A Whole New Comprehension about ncRNA-Encoded Peptides/Proteins in Cancers

Abstract

It is generally considered that non-coding RNAs do not encode proteins; however, more recently, studies have shown that lncRNAs and circRNAs have ORFs which are regions that code for peptides/protein. On account of the lack of 5'cap structure, translation of circRNAs is driven by IRESs, m6A modification or through rolling amplification. An increasing body of evidence have revealed different functions and mechanisms of ncRNA-encoded peptides/proteins in cancers, including regulation of signal transduction (Wnt/β-catenin signaling, AKT-related signaling, MAPK signaling and other signaling), cellular metabolism (Glucose metabolism and Lipid metabolism), protein stability, transcriptional regulation, posttranscriptional regulation (regulation of RNA stability, mRNA splicing and translation initiation). In addition, we conclude the existing detection technologies and the potential of clinical applications in cancer therapy.

Keywords: cancers; clinical applications; peptides/proteins encoded by ncRNAs; translation mechanism.

Figure 1

Translation mechanisms of ncRNA-encoded peptides/proteins. Peptides/proteins encoded by ncRNAs exhibited their effect through modulating signal transduction, cellular metabolism, protein stability, transcriptional and post-transcriptional activity in cancers.

Figure 2

NcRNA-encoded peptides/proteins regulated signal transduction. (a) β-Catenin-370aa and AXIN1-295aa competitively bound to component(GSK-3β, APC) in destruction complex to activate Wnt/β-catenin pathway, promoting proliferation and metastasis in HCC and GC. (b) CIP2A-BP competitively bound to CIP2A, prohibiting p-AKT and TNBC metastasis; HER2-103 induced EGFR/HER3 homo/heterodimer formation and downregulated PI3K/AKT activation, promoting proliferation and invasion in TNBC; AKT3-174aa combine with PDK1 to stimulate p-AKT activation, prohibiting proliferation in GBM. (c) MAPK1-109aa and SMIM30 interacted with MEK1, SRC/YES1 to regulate MAPK signaling, influencing proliferation and metastasis in GC and HCC; ASK1-272aa competitively boundto AKT1 to activate ASK1/JNK/p38 signaling, promoting apoptosis in LAUD.

Figure 3

NcRNA-encoded peptides/proteins regulated cellular metabolism. (a) CircFNDC3B-218aa enhanced FBP1 and alleviated the Warburg effect, prohibiting proliferation and metastasis in CC; HOXB-AS3 peptide suppressed PKM splicing and PKM2 formation that was critical to the reprogramming of glucose metabolism, prohibiting proliferation and metastasis in CRC. (b) p113 combined with ZRF1/BRD4 to activate ALDH3A1, NDUFA1, and NDUFAF5 that were needed in conversion of fatty aldehydes into FAO, promoting proliferation and metastasis in neuroblastoma.

Figure 4

NcRNA-encoded peptides/proteins regulated protein stability. (a) FBXW7-185aa competitively interacted with USP28 to release FBXW7α and facilitated c-Myc degradation, inhibiting proliferation and metastasis in TNBC or inhibiting proliferation in GBM; EIF6-224 aa interacted with MYH9 to prohibited MYH9 degradation, promoting proliferation and metastasis in TNBC; SHPRH-146aa protected SHPRH from ubiquitination and induced PCNA degradation, promoting proliferation in GBM; circMAPK14-175aa competitively bound to MKK6 to repress p-MAPK14 and facilitated FOXC1 degradation, inhibiting proliferation and metastasis in CRC; circPLCE1-411 interacted with HSP90α/RPS3 to induce RPS3 dissociation, RPS3 interacted with HSP70-CHIP to induce RPS3 degradation, inhibiting proliferation and metastasis in CRC. (b) rtEGFR interacted with EGFR to reduce EGFR endocytosis and decrease EGFR ubiquitination in lysosomes, promoting proliferation in GBM.

Figure 5

Regulation of NcRNA-encoded peptides/proteins at transcription and posttranscription level. (a) PINT87aa bound to FOXM1 to inhibit PHB2 transcription, promoting cell senescence and prohibiting proliferation in HCC; PINT87aa recruited PAF1 to CPEB1 promoter, limiting the transcriptional elongation of CPEB1 and prohibiting proliferation in GBM. (b) circARHGAP35 protein interacted with TFII-I and upregulated the levels of downstream gene FOS, promoting proliferation and metastasis in HCC. (c) RBRP enhanced the recruitment of IGF2BP1 to the m6A-modified mRNA CRD of c-Myc and strengthened the binding of HuR, MATK3, PABPC1 to c-Myc, stabilizing c-Myc and promoting proliferation and metastasis in CRC; Hsa_circ_0006401 peptide served as an RBP to decrease col6a3 mRNA decay, promoting proliferation and metastasis in CRC. (d) SRSP strengthened the recognition and interaction of SRSF3 to induced L-Sp4 formation, promoting proliferation and metastasis in CRC. (e) APPLE facilitated PABPC1-eIF4G interaction to induce oncoprotein synthesis, promoting proliferation and self-renewal in AML.