Expanding uncapped translation and emerging function of circular RNA in carcinomas and noncarcinomas

Wang, Yan; Wu, Chunjie; Du, Yu; Li, Zhongwei; Li, Minle; Hou, Pingfu; Shen, Zhigang; Chu, Sufang; Zheng, Junnian; Bai, Jin

doi:10.1186/s12943-021-01484-7

Molecular Cancer

Table 1 Overview of translated circRNAs and circ-proteins in carcinomas and noncarcinomas

From: Expanding uncapped translation and emerging function of circular RNA in carcinomas and noncarcinomas

Diseases	Translated circular RNAs				Circ-proteins						Ref.
Diseases	CircRNAs	Length (nt)	Ribosome binding	Translation mechanism	Circ-proteins	Length (aa)	Cellular location	Sequences covering domain of host protein	Expression (Up/Down)	Function and mechanism	Ref.
Carcinomas
GBM	circE-cadherin (hsa_circ _0039992)	733	reads across BSJ in ribosome-Seq	IRES	C-E-Cad	254	Membrane, same to E-cadherin	Unique 14-aa tail at C-termini of C-E-Cad besides shared aa 282-522 at N-terminal of E-cadherin	Up	Unique 14-aa had new function that bond to the CR2 domain of EGFR, promoted STAT3 phosphorylation and nuclear translocation to interact with EGFRvIII, inducing GBM.	[46]
GBM	circSMO (hsa_circ _0001742)	727	In M and L polysomes fractions	IRES	SMO-193a.a	193	Cytoplasm and Membrane, same to SMO	Shared aa 230-421 at N-terminal of SMO covering most seven transmembrane domains besides one Glu at its C-termini	Up	Shared motif bond to N-terminal of SMO to translocate cholesterol, freed SMO from patched transmembrane receptors to maintain CSC self-renewal, inducing GBM.	[51]
GBM	circEGFR (hsa_circ_0080229)	249	In M and L polysomes fractions	Rolling translation	rtEGFR	83	Membrane, same to EGFR	shared aa 561-627 across extracellular domain IV of EGFR besides unique 19 amino acids, has similar function with EGFR	Up	Shared motif bond to extracellular Domain IV of EGFR to increase EGFR stability and membrane localization, attenuating its endocytosis and degradation, inducing GBM.	[57]
GBM	circSHPRH (hsa_circ_0001649)	440	undetected	IRES	SHPRH-146aa	146	unknown	shared aa1520–1651 covering the SNF2 domain of SHPRH besides 8-aa at its C-termini	Up	Shared motif as a decoy competitively bond to DTL to prevent its ubiquitination SHPRH which could ubiquitinate PCNA, inhibiting GBM.	[52]
GBM	circLINC-PINT (hsa_circ_0082389)	1084	two readers across BSJ by RNC-seq	IRES	PINT87aa	87	Nucleus, same to PINT	shared amino acids at N-terminal of PINT besides 10-aa at its C-termini	Down	Bond to the domain of PAF1 as an anchor keeping PAF1 complex on target genes’ promoter to repress transcriptional elongation and GBM.	[63]
GBM	circAKT3 (hsa_circ_0017250)	524	undetected	IRES	AKT3-174aa	174	Cytoplasm, similar to AKT3	shared aa 62-232 covering PH-domain and thr-308 of AKT3 besides 3-aa at its C-termini	Down	Shared motif bond to PDK1 to activate it, blocking AKT phosphorylation, inhibiting GBM.	[54]
GBM	circFBXW7 (hsa_circ_022705)	620	undetected	IRES	FBXW7-185aa	185	unknown	shared 167-aa with FBXW7a besides 18-aa at its C-termini	Down	Shared motif as decoy competitively bond to USP28, releasing FBXW7a to degrade c-Myc, inhibiting GBM.	[53]
TNBC	circFBXW7 (hsa_circ_022705)	620	undetected	IRES	FBXW7-185aa	185	unknown	shared 167-aa with FBXW7a besides 18-aa at its C-termini	Down	Increased the abundance of FBXW7 and inducing c-Myc degradation, inhibiting TNBC.	[53]
TNBC	circHER2 (hsa_circ_0007766)	676	In M and L polysomes fractions	IRES	HER2-103	103	Membrane, same to HER2	shared 103 amino acids at N-terminal (aa 198-300) of HER2 covering most CR I domain of HER2 for EGFR/HER3 homo/heterodimer.	Up	Bond to CR I domain of HER2, stimulated EGFR/HER3 homo/heterodimer formation, phosphorylation and activation of AKT to sensitize Pertuzumab treatment of HER-103⁺ TNBC.	[64]
GC	circDIDO1 (hsa_circ_0061137)	1787	undetected	IRES	DIDO1-529aa	529	Nucleus, different from DIDO1-1a	shared 529 amino acids with NLS and PHD domain, lack of nuclear export sequence of DIDO1-1a	Down	Contrary to DIDO1-1a. bond to DNA binding domain and catalytic domain of PARP1 to block its activity, repressing GC,	[60]
GC	circMAPK1 (hsa_circ_0004872)	490	undetected	IRES	MAPK1-109aa	109	Cytoplasm, similar to MAPK1	shared aa 98-203 covering phosphorylated sites of MAPK1 besides 3-aa at its C-termini	Down	Contrary to MAPK1, competitively bond to MEK1 to block extracellular signals to intracellular signals for MAPK phosphorylation, repressing GC.	[59]
CC	circFNDC3B (hsa_circ_0006156)	526	undetected	IRES	circFNDC3B-218aa	218	Cytoplasm, similar to FNDC3B	shared 509 amino acids with FNDC3B besides 17-aa at its C-termini	Down	Attenuated Snail expression, enhanced FBP1-induced OXPHOS to repress CC.	[58]
HCC	circβ-catenin (hsa_circ_0004194)	1129	undetected	IRES	β-catenin-370aa	370	Cytoplasm, similar to β-catenin	shared 361 amino acids at N-terminal of β-catenin besides 9-aa at its C-termini	Up	As a decoy binding to GSK3β to prevent it degrade β-catenin, freed β-catenin activated Wnt/β-catenin pathway, promoting HCC.	[48]
HCC and CRC	circARHGAP35 (hsa_circ_0109744)	3867	in M polysomes fractions	m⁶A modification	p-circARHGAP35	1289	Nucleus, opposite to ARHGAP35	shared most amino acids at N-terminal of ARHGAP35 containing four FF domains lack of Rho GAP domain	Up	Contrary to ARHGAP35, shared motif interacted with nuclear TFII-I protein, promoting progression of HCC and CRC.	[56]
CRC	circPPP1R12A (has_circ_0000423)	1138	undetected	undetected	circPPP1R12A-73aa	73	unknown	shared 55 amino acids besides 17-aa unique tail	Up	Activated Hippo-YAP pathway to promote CRC, which is different from PPP1R12A.	[49]
CRC	circLgr4 (hsa_circ_02276)	unknown	undetected	undetected	circLgr4-peptide	19	Cytoplasm and nucleus	has 19-aa	Up	Interacted with extracellular domain LGR4 to activate Wnt/β-catenin pathway, promoting self-renewal and metastasis of CSC, driving CRC.	[50]
CRC	circPLCE1 (hsa_circ_0019223)	1570	undetected	IRES	circPLCE1 411	411	Cytoplasm	shared aa 1-403 at N-terminal of PLCE1 protein with distinct function with PLCE1, besides own 8-aa tail	Down	Bond to ATP binding domain of HSP90α to accelerate RPS3 to dissociate from the HSP90α/RPS3 complex, leading to the HSP70-induced ubiquitin-dependent degradation of RPS3 and suppression of NF-κB pathway, blocking CRC.	[61]
Bladder cancer	circGprc5a (hsa_circ_02838)	unknown	undetected	undetected	circGprc5a-peptide	11	unknown	unknown	Up	bind to Gprc5a to activate the GPCR signalling pathway and promote self-renewal and metastasis of cancer stem cells	[47]
MM	circCHEK1 hsa_circ_0024792	738	undetected	IRES	circCHEK1_246aa	246	unknown	shared N-terminus of CHEK1, has same function with CHEK1	Up	induced Chromosomal Instability and bone lesion formation by interaction with and decrease mutant CEP170	[62]
Cervical cancer	circE7	472	in polysomes fractions	m⁶A modification	E7 oncoprotein	98	Cytoplasm	Shared most amino acids with E7 protein harbouring unique sequences	Up	E7 oncoprotein is independent for the transforming activity of circE7 promoting progress of cervical cancer	[65]
Noncarcinomas
CR	circNlgn (hsa_circ_0003046)	813	In heavy polysomes fractions	IRES	Nlgn173	173	Nucleus, different from Nlgn	9-aa tail at Nlgn173 C-termini for nuclear localization besides 164-aa at N- terminal of Nlgn	Up	Unique 9-aa motif interacts with the LaminB1 forcing nuclear localization of Nlgn173 to promote SGK3 and inhibit ING4, inducing Cardiac Remodelling, which is different Nlgn.	[66]
AD	circAβ-a (hsa_circ_0007556)	524	undetected	IRES-like A/U-rich sequences	Aβ175	175	unknown	remaining 158-aa approaching to C-terminal of Amyloid β peptide	Up	Its expression raised in brain tissues of AD patients	[67]
Synaptic function	circMbl	unknown	Ribosome binding	IRES-like UTR	none	unknown	Cytoplasm	unknown	Up	maybe linked to regulation of synaptic function	[45]
DMD	circZNF609	unknown	M and L polysomes	IRES-like UTR	none	753	unknown	unknown	Up	Linked to myoblast proliferation	[38]
Lifespan extending	circSfl	unknown	Ribosome binding	unknown	none	unknown	unknown	Sharing N-terminus with cytoplasmic and transmembrane domain	Up	extending lifespan of fruit flies	[68]

ORF Open Reading Framework, BSJ back splice junction, IRES Internal Ribosome Entry Site, GBM glioblastoma, rtEGFR rolling translation EGFR, TNBC Triple-Negative Breast Cancer, GC gastric cancer, CC colon cancer, CRC colorectal carcinoma, HCC hepatocellular carcinoma, MM multiple myeloma, CR Cardiac Remodeling, AD Alzheimer’s Disease, DMD Duchenne Muscular Dystrophy, m⁶A, N6-methyladenosine, UTR Untranslated Region

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