Table 2.

Tumor suppressor roles of various circRNAs in GI tumorigenesis through regulation of target genes and signaling pathways (↑: upregulated, ↓: downregulated).

Cancer types	circRNAs	Clinical studies	Animal studies	Cell line studies	Target genes/signaling pathways	Clinicopathological characteristics	Description	Ref.
Esophageal cancer	Circ-Foxo3	ESCC tissues = 94 pairs	BALB/c nude mice	KYSE510, ECA109, TE‐1, TE‐13	miR-23a, PTEN	Age, TNM stage, gender, tumor size, histological grade	↓Circ-Foxo3, ↓ miR-23a, ↑PTEN: ↓ ESCC progression	[46]
	Circ-TNRC6B	-ESCC tissues = 53 - Healthy tissue = 48	–	TE-1, KYSE-170, KYSE-30, KYSE-150	miR-452-5p, DAG1	T stage	↓Circ-TNRC6B, ↓miR-452-5p, ↑DAG1: ↓ ESCC invasion and proliferation	[86]
	Circ_0007624	Tissue sample	–	–	-miR-224-5p, CPEB3 - EGFR/PI3K/AKT pathway	Poor prognosis	↓Circ_0007624, ↓miR-224-5p, ↑CPEB3, ↓ EGFR/PI3K/AKT pathway: ↓ ESCC development	[87]
Gastric cancer	CircFAT1(e2)	GC = 38 case	BALB/c mice	GSE-1, SGC-7901, AGS, BGC-823, MKN-28, MGC-803, MKN-45	miR-548 g/RUNX1	Overall survival	↓ CircFAT1(e2), ↓ miR-548 g, ↑ RUNX1: ↓ Tumor progression	[47]
	CircRHOBTB3	GC tissue = 75 pairs	BALB/C nude mice	AGS, MKN45, HGC27	-miR-654-3p - p21 signaling	Tumor stage	↓CircRHOBTB3, ↓miRNA-654-3p, ↑p21 signaling: ↓ GC growth	[88]
	CircRTN4	Tissue sample	–	–	miR-424-5p, LATS2	Low survival rate	↑CircRTN4, ↓miR-424-5p, ↓LATS2: ↓ GC development	[89]
	circ-HN1	GC tissue = 30 pairs	–	GES-1, MKN-28, HGC-27, SGC-7901, AGS	miR-485-5p, GSK3A	–	↓Circ-HN1, ↓miR-485-5p, ↑GSK3A: ↓ GC progression	[90]
	CircEIF4G3	-GC tissue = 103 pairs - Serum = 120 from GC individuals - Serum = 50 from gastritis individuals - Serum = 120 normal controls	BALB/c nude mice	AGS, GSE-1, HGC-27, MKN-45, HEK-293 T, SGC-7901	miR-4449, SIK1, β-catenin pathway	TNM stage, venous invasion	↑CircEIF4G3, ↓miR-4449, ↑SIK1, ↓β-catenin pathway: ↓ GC development and metastasis	[91]
	hsa_circ_0026344	–	–	–	miR-590-5p, PDCD4	Tumor size, TNM stage, LNM	↓hsa_circ_0026344, ↓miR-590-5p, ↑PDCD4: ↓GC progression	[92]
	CircPFKP	GC tissue = 25 pairs	Nude mice	HGC-27, GES-1, MKN45, NCI–N87, SGC-7901, AGS	miR-644, ADAMTSL5	–	↑CircPFKP, ↓ miR-644, ↑ADAMTSL5: ↓ GC metastasis and proliferation	[93]
Colorectal cancer	CircRHOBTB3	CRC = 83 pairs	BALB/c nude mice	RKO, NCM460, HCT116, FHC, SW480, HT29, SW620, DLD-1, HCE8693, Colo320	HuR/PTBP1	Advanced clinical stages and greater risk of metastases	↓CircRHOBTB3, ↓ PTBP1: ↓ metastasis	[48]
	Circ0104103	Tissue samples	BALB/c nude mice	NCM460, CACO2, HCT116, HT29, DLD1, HCT8, SW620, SW480	LACTB, miR‐373‐5p	TNM stage, tumor invasion depth	↓Circ0104103, ↓miR‐373‐5p, ↑LACTB: ↓ CRC progression	[94]
	CircCUL2	–	Nude mice	HT290, FHC, HCT116, SW620, SW480	miR-208a-3p, PPP6C	TNM stage and distant metastasis	↓CircCUL2, ↓miR-208a-3p, ↑PPP6C: ↓ CRC proliferation	[95]
	CircITGA7	–	Mice	SW480, FHC, RKO, DLD1, Caco-2, HCT116, LoVo, SW620	-miR-370-3p, ITGA7, RREB1 -Ras signaling	TNM stage, tumor size, distant metastasis, lymph metastasis	↓CircITGA7, miR-370-3p, ↑ITGA7, ↓ RREB1, ↓ Ras signaling: ↓CRC development and metastasis	[96]
Hepatocellular carcinoma	CircDLC1	HCC = 110 case	BALB/c nude mice	Huh-7, SNU449, Hep3B, SK-Hep1, HepG2	MMP1	AFP level, BCLC stage, TNM stage, macrovascular invasion, microvascular invasion, OS, RFS	↓CircDLC1, ↓MMP1: ↓ HCC progression	[97]
	CircMTO1	HCC tissue = 289 pairs	Nude mice	HepG2, SK-Hep1, QGY-7701, SMMC-7721,	miR-9, p21	–	↓CircMTO1, ↓miR-9, ↑p21: ↓ HCC progression	[98]
	cSMARCA5	HCC tissue = 208 pairs	BALB/c nude mice	HCCLM3, Huh7, Hep3B, SMMC-7721, MHCC97H	miR-17-3p, miR-181b-5p, TIMP3	Poorer tumor differentiation, microvascular invasion, advanced tumor stage, tumor size, OS	↓cSMARCA5, ↓miR-17-3p and miR-181b-5p, ↑TIMP3: ↓ HCC development and metastasis	[99]
	CircC3P1	HCC tissue = 47 pairs	BALB/c nude mice	BEL7402, HL-7702, Hep3B, MHCC97-L, HuH7	miR-4641, PCK1	Age, gender, AFP, size, TNM, vascular invasion	↓CircC3P1, ↓miR-4641, ↑PCK1: ↓ HCC development and metastasis	[49]
	CircTRIM33–12	HCC = 150 case	Nude mice	SMMC-7721, HCCLM3, Huh 7, HepG2, MHCC97L	miR-191, TET1	Poor prognosis	↓CircTRIM33–12, ↓miR-191, ↑TET1: ↓ HCC progression and metastasis	[100]
Pancreatic cancer	CircANAPC7	–	Athymic nude mice	AsPC-1, HPDE, MIA PaCa-2, CFPAC-1, Panc-1, BxPC-3	CREB, miR-373, PHLPP2	–	↑CircANAPC7, ↓miR-373, ↓CREB, ↓PHLPP2: ↓ PC tumor growth and muscle wasting	[50]
	Circ_0047744	Tissue samples	–	HPDE6-c7, PANC-1	miR-21, SOCS5	LNM, positively correlated with OS	↓circ_0047744, ↓miR-21, ↑SOCS5: ↓PDAC metastasis	[101]
	Circ-STK39	Tissue sample	–	–	miR-140-3p, TRAM2	–	↓Circ-STK39, ↓ ↓miR-140-3p, ↓TRAM2: ↓ PC progression	[102]
	hsa_circRNA_001587	PC tissue = 67 pairs	BALB/C nude mice	HPDE, PC-3, AsPC-1, COLO357, PANC-1	miR-223, SLC4A4, MMP-2, MMP-9	Tumor differentiation, LNM	↓hsa_circRNA_001587, ↓miR-223, ↑SLC4A4: ↓ PC angiogenesis, migration and invasion	[103]

Circ-Foxo3 circular RNA forkhead box O3, Circ-TNRC6B circular RNA trinucleotide repeat containing adaptor 6B, CircRTN4 circular RNA reticulon 4, CircEIF4G3 circular RNA enhancer of eIF4G3, CircITGA7 circular RNA integrin subunit alpha 7, CircMTO1 circular RNA mitochondrial translation optimization 1 homolog, Circ-STK39 circular RNA serine/threonine kinase 39, PTEN phosphatase and tensin homolog, PI3K phosphoinositide 3-kinase, RUNX1 runt-related transcription factor 1, SIK1 salt inducible kinase 1, PTBP1 polypyrimidine tract-binding protein 1, LACTB lactamase beta, PPP6C protein phosphatase 6 catalytic subunit, ITGA7 integrin subunit alpha 7, MMP1 matrix metallopeptidase 1, TIMP3 tissue inhibitor of metalloproteinases-3, PCK1 phosphoenolpyruvate carboxykinase 1, TET1 tet methylcytosine dioxygenase 1, TRAM2 translocating chain-associated membrane protein 2.