Beyond traditional translation: ncRNA derived peptides as modulators of tumor behaviors

Abstract

Within the intricate tapestry of molecular research, noncoding RNAs (ncRNAs) were historically overshadowed by a pervasive presumption of their inability to encode proteins or peptides. However, groundbreaking revelations have challenged this notion, unveiling select ncRNAs that surprisingly encode peptides specifically those nearing a succinct 100 amino acids. At the forefront of this epiphany stand lncRNAs and circRNAs, distinctively characterized by their embedded small open reading frames (sORFs). Increasing evidence has revealed different functions and mechanisms of peptides/proteins encoded by ncRNAs in cancer, including promotion or inhibition of cancer cell proliferation, cellular metabolism (glucose metabolism and lipid metabolism), and promotion or concerted metastasis of cancer cells. The discoveries not only accentuate the depth of ncRNA functionality but also open novel avenues for oncological research and therapeutic innovations. The main difficulties in the study of these ncRNA-derived peptides hinge crucially on precise peptide detection and sORFs identification. Here, we illuminate cutting-edge methodologies, essential instrumentation, and dedicated databases tailored for unearthing sORFs and peptides. In addition, we also conclude the potential of clinical applications in cancer therapy.

Keywords: Cancer; Peptides; Protein; circRNAs; lncRNAs; ncRNA.

Fig. 1

The mechanism of peptides in the process of tumor proliferation. A TP53-induced peptide TP53LC04 inhibited the proliferation. B FORCP peptide inhibited basal cell proliferation and induced cell apoptosis by inhibiting BRI3BP protein function in well-differentiated colorectal cancer cells under ER stress. C MAPK1–109aa inhibited MAPK1 phosphorylation through competitive binding, and inhibiting the activation of MAPK1 and its downstream factors in the MAPK pathway. D MIAC interacts with AQP2 (Aquaporin 2) to inhibit the actin cytoskeleton by regulating SEPT2 (Septin 2)/ITGB4 (Integrin Beta 4) and ultimately suppressing the tumor growth and metastasis of HNSCC. E KRASIM decreases the KRAS, leading to the inhibition of ERK signaling activity. F ASAP enhanced the ATP synthase construction by interacting with the subunits α and γ (ATP5A and ATP5C), increasing ATP synthase activity and mitochondrial oxygen consumption rate. G CircAXIN1 encodes AXIN1-295aa, which competitively binds to APC, leading to the release and nuclear translocation of β-catenin. H MM cells secrete circHNRNPU into the BM microenvironment to regulate SKP2 exon skipping and inhibit c-Myc ubiquitin. I Linc013026-68AA is expressed in HCC cells and plays a role in cell proliferation

Fig. 2

The mechanism of peptides in the process of tumor metastasis. A MPM acted with NDUFA7 to inhibit the level of NAD + /NADH, thus inhibiting the metastasis of tumor cells. B circDIDO1 encoded a novel 529aa protein that directly interacted with poly ADP-ribose polymerase 1 (PARP1) and inhibited its activity. C miPEP133 prevent HSPA9 from interacting with its binding partners, leading to the decrease of mitochondrial membrane potential and mitochondrial mass. D CIP2A-BP binds CIP2A, thus releasing PP2A activity, resulting in decreased expression levels of MMP-2, MMP-9, and Snail. E SEMA4B-211aa inhibits the formation of p85/p110 complex then decreased p110 protein and decreased PI3K signal, finally inhibiting the metastasis. F sPEP1 directly binds to eEF1A1 to promote its interaction with SMAD4, upregulation of downstream target genes, and promotion of self-renewal and tumor metastasis. G EIF6-224aa directly interacted with MYH9, and decreased MYH9 degradation by inhibiting the ubiquitin–proteasome pathway and subsequently activating the Wnt/β-catenin pathway. H cGGNBP2- 184aa interacts with the STAT3, phosphorylates its Thy705 site and initiates the transcription of downstream target genes of STAT3. I Hsa_circ_0006401 peptides decreased the mRNA and protein level of the host gene col6a3 by promoting col6a3 mRNA stabilization. J circCOL6A3_030 promoted GC cell migration by encoding a small peptide called circCOL6A3_030_198aa

Fig. 3

Mechanism of action of peptides in other characteristic phenotypic processes of tumors. A CORO1C-47aa via blocking the association between ARNT and TACC3 and then reduces the expression of VEGFA. B ASRPS directly bound to STAT3 and down-regulated STAT3 phosphorylation, which led to reduced expression of VEGF. C Gln starvation induces ER stress and UPR to activate XBP1 pathway, then XBP1s upregulates transcription of MLLT4-AS1 and expression of XBP1SBM, inhibiting the interaction of XBP1u and XBP1s to enhance the nuclear localization of XBP1s, thereby promoting the transcription and expression of VEGF, and finally drives the metastasis of TNBC. D MP31 limits lactate-pyruvate conversion in mitochondria by competing with mitochondrial lactate dehydrogenase (mLDH) for nicotinamide adenine dinucleotide (NAD +) and then inhibited glioblastoma xenografts. E APPLE promotes PABPC1-eIF4G interaction and facilitates mRNA circularization and eIF4F initiation complex assembly to support a specific pro-cancer translation program. F circCHEK1_ 246aa increased MM CIN and osteoclast differentiation. G Interaction between the HBVPTPAP and the PILRA endo-domain activated by the negative regulation of the downstream JAK/STAT pathway, which initiated the mitochondrial pathway to induce apoptosis. H pep-AP inhibits PPP, increasing the accumulation of ROS and mitochondrial dysfunction. I circMRPS35-168aa suppressed the cisplatin-induced apoptosis via inhibiting the cleavage of caspase-3. J PACMP not only prevents CtIP from ubiquitination by inhibiting the CtIP-KLHL15 association but also directly binds DNA damage-induced poly (ADP-ribose) chains