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Emerging Role of Long Noncoding RNA-Encoded Micropeptides in Cancer

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Emerging Role of Long Noncoding RNA-Encoded Micropeptides in Cancer Ye et al. Cancer Cell Int (2020) 20:506 https://doi.org/10.1186/s12935-020-01589-x Cancer Cell International REVIEW Open Access Emerging role of long noncoding RNA- encoded micropeptides in cancer Mujie Ye1,2† , Jingjing Zhang3†, Meng Wei1,2, Baihui Liu1,2 and Kuiran Dong1,2* Abstract Increasing evidence has indicated that long noncoding RNAs (lncRNAs) play various important roles in the develop- ment of cancers. The widespread applications of ribosome profling and ribosome nascent chain complex sequenc- ing revealed that some short open reading frames of lncRNAs have micropeptide-coding potential. The resulting micropeptides have been shown to participate in N6-methyladenosine modifcation, tumor angiogenesis, cancer metabolism, and signal transduction. This review summarizes current information regarding the reported roles of lncRNA-encoded micropeptides in cancer, and explores the potential clinical value of these micropeptides in the development of anti-cancer drugs and prognostic tumor biomarkers. Keywords:: lncRNA, Open reading frame, Coding potential, Micropeptide, Cancer Background potential to encode functional micropeptides [12]. Func- Te mammalian genome produces huge numbers of tran- tional micropeptides are usually encoded by open reading scripts during the transcription process; however, about frames (ORFs) in ncRNAs, including lncRNAs, circR- 98% of human RNA transcripts are non-coding [1]. Non- NAs, and pre-miRNAs [13]. Current studies on lncRNA- coding RNAs can be classifed into microRNAs (miR- encoded peptides in humans have mainly focused on NAs), long noncoding RNAs (lncRNAs), circular RNAs their role in malignant tumors. Tese micropeptides (circRNAs), and small nucleolar RNAs (snoRNAs), all serve as oncogenic drivers or tumor suppressors, simi- of which have diferent regulatory functions[2]. Among lar to coding and noncoding genes, and play functional them, lncRNAs are a class of RNAs > 200 nucleotides roles in processes including cancer onset, promotion, long that do not code for proteins[3, 4]. Dysregulation of and progression by taking part in tumor angiogenesis, lncRNAs has been shown to be involved in physiologi- N6-methyladenosine (m6A) modifcation, signaling path- cal processes such as the regulation of gene expression way transduction, and cancer metabolism[1, 14]. [5], chromatin remodeling [6], maintenance of pluripo- Tere are several reasons why previous studies may tency[7], DNA damage repair [8], competing endogenous have failed to detect these peptides. First, micropep- RNAs [9, 10], and it also can participate in some patho- tides difer from conventional proteins in being very logical processes such as tumorigenesis [11]. short (normally < 100 aa) and in having a physicochemi- Developments in next-generation sequencing and cal structure unsuitable for traditional mass spectrom- advances in bioinformatics have revealed novel insights etry[15–17]. Second, micropeptides are commonly not into the roles and functions of lncRNAs, including their conserved, and are thus young gene products, in terms of human evolution[17–19]. Tird, most micropeptides are expressed at low levels, below the mass spectrometry *Correspondence: [email protected] threshold for peptide identifcation[20]. New methods † Mujie Ye, Jingjing Zhang contributed equally to this work as frst authors are therefore urgently needed to identify these micro- 2 Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai 201102, China peptides, potentially using bioinformatics to predict Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://crea- tivecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdo- main/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Ye et al. Cancer Cell Int (2020) 20:506 Page 2 of 9 lncRNAs that might encode peptides, followed by experi- of lncRNA-encoded micropeptides are longer than 10 mental verifcation. aa, many remain undetected[33]. Although graded MS can detect more putative micropeptides, it uses a refer- Prediction micropeptides by ORF, IRES, and m6A ence database, which thus limits its ability to predict sites novel micropeptides [34]. Terefore, Cardon et al. [34] An ORF is a theoretical aa-coding region, which is gen- exploited a large-scale and unsupervised method based erally identifed by analyzing the DNA nucleic acid on cross-linking MS followed by shotgun proteomics to sequence. ORF usually starts with ATG/AUG and gather information on the functional role of novel iso- extends to a stop codon [21]. Short ORFs are usually < 300 forms and novel proteins (AltProts), mapping them with nucleotides long [22, 23]. ORF Finder and ORF Predictor known pathways by identifying their reference protein are commonly used to search for ORFs in lncRNAs [24]. (RefProts) interactors. In addition, OpenProt database Regulatory elements such as IRES and m6A-modifed not only annotates RefProts, but also AltProts. It also pro- conserved sites bind upstream in the ORF to mediate vides supporting evidence for each protein, such as MS, translation[25, 26]. IRES recruit ribosomes and initiate protein homology and predictions of functional domains protein translation [27, 28]. LncRNAs with an IRES could [35]. MS is thus a powerful method for the discovery and translate a micropeptide on a continuous ORF [29, 30]. verifcation of endogenously expressed micropeptides; IRESite, IRESfnder, and IRESPred are currently used to however, although the presence of a micropeptide in the predict the existence of IRES in lncRNAs[24]. Te m6A MS spectra strongly supports its existence, its absence modifcation plays essential roles in both mRNAs and from the spectra does not necessarily mean that it does lncRNAs, and is recently revealed to have important not exist. efects on the translation process. Various endogenous Adding Flag or GFP fusion proteins at the C-terminus translatable lncRNAs may have m6A sites. Further stud- before the stop codon is the usual approach for detecting ies of m6A have identifed numerous predicted m6A micropeptides[36], and immunofuorescence detection of sites, including M6APred-EL, M6AMRFS, SRAMP, and GFP expression or western blotting to detect specifc Flag m6Acomet [24]. bands provides efective evidence for the existence of the peptides [37]. Tis evidence is enhanced by mutation of Experimental verifcation of peptides the start codon for GFP or the ORF [38], while prepara- Most research on micropeptides has been based on Ribo- tion of specifc monoclonal antibodies also confrms the seq and RNC-seq [17, 24]. During translation, ribosomes existence of polypeptides and facilitates the subsequent bind and move along the mRNA chain to synthesize search for proteins that interact with polypeptides [37, a peptide based on the codons, while forming a ribo- 38]. some nascent chain complex [31]. Integrated Ribo-seq Chen et al. [39] developed a strategy that combines and RNC-seq analysis identifed thousands of lncRNAs ribosome profling, MS-based proteomics, and CRISPR- with the potential to encode polypeptide. In addition, Lu based screens to explore and characterize the widespread et al. [17] performed shotgun proteomics and detected translation of functional micropeptides. Terefore, 308 lncRNA-encoded peptides and further verifed 207 each method has specifc advantages and disadvantages unique peptides by peptide multiple reaction and parallel (Table 1), and combinations of Ribo-seq, RNC-seq, MS, reaction monitoring. and fusion proteins could provide more accurate results. Mass spectrometry (MS), as the current gold standard LncRNA-encoded micropeptides have recently begun for protein detection, provides strong evidence for the to attract widespread attention. Furthermore, increas- existence of micropeptides[32]. However, as only 40% ing interest in micropeptides and improvements in Table 1 Experimental verifcation of peptides Techniques Advantages Disadvantages Ribo-seq Discover more potential peptides Indirect evidence of translation, expensive, poor repeatability RNC-seq High sequence coverage Low sequencing accuracy, and detection efciency unable to obtain ribosome and ORF information Mass spectrometry Strong evidence, Require specifc expertise, detect translation directly rely on protein databases to search Fusion protein Easy to detect May afect the structure and function of original protein Ye et al. Cancer Cell Int (2020) 20:506 Page 3 of 9 sequencing technologies mean that more and more lncR- CRC progression. Mechanically, SRSP interacted with the NAs have been shown to have the potential to encode RNA splicing regulator, SRSF3, to regulate mRNA
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