Table 1.
Oncogenic 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 | LPAR3 | ESCC = 52 case | BALB/c nude mice | ECA109, HET-1A, TE-13, Kyse150, Kyse510, Kyse450 | -miR-198, MET -RAS/MAPK and PI3K/Akt axis |
Clinical stage and LNM | ↑ LPAR3, ↓ miR-198, ↑ MET, ↑ RAS/MAPK and PI3K/Akt signaling: ↑ Metastasis | [37] |
| CircAKT3 | EC = 82 case | Nude mice | KYSE-150, HEK-293T, TE-10, TE-1 | -miR-17-5p, RHOC, STAT3 | Tumor size, clinical tumor node metastasis staging, and lymphatic metastasis | ↑ CircAKT3, ↓ miR-17-5p, ↑ RHOC, STAT3: ↑ Cell proliferation, and metastasis | [51] | |
| Circ_LRP6 | ESCC = 78 pairs | Nude mice | TE-1, EC109 | -miR-182, Myc | Larger tumor size, later TNM stage | ↑Circ-LRP6, ↓ miR-182, ↑ Myc: ↑ Tumor progression | [52] | |
| hsa_circ_0067934 | EC = 51 pairs | – | TE-13, KYSE-410 | – | T stage, tumor differentiation, TNM stage | ↑hsa_circ_0067934: ↑ Cell proliferation | [53] | |
| hsa_circ_0000654 | ESCC = 55 case | BALB/c athymic nude mice | TE-1, HEEC, KYSE410, TE-13, KYSE45, ECA-109 | -miR-149-5p, IL-6, STAT3 | Higher T stage, local LNM | ↑hsa_circ_0000654, ↓ miR-149-5p, ↑ IL-6/STAT3: ↑ Cell proliferation, and metastasis | [32] | |
| Circ_0006168 | -EC at phase I + II = 17 case - EC at phase III + IV = 20 case |
– | ECA-109, HET-1A, KYSE-510 | miR-384, RBBP7 | – | ↑Circ_0006168, ↓miR-384, ↑RBBP7: ↑Cell proliferation, metastasis, and glycolysis | [54] | |
| CircFNDC3B | EC tissues = 23 pairs | – | ECA109, KYSE150 | FNDC3B | – | ↑CircFNDC3B, ↑FNDC3B: ↑Proliferation and metastasis | [55] | |
| hsa_circ_0000277 | ESCC tissues = 92 pairs | BALB/c nude mice | ECA109, Het1A, KYSE-410, EC9706, TE-1, KYSE-150, TE-10 | miR-4766-5p, LAMA1 | Advanced TNM stage, dismal prognosis | ↑hsa_circ_0000277, ↓miR-4766-5p, ↑LAMA1: ↑ ESCC progression | [56] | |
| CircNTRK2 | ESCC tissues = 56 pairs | BALB/c nude mice | Eca-109, Het-1A, EC-9706, TE-1, KYSE-150, KYSE-30 | miR-140-3p, NRIP1 | Advanced TNM stage, LNM | ↑CircNTRK2, ↓ miR-140-3p, ↑ NRIP1: ↑ ESCC development | [57] | |
| Gastric cancer | CircPVT1 | – | – | MGC-803, AGS | miR-125 family | Sex, age, tumor site, tumor size, differentiation grade, lymph node status, distant metastasis, TNM stage, T stage, lymphatic invasion, nervous invasion | ↑ CircPVT1, ↓ miR-125 family: ↑ Cell proliferation. | [58] |
| hsa_circ_0000745 | GC = 60 pairs | – | – | – | Lymphatic metastasis, differentiation, TNM stage, sex, age | ↓hsa_circ_0000745: ↑Gastric growth | [59] | |
| Circ_RanGAP1 | -GC tissue = 97 pairs. - GC plasma exosome = 30 case |
BALB/c (nu/nu) mice | HGC-27, AGS, MGC-803, GES-1, MKN45, KATOIII, BGC-823 |
VEGFA, miR-877-3p | Advanced TNM stage, LNM, and worse survival | ↑Circ-RanGAP1, ↓ miR-877-3p, ↑ VEGFA: ↑ Metastasis | [39] | |
| CiRS-7 | -GC tissue = 102 pairs. | BALB/c nude mice | HGC-27, MGC-803, GES-1 | -miR-7 -PTEN/PI3K/AKT signaling |
Tumor stages, distant metastasis, lymph node involvement, overall survival | ↑CiRS-7, ↓ miR-7, ↓PTEN: ↑ GC progression. | [60] | |
| CircAKT3 | GC tissues = 149 (cohorts 1, 2) | BALB/c nude mice | SGC7901, BGC823 | PIK3R1, miR-198 | Clinical stage, tumor size, histological grade | ↑CircAKT3, ↓miR-198, ↑PIK3R1: ↑ resistance to CDDP | [61] | |
| CircDLG1 | GC tissues = 126 case | BALB/c nude mice, C57BL/6 mice | HGC27, HEK293 T, BGC823, MFC, MKN45, MKN28, GES-1, SGC7901, AGS | miR-141-3p, CXCL12 | Age, Lauren's classification, sex, tumor size, peritoneal metastasis, tumor cell differentiation | ↑CircDLG1, ↓miR-141-3p, ↑CXCL12: ↑ GC progression and anti-PD-1 resistance | [62] | |
| CircNRIP1 | Tissue samples | BALB/c nude mice | BGC-823, GES-1, SGC-7901, HGC-27, MGC-803, AGS, MKN-45 | -miR-149-5p -AKT1/mTOR signaling |
Lymphatic invasion, tumor size, | ↑CircNRIP1, ↓miR-149-5p, ↑AKT1: ↑ Proliferation, invasion, and migration | [45] | |
| hsa_circ_0008035 | GC = 30 case | – | BGC-823, SGC-7901, GES-1, MGC-803, AGS | miR-375, YBX1 | – | ↑hsa_circ_0008035, ↓miR-375, ↑YBX1: ↑ Tumorigenesis | [63] | |
| Circ_0006282 | Tissue samples | BALB/c nude mice | BGC-823, GES-1, MKN-45, HGC-27, AGS | miR-155, FBXO22 | Tumor size, TNM stage, lymph node metastasis | ↑Circ_0006282, ↓miR-155, ↑FBXO22: ↑ GC progression | [33] | |
| hsa_circ_0001368 | GC tissue = 68 pairs | BALB/c (nu/nu) mice | HGC-27, HEK 293T, MGC-803, GES1, AGS, NUGC-3, | miR-6506–5p, FOXO3 | – | ↓hsa_circ_0001368, ↓miR-6506–5p, ↑FOXO3: ↓ GC progression | [64] | |
| Colorectal cancer | Circ_0084615 | CRC = 50 case | BALB/c athymic nude mice | HCT116, FHC, SW480, RKO, DLD1 | miR-599, DNMT3A | Age, gender, TNM stage, CEA, CA19-9, differentiation | ↑Circ_0084615, ↓ miR-599, ↑DNMT3A: ↑ CRC proliferation and metastasis | [40] |
| CircSPARC | CRC = 84 case | BALB/c female nude mice | HCT116, LoVo, SW620, HT-29, SW480, DLD1 | -miR-485-3p, p-STAT3 -JAK/STAT signaling |
Advanced TNM stage, poor survival, and LNM | ↑CircSPARC, ↓miR-485-3p, ↑JAK2: ↑ CRC proliferation and migration | [44] | |
| CircGLIS2 | CRC tissue = 3 pairs | – | NCM460, HCT-15, DLD1, HT-29, HCT-8, HCT116, RKO, | - miR-671 -NF-κB signaling |
– | ↑CircGLIS2, ↓miR-671, ↑ NF-κB signaling: ↑ CRC pro-metastasis microenvironment | [65] | |
| CircVAPA | CRC tissue = 60 pairs | – | HEK-293T, RKO, SW480, LoVo, SW620, HT29, HCT116, | miR-101 | Gender, age, tumor site, tumor size, lymphovascular invasion, differentiation, TNM stage, LNM | ↑CircVAPA, ↓miR-101: ↑ CRC progression | [66] | |
| hsa_circRNA_102958 | CRC = 58 case | BALB/c nude mice | LoVo, FHC, SW480, HCT116, SW620, HCT8, HT29 | miR-585/CDC25B | Tumor stage, LNM, differentiation, survival rate | ↑hsa_circRNA_102958, ↓miR-585, ↑CDC25B: ↑ Tumorigenesis | [67] | |
| hsa_circ_0007142 | Tissue sample | – | HT-29, HCT-116, LoVo, HCO | miR-103a-2-5p | Lymphatic metastasis and poor differentiation | ↑hsa_circ_0007142, ↓miR-103a-2-5p: ↑ CRC proliferation and migration | [68] | |
| CircSEMA5A | – | Nude mice | LoVo, NCM460, SW620, SW480, Caco-2 | miR-195-5p, CCNE1 | – | ↑CircSEMA5A, ↓miR-195-5p, ↑CCNE1: ↑ CRC development | [69] | |
| Circ-METTL9 | – | Nude mice | – | miR-551b-5p, CDK6 | – | ↑Circ-METTL9, ↓miR-551b-5p, ↑CDK6: ↑ CRC development | [70] | |
| CircLDLR | CRC tissue = 5 pairs | BALB/c nude mouse | HEK293T, Caco-2, HCT116, HT29, SW480, RKO, LoVo, SW620, HCT8, | miR-30a-3p/SOAT1 | TNM stage, overall survival | ↑CircLDLR, ↓miR-30a-3p, ↑SOAT1: ↑ CRC progression | [71] | |
| Hepatocellular carcinoma | CircRHOT1 | HCC tissue = 100 pairs | Nude mice | Huh7, Hep3B | NR2F6 | Overall survival | ↑CircRHOT1, ↑NR2F6: ↑ HCC progression | [72] |
| CircTMEM45A | HCC tissue = 68 pairs | BALB/c nude mice | LO2, Hep3B, HLE, Huh7, HCCLM6, BEL7402, HCCLM3, MHCC97H, SMCC7721, MHCC97L | miR-665, IGF2 | Poor prognosis, age, gender, HBsAg, cirrhosis, tumor size, tumor number, TNM stage, vascular invasion | ↑CircTMEM45A, ↓miR-665, ↑IGF2: ↑ HCC progression | [34] | |
| hsa_circ_0016788 | HCC tissue = 63 pairs | BALB/c nude mice | HepG2, LO2, Hep3B, MHCC97L, HCCLM3, Huh7 | miR-486, CDK4 | – | ↑hsa_circ_0016788, ↓miR-486, ↑CDK4: ↑ HCC tumorigenesis | [73] | |
| Circ-BIRC6 | HCC tissue = 55 pairs | BALB/c nude mice | HepG2, L02, Bel-7402, Rockville, Huh-7, MD, SMMC-7721, USA | miR-3918, Bcl2 | Age, serum alpha-fetoprotein level, gender, tumor size, TNM stage, vascular invasion | ↑Circ-BIRC6, ↓miR-3918, ↑Bcl2: ↑ HCC progression | [74] | |
| hsa_circRNA_103809 | HCC = 60 case | BALB/c nude mice | LO2, HCCLM3, MHCC97L, Hep3B, SK‐HEP‐1, Huh7 |
miR-377-3p, FGFR1, ERK, cyclin D1, CDK4, CDK6 | Age, AFP, HBsAg, cirrhosis, tumor size, Edmonson grade | ↑hsa_circRNA_103809, ↓miR-377-3p, ↑FGFR1, ↑ERK: ↑ HCC development | [75] | |
| CircMAT2B | – | Nude mice | Huh7, HepG2 | miR-338 -3p, PKM2 | Tumor size, Edmonson stage, vascular invasion, TNM stage, tumor encapsulation, tumor multiplicity |
↑CircMAT2B, ↓miR-338-3p, ↑PKM2: ↑ HCC glycolysis and malignancy | [76] | |
| hsa_circ_0000673 | HCC = 51 case | BALB/c (nu/nu) mice | Huh7, Hep3B | miR-767-3p, SET | Overall survival | ↑hsa_circ_0000673, ↓miR-767-3p, ↑SET: ↑ HCC malignancy | [77] | |
| Circ_0000517 | HCC = 45 case | BALB/c nude mice | THLE-2, HCCLM3, Huh7 | miR-326, IGF1R | – | ↑Circ_0000517, ↓miR-326, ↑IGF1R: ↑ HCC development | [78] | |
| CircMAST1 | HCC = 39 case | BALB/c nude mice | HepG2, SK-HepG1, L02, HCCLM3, Huh7 | miR-1299, CTNND1 | – | ↑CircMAST1, ↓miR-1299, ↑CTNND1: ↑HCC proliferation and migration | [79] | |
| hsa_circ_0056836 | Nude mice | HUH7, SK-HEP-1, SNU449, HEPG2 | miR-766-3p, FOSL2 | – | ↑hsa_circ_0056836, ↓miR-766-3p, ↑FOSL2: ↑ HCC proliferation and migration | [80] | ||
| Pancreatic cancer | Circ-PDE8A | PDAC = 93 case | Nude mice | BxPC-3, HEK-293, Capan-1, Aspc-1, Hs 766T, Hs 766T | -miR-338, MACC1 -MET signaling pathway |
TNM stage, lymphatic invasion, poor survival rate | ↑Circ-PDE8A, ↓miR-338, ↑MACC1, ↑MET/AKT, and ERK pathway: ↑ PDAC development and invasion | [81] |
| Circ-ADAM9 | PC tissue = 58 pairs | BALB/c nude mice | PANC1, HPDE, MiaPaca2, BxPC3, SW1990 | miR-217, PRSS3 | TNM stage, lymph node status | ↑Circ-ADAM9, ↓miR-217, ↑PRSS3: ↑ PC malignancy and behavior | [41] | |
| ciRS-7 | PDAC tissue = 41 pairs | – | PANC-1, BXPC-3, HPC-Y5 | -miR-7 - EGFR/STAT3 signaling |
Venous invasion, LNM | ↑ciRS-7, ↓miR-7, ↑EGFR/STAT3 signaling: ↑ PC proliferation and metastasis | [82] | |
| Circ CDR1as | PC = 27 case | BALB/c nude mice | PC-3, HPDE6-C7, PANC1, BXPC-3, ASPC1, MIApaCa-2, CFPAC-1 | miR-432-5p, E2F3 | – | ↑CircCDR1as, ↓miR-432-5p, ↑E2F3: ↑ PC progression | [83] | |
| hsa_circ_0006117 | PC = 20 case | – | SW1990, PaCa-2, BxPC-3, PANC-1, MIA, AsPC-1 | -miR-96-5p, -KRAS/MAPK Signaling | – | ↑hsa_circ_0006117, ↓miR-96-5p, ↑KRAS/MAPK Signaling: ↑ PC progression | [43] | |
| CircBFAR | PDAC = 208 case | SCID mice | BxPC-3, hTERT-HPNE, MIA PaCa-2, PANC-1, CFPAC-1 | -miR-34b-5p - MET/PI3K/Akt signaling |
Gender, age, BMI, smoking, tumor size, differentiation, T stage, TNM stage, Ki67 expression, neoadjuvant chemotherapy, lymphatic metastasis, adjuvant chemotherapy | ↑ CircBFAR, ↓ miR-34b-5p, ↑MET/PI3K/Akt signaling: ↑ PDAC progression | [42] | |
| hsa_circ_0014784 | PC = 10 case | Nude mice | SW1990, HPDE6-C7, PANC-1, AsPC-1, BxPC3, Capan-2 | miR-214-3p, YAP1 | – | ↑hsa_circ_0014784, ↓miR-214-3p, ↑YAP1: ↑ PC progression | [84] | |
| hsa_circ_0007367 | Frozen PC tissue = 25 pairs | BALB/c nude mice | AsPC-1, HPDE, BxPC-3, SW1990, Capan-1, PANC-1 | miR-6820-3p, YAP1 | LNM, advanced histological grade | ↑hsa_circ_0007367, ↓ miR-6820-3p, ↑ YAP1: ↑ PDAC progression | [85] |
PC pancreatic cancer, HCC hepatocellular cancer, GC gastric cancer, EC esophageal cancer, LPAR3 lysophosphatidic acid receptor 3, Circ_LRP6 circular RNA-lipoprotein receptor 6, CircPVT1 circular RNA plasmacytoma variant translocation 1, Circ_RanGAP1 circular RNA_ran GTPase-activating protein 1, CiRS-7 circular RNA sponge for miR-7, CircDLG1 circular RNA discs large homolog 1, CircSPARC circular RNA secreted protein acidic and rich in cysteine, CircSEMA5A circular RNA semaphorin 5A, Circ-METTL9 circular RNA methyltransferase like 9, CircLDLR circular RNA low-density lipoprotein receptor, CircTMEM45A circular RNA transmembrane protein 45A, CircMAST1 circular RNA microtubule associated serine/threonine kinase 1, Circ-PDE8A circular RNA phosphodiesterase 8A, Circ-ADAM9 circular RNA a disintegrin and metalloproteinase domain 9, MET mesenchymal epithelial transition, RHOC as homolog gene family member C, RBBP7 retinoblastoma-binding protein 7, VEGFA vascular endothelial growth factor A, DNMT3A DNA methyltransferase 3 alpha, JAK Janus kinase, STAT signal transducer and activator of transcription, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, CDC25B cell division cycle 25B, CCNE1 cyclin E1, CDK6 cyclin dependent kinase 6, SOAT1 sterol o-acyltransferase 1, NR2F6 nuclear receptor subfamily 2 group F member 6, CDK4 cyclin dependent kinase 4, Bcl2 B-cell lymphoma 2, PKM2 pyruvate kinase muscle 2, CTNND1 catenin delta 1, MACC1 metastasis-associated in colon cancer 1, PRSS3 protease, serine 3, KRAS kirsten rat sarcoma viral oncogene homolog, YAP1 yes-associated protein 1.