Background

The mammalian genome produces huge numbers of transcripts during the transcription process; however, about 98% of human RNA transcripts are non-coding [20]. New methods are therefore urgently needed to identify these micropeptides, potentially using bioinformatics to predict lncRNAs that might encode peptides, followed by experimental verification.

Prediction micropeptides by ORF, IRES, and m6A sites

An ORF is a theoretical aa-coding region, which is generally identified by analyzing the DNA nucleic acid sequence. ORF usually starts with ATG/AUG and extends to a stop codon [35]. MS is thus a powerful method for the discovery and verification of endogenously expressed micropeptides; however, although the presence of a micropeptide in the MS spectra strongly supports its existence, its absence from the spectra does not necessarily mean that it does not exist.

Adding Flag or GFP fusion proteins at the C-terminus before the stop codon is the usual approach for detecting micropeptides[36], and immunofluorescence detection of GFP expression or western blotting to detect specific Flag bands provides effective evidence for the existence of the peptides [37]. This evidence is enhanced by mutation of the start codon for GFP or the ORF [38], while preparation of specific monoclonal antibodies also confirms the existence of polypeptides and facilitates the subsequent search for proteins that interact with polypeptides [37, 38].

Chen et al. [39] developed a strategy that combines ribosome profiling, MS-based proteomics, and CRISPR-based screens to explore and characterize the widespread translation of functional micropeptides. Therefore, each method has specific advantages and disadvantages (Table 1), and combinations of Ribo-seq, RNC-seq, MS, and fusion proteins could provide more accurate results.

Table 1 Experimental verification of peptides
Full size table
Table 2 Information of micropeptides encoded by lncRNAs in cancers
Full size table

LncRNA-encoded micropeptides have recently begun to attract widespread attention. Furthermore, increasing interest in micropeptides and improvements in sequencing technologies mean that more and more lncRNAs have been shown to have the potential to encode micropeptides, especially in cancers. In this review, we summarize the functional reported micropeptides encoded by lncRNAs in cancers. The new roles of lncRNAs may provide novel perspectives for cancer diagnosis and treatment.

Tumor-related micropeptides encoded by lncRNAs

To date, lncRNAs have been shown to encode several functional micropeptides in various cancers. They are summarized as follows.

SMIM30

Through RIP-seq assay of ribosomal protein S6 (RPS6), Pang et al. focused on one lncRNA, linc00998, with coding potential in hepatocellular carcinoma (HCC). The small endogenous peptide encoded by linc00998 was named SMIM30 (Fig. 1A, Table 2). They also explored the function and mechanism of the micropeptide in HCC. The results showed patients with higher levels of SMIM30 had a poorer survival rate. SMIM30, rather than the lncRNA itself, facilitated HCC tumorigenesis by regulating cell proliferation and migration. Moreover, c-Myc increased SMIM30 transcription and SMIM30 promoted the non-receptor tyrosine kinase SRC/YES1, thus activating the MAPK signaling pathway[40].

Fig. 1
figure 1

Micropeptides encoded by lncRNAs regulate tumor malignant behaviors

a Linc00998 encodes micropeptide SMIM30 promotes HCC development by inducing SRC/YES1 membrane anchoring and MAPK pathway activation. b lncRNA LOC90024 encodes small protein SRSP induces "cancerous" Sp4 splicing variant formation. c Linc00908 encodes peptide ASPRS, which interacts directly with STAT3, thereby suppressing STAT3 phosphorylation. ASPRS also decreased VEGF levels and inhibited angiogenesis. d Linc00266 encodes RBRP peptide and RBRP interacts directly with IGF2BP1 thus promoting the mRNA stability of c-Myc by enhancing m6A recognition. e Micropeptide CASIMO1 are exerted via the SQLE protein and downstream ERK signaling pathway, thus affecting the cell metabolism equilibrium f LncRNA CRNDE encodes a peptide, CRNDEP, and the peptide promotes the formation of stress granules and affects cell proliferation and oxygen metabolism. g LncRNA HOXB-AS3 encodes the peptide HOXB-AS3 aa, which competitively binds hnRNP A1 and antagonizes hnRNP A1-mediated PKM splicing regulation. h IRES-dependent MELOE-3 aa antigens provide promising T cell targets for immunotherapy of melanoma. i Linc01420 encodes nobody, which binds EDC4 to regulate mRNA degradation. Linc01420 may promote nasopharyngeal carcinoma invasion and metastasis via this pathway. j LncRNA UBAP1-AST6 encodes UBAP1-AST6, which is a cancer-promoting factor in lung cancer cells.

Full size image

SRSP

Yan’s team discovered lncRNA LOC90024 encoded a small 130 aa micropeptide found in colorectal cancer (CRC), termed SRSP (Fig. 1B, Table 2). High expression of SRSP was positively associated with malignant phenotypes and poor prognosis in CRC patients. SRSP, not LOC90024 itself, promoted CRC carcinogenesis and development. And downregulation of SRSP inhibited CRC progression. Mechanically, SRSP interacted with the RNA splicing regulator, SRSF3, to regulate mRNA splicing. SRSP promoted SRSF3 binding to transcription factor Sp4 exon 3, contributed to promoting the formation of the “oncogene” long Sp4 isoform, and restrained the formation of the “tumor suppressor” short Sp4 isoform. Overall, their findings revealed that the lncRNA-encoded micropeptide SRSP promoted “oncogene” Sp4 splicing variant formation. SRSP is a potential prognostic biomarker and therapeutic target for CRC patients[41].

ASPRS

Linc00908 had been reported to be highly expressed in liver cancer and to interact with SOX4, thereby increasing its stability by inhibiting proteasomal degradation[42]. Linc00908 sponges with miR-483-5p in prostate cancer, and competitively reduces miR-483-5p targeting to TSPYL5 (testis-specific Y-encoded-like protein 5) to exert its anticancer function[43]. A recent study reported on a small 60 aa regulatory micropeptide of STAT3 (ASPRS) encoded by linc00908 in patients with triple negative breast cancer (TNBC) (Fig. 1C, Table 2). The peptide is downregulated in TNBC and its expression is negatively related to tumor growth and overall survival. Molecular research revealed that estrogen receptor alpha (one of the three most common breast cancer markers) bound to the promoter region of linc00908 and regulated ASPRS expression. Furthermore, ASPRS interacts directly with the STAT3 CCD domain (important for STAT3 autophosphorylation), thereby suppressing STAT3 phosphorylation. ASPRS also decreased vascular endothelial growth factor (VEGF) levels and inhibited angiogenesis. In addition, VEGF expression is obviously higher in TNBC than non-TNBC tissues. These studies suggest that the ASPRS peptide functions as a tumor suppressor via the STAT3/VEGF signaling pathway, and may represent a potential therapeutic target in patients with TNBC [37].

RBRP

Linc00266-1 was previously annotated as a lncRNA, but there were no relevant reports for it. However, Yang et al. predicted that linc00266 had the potential to code for a 71 aa polypeptide, referred to as RBRP (Fig. 1D, Table 2). RBRP is upregulated in CRC tissues and cells compared with controls, and high expression of RBRP is associated with a poor overall survival rate, and it acts as an independent prognostic factor in patients with CRC. In vitro and in vivo assays indicate that RBRP promoted CRC progression by affecting cell proliferation and metastasis. Further research demonstrated that RBRP interacted directly with the m6A reader insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) via a specific domain. RBRP, rather than linc00266-1, promoted the mRNA stability of the well-known oncogene c-Myc by enhancing m6A recognition on c-Myc mRNA via IGF2BP1. The study of the oncopeptide RBRP has thus revealed the diverse functions of lncRNAs and the close association between lncRNAs and m6A in carcinogenesis[36].

CASIMO1

CASIMO1, also known as small integral membrane protein 22 (SMIM22), was previously incorrectly annotated as a lncRNA, prior to the discovery of a novel 10 kDa microprotein (Fig. 1E, Table 2). It is upregulated in estrogen receptor/progesterone receptor-positive compared with hormone-negative breast cancers. Furthermore, knockdown of CASIMO1 leads to G0/G1 cell cycle arrest and inhibition of cancer cell proliferation, and this inhibition was shown to be caused by CASIMO1, rather than by the lncRNA. Loss of CASIMO1 is associated with disruption of the actin cytoskeleton organization, resulting in attenuated cell motility. Regarding its mechanism, CASIMO1 positively regulates squalene epoxidase (SQLE) and its downstream extracellular signal-regulated kinase phosphorylation as CASIMO1 interacted with SQLE spatially. SQLE is a known oncogene product and an essential enzyme in cholesterol synthesis in breast cancer. Furthermore, knockdown of SQLE results in a similar phenotype to CASIMO1 downregulation, and overexpression of SQLE partly rescues the effect of CASIMO1-knockdown. These results suggest that the effects of the micropeptide CASIMO1 are exerted via the SQLE protein and downstream ERK signaling pathway, thus affecting the cell metabolism equilibrium[44].

CRNDEP

Colorectal neoplasia differentially expressed (CRNDE) is a well-known lncRNA with key roles via various mechanisms in different kinds of cancers [63].

UBAP1-AST6

Ribo-seq and ribosome nascent chain complex sequencing (RNC-seq) were carried out to investigate lncRNAs that might encode micropeptides, and identified thousands of lncRNAs bound to ribosomes with putative protein-encoding capabilities. Based on laboratory evidence (mass spectrometry, bioinformatics, antibodies), > 300 proteins encoded by lncRNAs were verified, including UBAP1-AST6, which is widely present in human cell lines (lung cancer and hepatic carcinoma) and tissues (joint, placenta, and prepuce). Subsequent research showed that this micropeptide was located in the nucleus (Fig. 1J, Table 2). Moreover, UBAP1-AST6 promoted A549 cell proliferation and colony formation, and rescue assay confirmed the function of UBAP1-AST6 in lung cancer cells[17].

Other functional lncRNA-encoded micropeptides

In addition to directly participating in tumorigenesis, lncRNA-encoded micropeptides also exert important effects in inflammation, metabolism, and signal transduction pathways, which are also closely associated with cancer.

Metabolism

Linc00116 encodes a 56 aa peptide, Mtln, which is localized in mitochondria. Mtln interacts with NADH-dependent cytochrome b5 reductase and disrupts its mitochondrial localization, thereby increased oxygen consumption and respiratory complex I activity [64]. Consistent with this, another study also revealed that Mtln promoted Ca2+ buffering ability and mitochondrial respiration while inhibiting reactive oxygen species, thus enhancing respiratory efficiency [65].

Inflammation

Inflammation-modulating micropeptide (IMP) is a 44 aa micropeptide encoded by an unrecognized ORF of lncVLDLR. IMP was shown to be highly homologous to transcription factors related to inflammatory immune response factors, such as nuclear factor-κB. Overexpression of IMP in THP1 macrophages induces chemokine and cytokines levels, suggesting that it is involved in an inflammatory response by interacting with transcriptional coactivators [66].

Signaling

Micropeptides also participate in signaling pathways. For example, stress- and tumor necrosis factor (TNF)-α-activated ORF micropeptide (STORM) derived from linc00689 is actuated by TNF-α-induced and mammalian ste20-like kinase mediated phosphorylation of translation initiation factor eIF4E [67]. In addition, the micropeptide Toddler accelerates gastrulation by activating APJ/Apelin receptor signaling[68].

Future perspectives of micropeptides

New cancer treatments, such as immunotherapy and targeted therapy, have emerged in recent years, and their combinations with traditional surgery, radiotherapy, and chemotherapy have greatly improved the prognosis of some cancer patients; however, the overall survival rate for most patients remains poor[69, 70]. The health hazards and huge social burden associated with cancer have stimulated extensive research. Cancer-related lncRNAs are currently a hot research topic, especially in relation to lncRNA-encoded micropeptides. LncRNAs have been reported to be involved in carcinogenesis and tumor development in various ways, and the increasing role of lncRNA-encoded micropeptides has attracted a great deal of attention. Research has confirmed the existence and importance of lncRNA-encoded functional micropeptides. However, it is still difficult to assess lncRNA coding potential as the database used to predict the conservation of ORFs, IRES sequences, and m6A sites in lncRNAs is incomplete, and experimental validation approaches are still immature. Therefore, the actual number of micropeptides and their potential biological functions remain unclear.

In this paper, we reviewed the current literature on cancer-related lncRNA encoded-micropeptides and other classic peptides that are associated with inflammation, metabolism, and signal transduction. These studies provided novel perspectives on lncRNA biological functions and molecular mechanisms. Among them, ASPRS and HOXB-AS3 are tumor suppressors while RBRP, CASIMO1, CRNDEP, NoBody, UBAP1-AST6, and MELOE are defined as oncogenes. Similar to lncRNAs or coding genes, micropeptides are distributed in the cytoplasm and bind to specific proteins involved in signaling pathways [37, 44], or may be concentrated in the nucleus to impact mRNA stability [36] or kinase splicing [38]. Some of these micropeptides are conserved[38, 44, 49, 71], while many undiscovered micropeptides are likely to be non-conservative because they are the products of young genes. This indirectly suggests that known tumor-associated lncRNA-encoded conservative micropeptides are not produced by young genes in terms of human evolution, and these conserved micropeptides are likely to play an irreplaceable role in the biological process. As for the currently reported tumor-related lncRNA-encoded micropeptides, some are conserved, probably because conservation may reflect biological importance. But the majority of micropeptides are not conserved and it is not clear whether they have any biological function as they may be rapidly degraded after translation.

Indeed, in addition to lncRNA-encoded micropeptides, circRNAs and pri-miRNAs may also encode functional micropeptides[

Availability of data and materials

Not applicable.

Abbreviations

LncRNA:

Long noncoding RNA

circRNAs :

Circular RNAs

snoRNAs :

Small nucleolar RNAs

m6A :

N6-methyladenosine

BMP :

Bone morphogenetic protein

ORF :

Open reading frame

RPS6:

Ribosomal protein S6

HCC :

Hepatocellular carcinoma

CRC :

Colorectal cancer

ASPRS :

A small regulatory peptide of STAT3

TSPYL5 :

Testis-specific Y-encoded-like protein 5

TNBC:

Triple negative breast cancer

VEGF :

Vascular endothelial growth factor

RBRP :

RNA binding regulatory peptide

IGF2BP1 :

Insulin-like growth factor 2 mRNA-binding protein 1

CASIMO1 :

Cancer-associated small integral membrane open reading frame 1

SMIM22 :

Small integral membrane protein 22

SQLE :

Squalene epoxidase

CRNDE :

Colorectal neoplasia differentially expressed

HOXB-AS3 :

HOXB cluster antisense RNA 3

HNRNPA1 :

Heterogeneous nuclear ribonucleoprotein A1

PKM :

Pyruvate kinase M

IRES :

Internal ribosome entry site

NoBody :

Non-annotated P-body dissociating micropeptide

EDC4:

Enhancer of decap** proteins 4

Ribo-seq:

Ribosome profiling

RNC-seq :

Ribosome nascent chain complex sequence

aa :

Amino acid

CCNB1 :

Cyclin B1

EMT :

Epithelial-mesenchymal transition

SPAR :

Small regulatory polypeptide of amino acid response

SR :

Sarcoplasmic reticulum

DWORF :

Dwarf open reading frame

IMP:

Inflammation-modulating micropeptide

STORM :

Stress- and TNF-α-activated ORF micropeptide

MS :

Mass spectrometry

References

  1. Wu P, Mo Y, Peng M, Tang T, Zhong Y, Deng X, **ong F, Guo C, Wu X, Li Y, et al. Emerging role of tumor-related functional peptides encoded by lncRNA and circRNA. Mol Cancer. 2020;19(1):22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Adams BD, Parsons C, Walker L, Zhang WC, Slack FJ. Targeting noncoding RNAs in disease. J Clin Invest. 2017;127(3):761–71.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lan X, Wu N, Wu L, Qu K, Osoro EK, Guan D, Du X, Wang B, Chen S, Miao J, et al. The Human Novel Gene LNC-HC Inhibits Hepatocellular Carcinoma Cell Proliferation by Sequestering hsa-miR-183-5p. Mol Ther Nucleic Acids. 2020;20:468–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhang J, Chen G, Gao Y, Liang H. HOTAIR/miR-125 axis-mediated Hexokinase 2 expression promotes chemoresistance in human glioblastoma. J Cell Mol Med. 2020;24(10):5707–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Moghaddas SH, Hejazian M, Hosseinian KS, Ardalan M, Zununi VS. Long non-coding RNAs: An essential emerging field in kidney pathogenesis. Biomed Pharmacother. 2018;99:755–65.

    Article  CAS  Google Scholar 

  6. Han P, Chang CP. Long non-coding RNA and chromatin remodeling. RNA Biol. 2015;12(10):1094–8.

    Article  PubMed  PubMed Central  Google Scholar 

  7. **g R, Guo X, Yang Y, Chen W, Kang J, Zhu S. Long Noncoding RNA Q Associates with Sox2 and Is Involved in the Maintenance of Pluripotency in Mouse Embryonic Stem Cells. Stem Cells 2020.

  8. Liu R, Zhang Q, Shen L, Chen S, He J, Wang D, Wang Q, Qi Z, Zhou M, Wang Z. Long noncoding RNA lnc-RI regulates DNA damage repair and radiation sensitivity of CRC cells through NHEJ pathway. Cell Biol Toxicol 2020.

  9. Zhang R, Huang XQ, Jiang YY, Li N, Wang J, Chen SY. LncRNA TUG1 regulates autophagy-mediated endothelial-mesenchymal transition of liver sinusoidal endothelial cells by sponging miR-142-3p. Am J Transl Res. 2020;12(3):758–72.

    PubMed  PubMed Central  Google Scholar 

  10. Ye M, Ma J, Liu B, Liu X, Ma D, Dong K. Linc01105 acts as an oncogene in the development of neuroblastoma. ONCOL REP 2019.

  11. Sun P, Sun L, Cui J, Liu L, He Q. Long noncoding RNA HAS2-AS1 accelerates non-small cell lung cancer chemotherapy resistance by targeting LSD1/EphB3 pathway. AM J TRANSL RES. 2020;12(3):950–8.

    PubMed  PubMed Central  Google Scholar 

  12. Wang S, Mao C, Liu S. Peptides encoded by noncoding genes: challenges and perspectives. Signal Transduct Target Ther. 2019;4:57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhu S, Wang J, He Y, Meng N, Yan GR. Peptides/Proteins Encoded by Non-coding RNA: A Novel Resource Bank for Drug Targets and Biomarkers. FRONT PHARMACOL. 2018;9:1295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang J, Zhu S, Meng N, He Y, Lu R, Yan GR. ncRNA-Encoded Peptides or Proteins and Cancer. MOL THER. 2019;27(10):1718–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chen Y, Li Y, Zhong J, Zhang J, Chen Z, Yang L, Cao X, He QY, Zhang G, Wang T. Identification of Missing Proteins Defined by Chromosome-Centric Proteome Project in the Cytoplasmic Detergent-Insoluble Proteins. J PROTEOME RES. 2015;14(9):3693–709.

    Article  CAS  PubMed  Google Scholar 

  16. Omenn GS, Lane L, Overall CM, Corrales FJ, Schwenk JM, Paik YK, Van Eyk JE, Liu S, Snyder M, Baker MS, et al. Progress on Identifying and Characterizing the Human Proteome: 2018 Metrics from the HUPO Human Proteome Project. J PROTEOME RES. 2018;17(12):4031–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lu S, Zhang J, Lian X, Sun L, Meng K, Chen Y, Sun Z, Yin X, Li Y, Zhao J, et al. A hidden human proteome encoded by 'non-coding' genes. NUCLEIC ACIDS RES. 2019;47(15):8111–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhang G, Wang T, He Q. How to discover new proteins-translatome profiling. SCI CHINA LIFE SCI. 2014;57(3):358–60.

    Article  PubMed  Google Scholar 

  19. Franchini LF, Pollard KS. Genomic approaches to studying human-specific developmental traits. DEVELOPMENT. 2015;142(18):3100–12.

    Article  CAS  PubMed  Google Scholar 

  20. Khatun J, Yu Y, Wrobel JA, Risk BA, Gunawardena HP, Secrest A, Spitzer WJ, ** for ENCODE cell line data: identifying protein-coding regions. BMC GENOMICS. 2013;14:141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mo Y, Wang Y, **ong F, Ge X, Li Z, Li X, Li Y, Li X, **ong W, Li G, et al. Proteomic Analysis of the Molecular Mechanism of Lovastatin Inhibiting the Growth of Nasopharyngeal Carcinoma Cells. J CANCER. 2019;10(10):2342–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Frith MC, Forrest AR, Nourbakhsh E, Pang KC, Kai C, Kawai J, Carninci P, Hayashizaki Y, Bailey TL, Grimmond SM. The abundance of short proteins in the mammalian proteome. PLOS GENET. 2006;2(4):e52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Choi SW, Kim HW, Nam JW. The small peptide world in long noncoding RNAs. BRIEF BIOINFORM. 2019;20(5):1853–64.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Wu P, Mo Y, Peng M, Tang T, Zhong Y, Deng X, **ong F, Guo C, Wu X, Li Y, et al. Emerging role of tumor-related functional peptides encoded by lncRNA and circRNA. MOL CANCER. 2020;19(1):22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Legnini I, Di Timoteo G, Rossi F, Morlando M, Briganti F, Sthandier O, Fatica A, Santini T, Andronache A, Wade M, et al. Circ-ZNF609 Is a Circular RNA that Can Be Translated and Functions in Myogenesis. MOL CELL. 2017;66(1):22–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhang M, Zhao K, Xu X, Yang Y, Yan S, Wei P, Liu H, Xu J, **ao F, Zhou H, et al. A peptide encoded by circular form of LINC-PINT suppresses oncogenic transcriptional elongation in glioblastoma. NAT COMMUN. 2018;9(1):4475.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. King HA, Cobbold LC, Willis AE. The role of IRES trans-acting factors in regulating translation initiation. Biochem Soc Trans. 2010;38(6):1581–6.

    Article  CAS  PubMed  Google Scholar 

  28. Stoneley M, Willis AE. Cellular internal ribosome entry segments: structures, trans-acting factors and regulation of gene expression. ONCOGENE. 2004;23(18):3200–7.

    Article  CAS  PubMed  Google Scholar 

  29. Meganck RM, Borchardt EK, Castellanos RR, Scalabrino ML, Wilusz JE, Marzluff WF, Asokan A. Tissue-Dependent Expression and Translation of Circular RNAs with Recombinant AAV Vectors In Vivo. Mol Ther Nucleic Acids. 2018;13:89–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dudekula DB, Panda AC, Grammatikakis I, De S, Abdelmohsen K, Gorospe M. CircInteractome: A web tool for exploring circular RNAs and their interacting proteins and microRNAs. RNA BIOL. 2016;13(1):34–42.

    Article  PubMed  Google Scholar 

  31. Wang T, Cui Y, ** J, Guo J, Wang G, Yin X, He QY, Zhang G. Translating mRNAs strongly correlate to proteins in a multivariate manner and their translation ratios are phenotype specific. NUCLEIC ACIDS RES. 2013;41(9):4743–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Johansson HJ, Socciarelli F, Vacanti NM, Haugen MH, Zhu Y, Siavelis I, Fernandez-Woodbridge A, Aure MR, Sennblad B, Vesterlund M, et al. Breast cancer quantitative proteome and proteogenomic landscape. NAT COMMUN. 2019;10(1):1600.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Ji Z, Song R, Regev A, Struhl K. Many lncRNAs, 5'UTRs, and pseudogenes are translated and some are likely to express functional proteins. ELIFE. 2015;4:e8890.

    Google Scholar 

  34. Cardon T, Franck J, Coyaud E, Laurent E, Damato M, Maffia M, Vergara D, Fournier I, Salzet M. Alternative proteins are functional regulators in cell reprogramming by PKA activation. NUCLEIC ACIDS RES 2020.

  35. Vergara D, Verri T, Damato M, Trerotola M, Simeone P, Franck J, Fournier I, Salzet M, Maffia M. A Hidden Human Proteome Signature Characterizes the Epithelial Mesenchymal Transition Program. Curr Pharm Des. 2020;26(3):372–5.

    Article  CAS  PubMed  Google Scholar 

  36. Zhu S, Wang JZ, Chen, He YT, Meng N, Chen M, Lu RX, Chen XH, Zhang XL, Yan GR. An oncopeptide regulates m(6)A recognition by the m(6)A reader IGF2BP1 and tumorigenesis. NAT COMMUN. 2020;11(1):1685.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang Y, Wu S, Zhu X, Zhang L, Deng J, Li F, Guo B, Zhang S, Wu R, Zhang Z, et al: LncRNA-encoded polypeptide ASRPS inhibits triple-negative breast cancer angiogenesis. J EXP MED 2020, 217(3).

  38. Huang JZ, Chen M, Chen, Gao XC, Zhu S, Huang H, Hu M, Zhu H, Yan GR. A Peptide Encoded by a Putative lncRNA HOXB-AS3 Suppresses Colon Cancer Growth. MOL CELL. 2017;68(1):171–84.

    Article  CAS  PubMed  Google Scholar 

  39. Chen J, Brunner AD, Cogan JZ, Nunez JK, Fields AP, Adamson B, Itzhak DN, Li JY, Mann M, Leonetti MD, et al. Pervasive functional translation of noncanonical human open reading frames. SCIENCE. 2020;367(6482):1140–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pang Y, Liu Z, Han H, Wang B, Li W, Mao C, Liu S. Peptide SMIM30 promotes HCC development by inducing SRC/YES1 membrane anchoring and MAPK pathway activation. J HEPATOL 2020.

  41. Meng N, Chen M, Chen, Chen XH, Wang JZ, Zhu S, He YT, Zhang XL, Lu RX, Yan GR. Small Protein Hidden in lncRNA LOC90024 Promotes "Cancerous" RNA Splicing and Tumorigenesis. Adv Sci (Weinh). 2020;7(10):1903233.

    Article  CAS  Google Scholar 

  42. Hu X, Li Q, Zhang J. The Long Noncoding RNA LINC00908 Facilitates Hepatocellular Carcinoma Progression Via Interaction With Sox-4. CANCER MANAG RES. 2019;11:8789–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fan L, Li H, Zhang Y. LINC00908 negatively regulates microRNA-483-5p to increase TSPYL5 expression and inhibit the development of prostate cancer. CANCER CELL INT. 2020;20:10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Polycarpou-Schwarz M, Gross M, Mestdagh P, Schott J, Grund SE, Hildenbrand C, Rom J, Aulmann S, Sinn HP, Vandesompele J, et al. The cancer-associated microprotein CASIMO1 controls cell proliferation and interacts with squalene epoxidase modulating lipid droplet formation. ONCOGENE. 2018;37(34):4750–68.

    Article  CAS  PubMed  Google Scholar 

  45. **e H, Ma B, Gao Q, Zhan H, Liu Y, Chen Z, Ye S, Li J, Yao L, Huang W. Long non-coding RNA CRNDE in cancer prognosis: Review and meta-analysis. CLIN CHIM ACTA. 2018;485:262–71.

    Article  CAS  PubMed  Google Scholar 

  46. Liang C, Zhang B, Ge H, Xu Y, Li G, Wu J: Long non-coding RNA CRNDE as a potential prognostic biomarker in solid tumors: A meta-analysis. CLIN CHIM ACTA 2018, 481:99–107.

  47. Bai X, Wang W, Zhao P, Wen J, Guo X, Shen T, Shen J, Yang X. LncRNA CRNDE acts as an oncogene in cervical cancer through sponging miR-183 to regulate CCNB1 expression. CARCINOGENESIS. 2020. 41(1):111–21.

    Article  PubMed  Google Scholar 

  48. Zhu L, Yang N, Du G, Li C, Liu G, Liu S, Xu Y, Di Y, Pan W, Li X. LncRNA CRNDE promotes the epithelial-mesenchymal transition of hepatocellular carcinoma cells via enhancing the Wnt/beta-catenin signaling pathway. CELL BIOCHEM 2018.

  49. Szafron LM, Balcerak A, Grzybowska EA, Pienkowska-Grela B, Felisiak-Golabek A, Podgorska A, Kulesza M, Nowak N, Pomorski P, Wysocki J, et al. The Novel Gene CRNDE Encodes a Nuclear Peptide (CRNDEP) Which Is Overexpressed in Highly Proliferating Tissues. PLOS ONE. 2015;10(5):e127475.

    Article  CAS  Google Scholar 

  50. Jiang W, Kai J, Li D, Wei Z, Wang Y, Wang W. lncRNA HOXB-AS3 exacerbates proliferation, migration, and invasion of lung cancer via activating the PI3K-AKT pathway. J CELL PHYSIOL 2020.

  51. Zhang XM, Chen H, Zhou B, Zhang QY, Liao Y, Wang JS, Wang ZH. lncRNA HOXB-AS3 promotes hepatoma by inhibiting p53 expression. Eur Rev Med Pharmacol Sci. 2018;22(20):6784–92.

    PubMed  Google Scholar 

  52. Papaioannou D, Petri A, Dovey OM, Terreri S, Wang E, Collins FA, Woodward LA, Walker AE, Nicolet D, Pepe F, et al. The long non-coding RNA HOXB-AS3 regulates ribosomal RNA transcription in NPM1-mutated acute myeloid leukemia. NAT COMMUN. 2019;10(1):5351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhuang XH, Liu Y, Li JL. Overexpression of long noncoding RNA HOXB-AS3 indicates an unfavorable prognosis and promotes tumorigenesis in epithelial ovarian cancer via Wnt/beta-catenin signaling pathway. Biosci Rep 2019, 39(8).

  54. Wang T, Cui Y, ** J, Guo J, Wang G, Yin X, He QY, Zhang G. Translating mRNAs strongly correlate to proteins in a multivariate manner and their translation ratios are phenotype specific. NUCLEIC ACIDS RES. 2013;41(9):4743–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Godet Y, Moreau-Aubry A, Guilloux Y, Vignard V, Khammari A, Dreno B, Jotereau F, Labarriere N. MELOE-1 is a new antigen overexpressed in melanomas and involved in adoptive T cell transfer efficiency. J EXP MED. 2008;205(11):2673–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Godet Y, Moreau-Aubry A, Mompelat D, Vignard V, Khammari A, Dreno B, Lang F, Jotereau F, Labarriere N. An additional ORF on meloe cDNA encodes a new melanoma antigen, MELOE-2, recognized by melanoma-specific T cells in the HLA-A2 context. Cancer Immunol Immunother. 2010;59(3):431–9.

    Article  CAS  PubMed  Google Scholar 

  57. Charpentier M, Croyal M, Carbonnelle D, Fortun A, Florenceau L, Rabu C, Krempf M, Labarriere N, Lang F. IRES-dependent translation of the long non coding RNA meloe in melanoma cells produces the most immunogenic MELOE antigens. Oncotarget. 2016;7(37):59704–13.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Carbonnelle D, Vignard V, Sehedic D, Moreau-Aubry A, Florenceau L, Charpentier M, Mikulits W, Labarriere N, Lang F: The melanoma antigens MELOE-1 and MELOE-2 are translated from a bona fide polycistronic mRNA containing functional IRES sequences. PLOS ONE 2013, 8(9):e75233.

  59. Yang L, Tang Y, He Y, Wang Y, Lian Y, **ong F, Shi L, Zhang S, Gong Z, Zhou Y, et al. High Expression of LINC01420 indicates an unfavorable prognosis and modulates cell migration and invasion in nasopharyngeal carcinoma. J CANCER. 2017;8(1):97–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Konina DO, Filatova AY, Skoblov MY. LINC01420 RNA structure and influence on cell physiology. BMC GENOMICS. 2019;20(Suppl 3):298.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Zhai H, Zhang X, Sun X, Zhang D, Ma S. Long Non-coding RNA LINC01420 Contributes to Pancreatic Cancer Progression Through Targeting KRAS Proto-oncogene. Dig Dis Sci. 2020;65(4):1042–52.

    Article  CAS  PubMed  Google Scholar 

  62. Luo JZ, Qin L, Zhang LJ. Expression and function of long non-coding RNA LINC01420 in thyroid cancer. ONCOL LETT. 2020;19(1):399–405.

    CAS  PubMed  Google Scholar 

  63. D'Lima NG, Ma J, Winkler L, Chu Q, Loh KH, Corpuz EO, Budnik BA, Lykke-Andersen J, Saghatelian A, Slavoff SA. A human microprotein that interacts with the mRNA decap** complex. NAT CHEM BIOL. 2017;13(2):174–80.

    Article  CAS  PubMed  Google Scholar 

  64. Chugunova A, Loseva E, Mazin P, Mitina A, Navalayeu T, Bilan D, Vishnyakova P, Marey M, Golovina A, Serebryakova M, et al. LINC00116 codes for a mitochondrial peptide linking respiration and lipid metabolism. Proc Natl Acad Sci U S A. 2019;116(11):4940–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Stein CS, Jadiya P, Zhang X, McLendon JM, Abouassaly GM, Witmer NH, Anderson EJ, Elrod JW, Boudreau RL. Mitoregulin: A lncRNA-Encoded Microprotein that Supports Mitochondrial Supercomplexes and Respiratory Efficiency. CELL REP. 2018;23(13):3710–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hartford C, Lal A. When Long Noncoding Becomes Protein Coding. MOL CELL BIOL 2020, 40(6).

  67. Min KW, Davila S, Zealy RW, Lloyd LT, Lee IY, Lee R, Roh KH, Jung A, Jemielity J, Choi EJ, et al. eIF4E phosphorylation by MST1 reduces translation of a subset of mRNAs, but increases lncRNA translation. Biochim Biophys Acta Gene Regul Mech. 2017;1860(7):761–72.

    Article  CAS  PubMed  Google Scholar 

  68. Pauli A, Norris ML, Valen E, Chew GL, Gagnon JA, Zimmerman S, Mitchell A, Ma J, Dubrulle J, Reyon D, et al. Toddler: an embryonic signal that promotes cell movement via Apelin receptors. SCIENCE. 2014;343(6172):1248636.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Cortes J, Perez-Garcia JM, Llombart-Cussac A, Curigliano G, El SN, Cardoso F, Barrios CH, Wagle S, Roman J, Harbeck N, et al. Enhancing global access to cancer medicines. CA Cancer J Clin. 2020;70(2):105–24.

    Article  PubMed  Google Scholar 

  70. Park J, Hsu G, Siden EG, Thorlund K, Mills EJ. An overview of precision oncology basket and umbrella trials for clinicians. CA Cancer J Clin. 2020;70(2):125–37.

    Article  PubMed  PubMed Central  Google Scholar 

  71. D'Lima NG, Ma J, Winkler L, Chu Q, Loh KH, Corpuz EO, Budnik BA, Lykke-Andersen J, Saghatelian A, Slavoff SA. A human microprotein that interacts with the mRNA decap** complex. NAT CHEM BIOL. 2017;13(2):174–80.

    Article  CAS  PubMed  Google Scholar 

  72. Yang Y, Gao X, Zhang M, Yan S, Sun C, **ao F, Huang N, Yang X, Zhao K, Zhou H, et al: Novel Role of FBXW7 Circular RNA in Repressing Glioma Tumorigenesis. J Natl Cancer Inst 2018, 110(3).

  73. Zhang M, Huang N, Yang X, Luo J, Yan S, **ao F, Chen W, Gao X, Zhao K, Zhou H, et al: A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis. ONCOGENE 2018, 37(13):1805–1814.

  74. Brosa M, Garcia DM, Mora J, Villacampa A, Pozo T, Adan C, Grande M, Garcia E, Cubells L. Economic Considerations On the Use of Mifamurtide In the Treatment of Osteosarcoma In Spain. VALUE HEALTH. 2014;17(7):A526–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

The review was supported by National Natural Science Foundation of China (no. 81771633 and no. 81572324).

Author information

Author notes

  1. Mujie Ye, **g**g Zhang contributed equally to this work as first authors

Authors and Affiliations

  1. Department of Pediatric Surgery, Children’s Hospital of Fudan University, No.399 Wanyuan Road, Minhang District, Shanghai, 201102, China

    Mujie Ye, Meng Wei, Baihui Liu & Kuiran Dong

  2. Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, 201102, China

    Mujie Ye, Meng Wei, Baihui Liu & Kuiran Dong

  3. Department of Medical Imaging, Nan**g Hospital of Chinese Medicine Affiliated to Nan**g University of Chinese Medicine, Nan**g, 210001, China

    **g**g Zhang

Authors
  1. Mujie Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. **g**g Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meng Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Baihui Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kuiran Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

DK supervised the whole work and revised the manuscript, YM and ZJ made literature search and draft the manuscript of this review, WM and LB edited the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Kuiran Dong.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors agree with the final version of the manuscript and give their consent for its publication.

Competing interests

The authors declare that they have no competing interests.

Rights and permissions

Open Access 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://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ye, M., Zhang, J., Wei, M. et al. Emerging role of long noncoding RNA-encoded micropeptides in cancer. Cancer Cell Int 20, 506 (2020). https://doi.org/10.1186/s12935-020-01589-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12935-020-01589-x

Keywords: