The Role of Fusobacterium nucleatum in Colorectal Cancer Cell Proliferation and Migration
"> Figure 1
<p>An overview of the EMT process during which Fn is involved in the development of CRC.</p> "> Figure 2
<p>Fn reprograms the TME by recruiting tumor-infiltrating immune cells and prometastatic cytokines.</p> "> Figure 3
<p>A schematic of the effect of FadA in disrupting adherence junctions in CRC cells. In adherence junctions, E-cadherin and β-catenin form complexes on epithelial cell membranes and bind to the actin cytoskeleton to maintain cell–cell adhesion. When FadA invades, it can bind to E-cadherin, resulting in its separation from β-catenin and subsequent activation of β-catenin signaling, leading to a reduction in cell–cell adherence between cancer cells.</p> "> Figure 4
<p>A schematic of oncogene expression regulated by Fn in CRC metastasis.</p> "> Figure 5
<p>An overview of the molecular mechanisms by which Fn is associated with CRC proliferation and migration.</p> ">
Abstract
:Simple Summary
Abstract
1. Introduction
2. Potential Mechanisms by Which Fn May Promote CRC Proliferation and Migration
2.1. Proliferative Effects on Primary Tumor
2.2. Induction of Epithelial–Mesenchymal Transition
2.2.1. E-Cadherin/β-Catenin Complex
2.2.2. Cancer Stem-Like Cells
2.2.3. Autophagy Signaling
2.3. Reshaping the Tumor Microenvironment
2.3.1. Tumor-Infiltrating Immune Cells
2.3.2. Prometastatic Cytokines
2.3.3. Tumor Metabolism
2.3.4. Tumor-Associated Microbiota
2.4. Oncogenic ncRNAs
2.4.1. LncRNAs
2.4.2. miRNAs
2.5. DNA Damage
3. Discussion
3.1. Current Status
3.2. Future Directions
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Abbreviations | Full Name | Abbreviations | Full Name |
---|---|---|---|
APC | adenomatous polyposis coli | lncRNAs | long noncoding RNAs |
ATCC | American Type Culture Collection | MDSCs | myeloid-derived suppressor cells |
CCSCs | colorectal cancer stem-like cells | miRNAs | microRNAs (small ncRNAs) |
CDX | cell-derived xenograft | ncRNAs | noncoding RNAs |
CSCs | cancer stem-like cells | PDX | patient-derived xenograft |
ECM | extracellular matrix | TAMs | tumor-associated macrophages |
EMT | epithelial–mesenchymal transition | TANs | tumor-associated neutrophils |
FadA | Fusobacterium nucleatum adhesin A | TEXs | tumor-derived exosomes |
Fn | Fusobacterium nucleatum | TME | tumor microenvironment |
Mechanisms | References | Fn Strain | Models | Findings | Experiment | Metastatic Sites | ||
---|---|---|---|---|---|---|---|---|
Signaling | Upregulates | Downregulates | ||||||
Induced EMT | ||||||||
E-cadherin/β-catenin | [24] | F01 ATCC 10953 | CRC tissue SW480, Caco-2 | Activates β-catenin signaling via a TLR4/p-PAK1/β-catenin S675 cascade | β-catenin TLR4 PAK1 c-Myc cyclin D1 | In vitro | ||
[25] | ATCC 25586 | CRC tissue DLD-1, SW480 | Activates Wnt/β-catenin and IL-6/STAT3 signaling via upregulation of Cdk5 | CDK5 β-catenin c-Myc cyclin D1 p-STAT3 IL-6,8 COX-2 TNF-β | In vitro | |||
[3] | ATCC 25586 | AOM/DSS mice | Impairs the function of the intestinal barrier and the aberrant activation of EMT | Ki-67 NETO2 ANGPTL4 PCK1 | E-cadherin | In vivo | ||
[26] | ATCC 25586 (FadA) | CRC tissue HCT29, HT116 CDX mice, APCMin/+ mice | Activates the E-cadherin/β-catenin pathway, leading to the upregulation of chk2 | chk2 β-catenin Ki-67 PCNA | E-cadherin | In vitro In vivo | ||
[27] | ATCC 25586 | NCM460 | Interacts with E-cadherin and enhances the malignant phenotype of CRC cells | NF-κB p65 IL-6 IL-1β MMP-13 TNF-α | In vitro | |||
[29] | Fn-Ex (TEXs) | HCT116, SW480 CDX mice | Activates the Wnt/β-catenin pathway | β-catenin vimentin c-Myc cyclin D1 | E-cadherin | In vitro In vivo | Liver lung | |
[30] | ATCC 12230 US1U SF81 (FadA) | CRC tissue HCT116, DLD1, HT29, SW480, RKO CDX mice | Regulates the inflammatory and oncogenic responses via E-cadherin/β-catenin | β-catenin NF-κB IL-6,8,18 LEF/TCF c-Myc cyclin D1 | E-cadherin | In vitro In vivo | ||
[17] | WAL12230 ATCC 25586 (FadA) | CRC tissue 10C, HCT116, DLD1, RKO, SW480, HT29 CDX mice, APCMin/+ mice | Induces the Wnt/β-catenin modulator Annexin A1 | Annexin A1 β-catenin cyclin D1 | E-cadherin | In vitro In vivo | ||
[31] | ATCC 23726 ATCC 25586 (formate) | CRC tissue HCT116, Caco-2 CDX mice | Induces cancer stemness and thereby metastatic dissemination by activation of the AhR-Wnt/β-catenin pathway | AhR β-catenin IL8 Th17 MAPK ERK MEK-p38 NF-κB p65 | In vitro In vivo | lung | ||
[32] | CRC tissue HCT116, LoVo, SW480, SW620, HT29 CDX mice | Enhances the translation of EMT-related factors by the lncRNA EVADR-YBX1 axis | N-cadherin vimentin Snail Slug Zeb1 | E-cadherin | In vitro In vivo | liver lung | ||
CSCs | [35] | CRC tissue | Potential involvement of Fn in EMT–CSC crosstalk | N-cadherin Nanog Oct-4 Sox-2 | E-cadherin | In vitro | lung, liver ovary node | |
[36] | LOVO, HCT8, LS174T AOM/DSS mice | Promotes the EMT through EGFR/AKT/ERK signaling and increases the stemness of CRC cells | Fibronectin N-cadherin Snail Slug CD44+ CD133+ IL-1β, 6 p-EGFR p-AKT p-ERK | E-cadherin ZO-1 | In vitro In vivo | |||
[37] | ATCC 25586 | CRC tissue CCSCs, HEK293, HT29, HCT116 CDX mice | Promotes Numb degradation and activates Notch signaling in non-CCSCs; enhances CPT1B-mediated FAO via the TLR4/MYD88/NF-κB in CCSCs | ALDH1 CD133+ CD44+ Lgr5 Olfm4 Sox9 Aldh1 FASN NICD MDM2 CPT1B NF-κB | Numb | In vitro In vivo | ||
Autophagy | [38] | F01 ATCC10953 | CRC tissue SW480, HCT116, CT26 xenograft mice APCMin/+ mice | Activates autophagy signaling by upregulating CARD3 | CARD3 LC3-II beclin1 vimentin ATG5,7 MAPK | E-cadherin p62 | In vitro In vivo | Lung liver node |
Reprogramed TME | ||||||||
MDSCs | [40] | EAVG_002 | CRC tissue APCMin/+ mice | Generates a proinflammatory microenvironment through the recruitment of tumor-infiltrating immune cells | MDSCs (CD11b+) TANs, TAMs DCs COX-2 IL1,6,8, TNF MMP3 NF-κB p65 | In vitro In vivo | ||
[41] | CRC tissue APCMin/+ mice | The presence of Fn is associated with a lower density of CD8+ T cells and a higher density of MDSCs in CRC liver metastases | MDSCs (CD33+) TAMs (CD163+) Ki67 TIL- 6 TNF-α | CD8+ | In vitro In vivo | liver | ||
M2 polarization | [46] | ATCC 25586 | CRC tissue HCT116, LoVo CDX mice | Promotes M2 polarization through the NF-κB pathway | F4/80+ CCR6+ CD206+ ARG1 MRC1 IL-10 TGF-β | In vitro In vivo | lung | |
[47] | ATCC 25586 | CRC tissue HCT116, SW480, THP-1 CDX mice | Promotes M2 polarization via the TLR4/NF-κB/S100A9 pathway | CD206+ IL-10 S100A9 TLR4 NF-κB p65 PCNA N-cadherin VEGF TGF-β | CD86+ iNOS TNF-α | In vitro In vivo | ||
[42] | ATCC10953 F01 | CRC tissue RAW 264.7 APCMin/+ mice | Promotes the M2 polarization of macrophages via the TLR4/IL-6/p-STAT3/c-Myc cascade | CD206+ IL-10 TGF-β TLR4 IL-6 p-STAT3 c-Myc | CD86+ IL-12 TGF-α | In vitro In vivo | ||
[48] | ATCC 51,191 (LPS/OMVs) | CHO-Siglec-7-Fc, U937, moDCs, moM¢s | Promotes M2 polarization and a proinflammatory environment via the Fn–Siglec-7 interaction | Siglec-7 IL-8 I-10 IL-10 PD-L1 | CD86+ TNF-α | In vitro | ||
Prometastatic cytokines | [49] | ATCC 23,726 (FadA, Fap2) | HCT116 | Induces the secretion of the proinflammatory and prometastatic cytokines | IL-8 CXCL1 | In vitro | ||
[29] | Fn-Ex (TEXs) | HCT116, SW480 CDX mice | stimulates the CXCL16/RhoA/IL-8 exosomes | IL-8 CXCL16 RhoA | CXCR6 | In vitro In vivo | Liver lung | |
[50] | ATCC 25586 | CT26-Luc mice | Affects the secretion of inflammatory cytokines and modulates the hepatic immune response | IL-6,12, 9 IL-17A CXCL1 MCP-1 TNF-α IFN-γ CD11b+ Treg | CD3+ CD4+ CD8+ NK Th17 | In vivo | liver | |
[51] | ATCC 25586 ATCC 10953 | CRC tissue HCT116, LoVo, HUVECs CDX/PDX mice | Promotes CRC cell adhesion to endothelial cells and metastasis by activating the NF-κB/ICAM1 axis | ICAM1 ALPK1 NF-κB p65 | In vitro In vivo | Liver Lung node | ||
Tumor metabolism | [53] | ATCC 25586 | CRC tissue SW480 AOM mice | Regulates amino acid metabolism | lactic acid aspartic acid glutamate glutathione Bcl-2 caspase 3 | propionic acid leucine isoleucine Bax | In vitro In vivo | |
[54] | ATCC 25586 | CRC tissue DLD1, SW480, HT-29, HCT-116 CDX mice | Promotes glycolysis via the induction of ANGPTL4 and facilitates the colonization of Fn | ANGPTL4 H3K27ac ECAR GLUT1 | HDAC | In vitro In vivo | ||
[55] | CRC tissue HCT116, DLD1 CDX mice | Promotes CRC glycolysis via ENO1 | lactic acid ECAR | In vitro In vivo | ||||
[3] | ATCC 25586 | AOM/DSS mice | Alters the colon mucosal microbiota | FABP1 VAV2 GalR1 | E-cadherin | In vivo | ||
Oncogenic ncRNAs | ||||||||
lncRNAs | [32] | CRC tissue HCT116, LoVo, HT29, SW480, SW620 CDX mice | Regulates the lncRNA EVADR-YBX1 axis | EVADR YBX1 | In vitro In vivo | Liver lung | ||
[60] | CRC tissue HCT116, LoVo CDX mice | Upregulates KRT7-AS/KRT7 by activating the NF-κB pathway | KRT7-AS KRT7 NF-κB p65 | IκB-α | In vitro In vivo | lung | ||
[55] | CRC tissue HCT116, DLD1 CDX mice | Targets lncRNA ENO1- IT1 to promote glycolysis and oncogenesis | ENO1-IT1 ENO1 KRT7 | In vitro In vivo | ||||
miRNAs | [29] | Fn-Ex (TEXs) | HCT116, SW480 CDX mice | Stimulates tumor cells to generate miR-1246/92b- 3p/27a- 3p- rich | miR-1246 miR-92b-3p miR-27a-3p | GSK3β | In vitro In vivo | Liver lung |
[21] | CRC tissue Caco-2, HEK-293 | Upregulates miR-4474/4717 by post transcriptionally regulating the target gene, CREBBP | miR-4474 miR-4717 STAT1 TP53 EWSR1 | CREBBP JUN PRKACB CAMK2B | In vitro | |||
[18] | CRC tissue HCT116, HT29, LOVO, SW480 CDX mice, APCMin/+ mice | Regulates miR21 expression through the TLR4/MYD88/NF-κB pathway | miR-21 IL-17,21,22 MIP3a TLR4,2 MYD88 NF-κB p65 MAPK | RASA1 PDCD4 PTEN RECK SPRY1 RHOB IκB-α | In vitro In vivo | |||
[22] | ATCC 25586 | CRC tissue HCT116, LoVo, RKO, SW620 PDX mice | Reduces m6A modifications through the Hippo-YAP/FOXD3/METTL3/KIF26B axis | KIF26B YAP NF-κB | FOXD3 METTL3 m6A NF2 KIBRA Willin\FRMD6 | In vitro In vivo | Liver bone | |
[46] | ATCC 25586 | CRC tissue HCT116, LoVo CDX mice | Regulates miR-1322/CCL20 expression through the NF-κB pathway | CCL20 | miR-1322 | In vitro In vivo | lung | |
DNA damage | ||||||||
[64] | ATCC 25586 | CRC tissue EDMs APC Min/+ mice | Induces the downregulation of NEIL2 and the consequent accumulation of DNA damage | NTH1 MSH2 MSH6 Ku70 IL-8 pATM p-γH2AX | NEIL2 NEIL1 PMS2 | In vitro In vivo | ||
[26] | ATCC 25586 (FadA) | CRC tissue HCT29, HT116 CDX mice, APC Min/+ mice | Elevates DNA damage and increases the number of CRC cells in the S phase of the cell cycle | chk2 γH2AX | In vitro In vivo |
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Wu, Z.; Ma, Q.; Guo, Y.; You, F. The Role of Fusobacterium nucleatum in Colorectal Cancer Cell Proliferation and Migration. Cancers 2022, 14, 5350. https://doi.org/10.3390/cancers14215350
Wu Z, Ma Q, Guo Y, You F. The Role of Fusobacterium nucleatum in Colorectal Cancer Cell Proliferation and Migration. Cancers. 2022; 14(21):5350. https://doi.org/10.3390/cancers14215350
Chicago/Turabian StyleWu, Zihong, Qiong Ma, Ying Guo, and Fengming You. 2022. "The Role of Fusobacterium nucleatum in Colorectal Cancer Cell Proliferation and Migration" Cancers 14, no. 21: 5350. https://doi.org/10.3390/cancers14215350