Table 1

Overview of circRNA functions and mechanisms in multiple signaling pathways

PI3K/AKT/mTOR signaling pathway
Pathway	Cancer	CircBase name	Location	Regulation	Mechanism		Putative function
PI3K/AKT/mTOR	CRC	circCDYL	C	Down	miR sponge/ceRNA	circCDYL/miR-150-5p promotes apoptosis	Represses cellular growth and migration
		circ_0001313	NI	Up		circ-0001313/miR-510-5p/AKT2 axis	Promotes development and progression of cancer
		hsa_circ_002144	C	Up		hsa_circ_002144/miR-615-5p/LARP1/mTOR axis	Promotes growth and metastasis
		circIL4R	C	Up		circIL4R/miR-761/TRIM29/PHLPP1	Promotes proliferation and metastasis
	GC	circNRIP1	C	Up		circNRIP1/miR-149-5p/AKT1/mTOR	Promotes GC proliferation, migration, and invasion
	Glioma	circ_0014359	C	Up		circ_0014359/miR-153/PI3K	Promotes glioma progression
	NSCLC	circFGFR3	NI	Up		circFGFR3/miR-22-3p/Galectin-1-AKT/ERK1/2 signaling	Galectin-1-AKT/ERK1/2 signaling
	HCC	circRNA-100338	C	Up		circRNA-100338/miR-141-3p/RHEB/mTOR	Poor prognosis
	Ovarian cancer	circPLEKHM3	C	Down		circPLEKHM3/miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis	Inhibits cell growth, migration, and EMT
	Breast cancer	circKDM4B	C	Down		circKDM4B/miR-675/NEDD4L	Inhibits cell angiogenesis and tumor metastasis
	PTC	circ_0067934	NI	Up		circ_0067934/miR-1301-3p/PI3K/AKT signaling pathway	Promotes cancer progression
	Pancreatic cancer	circ-ANAPC7	C	Down		circ-ANAPC7/miR-373/PHLPP2	Inhibits muscle wasting and cancer cachexia
	CRC	circ_LNLM	C	Up	Scaffold/binding with AKT	Blocks ubiquitination of AKT	Promotes the early metastasis especially for lymph node-negative CRC patients with synchronous liver metastasis
	OSCC	circ_0007059	NI	Down	Epigenetic modification	AKT/mTOR signaling pathway	Suppresses cell growth, migration, and invasion; facilitates apoptosis
	Glioblastoma	circ-AKT3	C	Down	Translation	AKT3-174 aa competitively interacts with phosphorylated PDK1	Inhibits glioblastoma tumorigenicity

Wnt/β-catenin signaling pathway
Pathway	Cancer	CircBase name	Location	Regulation	Mechanism		Putative function
Wnt/β-catenin	CRC	hsa_circ_0000523	NI	Down	miR sponge/ceRNA	hsa_circ_0000523Wnt/β-catenin	Inhibits cancer progression
		hsa_circ_0009361	C	Down		hsa_circ_0009361/miR-582/APC2 network	Induces cancer progression and EMT
		circRNA_100290	NI	Up		circRNA_100290/miR-516b/FZD4/Wnt/β-catenin	Oncogenic function
	DLBL	circEAF2	NI	Up		miR-BART19-3p/APC/β-catenin axis	Oncogenic function
	EC	hsa_circ_0002577	NI	Up		miR-197/CTNND1 axis, Wnt/β-catenin pathway	Oncogenic function
	Glioma	hsa_circ_0000177	NI	Up		hsa_circ_0000177/miR-638/FZD7-Wnt	Promotes cancer proliferation and invasion
	Bladder cancer	circPRMT5	C	Up		circPRMT5/miR-30c/Snail/E-cadherin	EMT and cancer metastasis
	Lung cancer	circ_0007059	NI	Down		circ_0007059/miR-378/Wnt/β-catenin	Inhibits progression and EMT process
	GC	circAXIN1	C	Up	Translation	Competitively interacts with APC	AXIN1-295 aa promotes GC progression
	TNBC	circ-EIF6	C	Up		circ-EIF6/EIF6-224 aa/MYH9/Wnt/β-catenin	Promotes TNBC progression
	Liver cancer	circβ-catenin	C	Up		Stabilizes full-length β-catenin by antagonizing degradation	Promotes liver cancer cell growth
	Colon cancer	circFNDC3B	C	Down		circFNDC3B-218 aa/Snail/FBP1	Inhibits cell proliferation, invasion, migration, and EMT
	RCC	circESRP1	C	Down	Feedback loop	circESRP1/miR-3942/CTCF/c-Myc/EMT	Inhibits cell proliferation and EMT
	HCC	circ-ZNF652	C	Up		circ-ZNF652/miR-203/Snail feedback loop	EMT and cancer metastasis
						circ-ZNF652/miR-502-5p/Snail feedback loop	EMT and carcinoma metastasis
	PTC	circRNA_102171	N	Up	TF	Modulates CTNNBIP1-dependent activation of the β-catenin pathway	Promotes PTC progression
	LSCC	circMTCL1	C	Up		Inhibits C1QBP ubiquitin degradation	Promotes progression

Notch and Hippo signaling pathways
Pathway	Cancer	CircBase name	Location	Regulation	Mechanism		Putative function
Notch	Glioma	circNFIX	NI	Up	miR sponge/ceRNA	circNFIX/miR-34a-5p/NOTCH1 pathway	Oncogenic function
	LADC	circ-MTO1	NI	Down		circ-MTO1/miR-17/QKI-5 feedback loop	Negatively regulates LUAD
	Breast cancer	circFAT1	NI	Up		circFAT1/miR-525-5p/spindle	Promotes cancer cell metastasis
	PDAC	circ-ASH2L	C	Up		circ-ASH2L/miR-34a	Oncogenic function
	CRC	circAPLP2	NI	Up		circAPLP2/miR-101-3p inhibits apoptosis	Promotes proliferation and metastasis
	T-ALL	circPVT1	NI	Up		circPVT1/miR-30e/DLL4	Promotes cell proliferation
	RCC	circPDK1	C	Up		circPDK1/miR-377-3P-NOTCH1	Promotes RCC cell migration and invasion
Hippo	GC	circRNA-000425	NI	Down	miR sponge/ceRNA	YAP1/circRNA-000425/miR-17 and miR-106	Inhibits cancer cell growth
	HCC	circ_104075	NI	Up		circ_104075/miR-582-3p/YAP1	Oncogenic function
	Osteosarcoma	circPIP5K1A	NI	Up		circPIP5K1A/miR-515-5p/YAP axis	Promotes cancer cell invasion and migration, and cancer stemness
	ICC	circACTN4	N and C	Up		circACTN4/miR-424-5p/YBX1/FZD7	Promotes tumor progression
	CRC	circ-LECRC	C	Down	Feedback loop	circ-LECRC/miR-135b-5p/KLF4; suppresses activation of YAP signaling	Inhibits tumor growth
	Colon cancer	circPPP1R12A	C	Up	Translation	circPPP1R12A-73 aa/Hippo-YAP	Promotes tumor pathogenesis and metastasis
	CRC	circ1662	C	Up	Nuclear accumulation	Promotes YAP1 nuclear accumulation and regulates smad3	Promotes CRC cell invasion and migration
	Breast cancer	circYap	NI	Down		circYap/eIF4G/PABP; negatively regulates YAP translation	Inhibits tumor growth

p53/Bcl2 signaling pathway
Pathway	Cancer	CircBase name	Location	Regulation	Mechanism		Putative function
p53/Bcl2	NSLC	circVANGL1	NI	Up	miR sponge/ceRNA	circVANGL1/miR-195/Bcl-2 axis	Inhibits proliferation and induced apoptosis
	HCC	circ-BIRC6	C	Up		circ-BIRC6/miR-3918/Bcl2 axis	Oncogenic function
	CRC	circ_0021977	NI	Down		circ_0021977/miR-10b-5p/p21/p53 axis	Suppresses cancer proliferation, migration, and invasion
	HNSCC	circPVT1	NI	Up		circPVT1/miR-497-5p/mut-p53/YAP/TEAD complex	Oncogenic function
	NSCLC	hsa_circ_0002874	NI	Up		hsa_circ_0002874/miR-1273f/MDM2/p53	Promotes resistance of NSCLC
	GC	hsa_circ_006100	NI	Up		hsa_circ_006100/miR-195/GPRC5A/Bcl-2 axis	Oncogenic function
	Osteosarcoma	circ_0001785	NI	Up		circ_0001785/miR-1200/HOXB2/Bcl-2 family	Oncogenic function
	OSCC	hsa_circ_0055538	NI	Down	Apoptosis	p53/Bcl-2/caspase signaling pathway	Inhibits tumor growth
	Osteosarcoma	circ_0007534	NI	Up		Bcl-2/caspase-3, AKT/GSK-3β pathway	Regulates cancer growth and apoptosis
	CRC	circZNF609	C	Down		circZNF609/p53	Promotes cancer apoptosis
	Glioma	circCHAF1A	NI	Up	Feedback loop	circCHAF1A/miR-211-5p/HOXC8/MDM2-p53	Facilitates glioma proliferation and tumorigenesis
		CDR1as	N	Down	Disruption of the p53/MDM2 complex	CDR1as directly interacts with p53	Inhibits gliomagenesis
	Breast cancer	circ-Ccnb1	NI	Down	mut-p53	circ-Ccnb1/H2AX/Bclaf1 complex inhibits mut-p53	Inhibits breast cancer progression
		circ-DNMT1	NI	Up	p53 nuclear translocation	Binding to p53 promotes nuclear translocation of both p53 and AUF1	Enhances breast cancer progression

TGF-β/Smad signaling pathway inducing EMT
Pathway	Cancer	CircBase name	Location	Regulation	Mechanism		Putative function
TGF-β/Smad	Bladder cancer	circRIP2	C	Down	miR sponge/ceRNA	circRIP2/miR-1305/TGF-β2/smad3	EMT and cancer progression
	NSCLC	circPTK2	C	Down		circPTK2/miR-429/miR-200b-3p/TGF-β/Smad	Inhibits EMT and metastasis
	OSCC	circANKS1B	C	Up		circANKS1B/miR-515-5p	Affects metastatic potential, EMT, and cisplatin resistance
	TNBC	circANKS1B	C	Up		circANKS1B/miR-148a-3p and miR-152-3pUSF1/TGF-β1/Smad	EMT and metastasis
	ESCC	circ-DOCK5	C	Down	Feedback loop	ZEB1/circ-DOCK5/miR-627-3p/TGF-β/Smad	EMT and metastasis
	OSCC	circUHRF1	C	Up		circUHRF1/miR-526b-5p/c-Myc/TGF-β1/ESRP1 feedback loop	Accelerates EMT and tumorigenesis
	CRC	circPTEN1	C and N	Down		Decreases nuclear translocation of Smad complexes	Suppresses cancer progression and EMT

C, cytoplasm; N, nucleus; NI, not investigated.