/MMP9 axis in CRC. Two E3-ligase enzymes MAEA and RMND5A mediated the ubiquitin–protease-system-related degradation of MBOP. This study indicates that MBOP might be a candidate prognostic indicator and a potential target for clinical therapy of CRC.Keywords:peptide;MBOP;LncRNA;colorectal cancer;MAPK signaling pathway