Table 2.
The summary of factors affecting the invasion of gastric cancer (excluding ncRNA). cnRNA = non-coding RNA, EMT = epithelial–mesenchymal transition, GC = gastric cancer, Treg = regulatory T cell, PAR1 = Proteinase-activated receptor1, RhoGDI2 = Rho GDP differentiation inhibitor 2, ADMA = asymmetric dimethylarginine, HIF-1α = hypoxia-inducible factor-1α, NF-κB = nuclear factor-kappa B, PI3K = phosphatidylinositol-3 kinase, mTOR = mammalian target of rapamycin, FAK = focal adhesion kinase, BAG4 = Bcl2-associated athanogene 4, CEACAM6 = Carcinoembryonic antigen-related cell adhesion molecule 6, CSNK2 = casein kinase II, STAT3 = signal transducer and activator of transcription 3, GDF15 = growth differentiation factor 15, S100A16 = S100 calcium-binding protein A16, CRYABZ = Alpha B-crystallin, CHIP = carboxyl terminus of Hsc-70-interacting protein, ZBTB20 = Zinc finger and BTB domain containing 20, TGF-β = Transforming growth factor-β, TRPV2 = transient receptor potential vanilloid 2, DACH1 = Dachshund homolog 1, TAF15 = TATA-box-binding protein-associated Factor 15, MAGI1 = membrane-associated guanylate kinase inverted 1, MMP = matrix metalloproteinase, uPA = urokinase-type plasminogen activator, uPAR = uPA receptor, CAF = cancer-associated fibroblast, TME = tumor microenvironment, BM = basement membrane, FAP = fibroblast activation protein, IQGAP1 = IQ motif-containing GTPase-activating protein 1, ATP5B = adenosine triphosphate synthase F1 β subunit, ↓ = downregulation; ↑ = upregulation, N.A. = not applicable.
| Classification | Specific Elements | Alterations | Comments | Ref |
|---|---|---|---|---|
| Invasion | ||||
| phenotype | ||||
| EMT | Collagen type IVα1 | ↑ | Prompts EMT and the invasion ability of GC cells via the Hedgehog signaling pathway. | [25] |
| MAT | ROCK | ↑ | ROCK activities induce MAT in scirrhous GC. | [31] |
| Signaling pathway | ||||
| Rho/ROCK signaling | PAR1 | ↑ | PAR-1 by thrombin prompts GC cell invasion by the acquisition of morphological change by targeting RhoA and Rac1. | [48] |
| RhoJ | ↑ | Relates to the EMT procedure to increase the invasion via IL-6/STAT3. | [49] | |
| G17E (RhoA mutant) | ↑ | Upregulates Vav1 expression and facilitates the invasion via MMP-9. | [50] | |
| RhoGDI2 | ↑ | Prompts Rac1 activity and enhances the binding between Rac1 and Filamin A, which leads to increased invasion. | [52] | |
| Wnt/β-catenin signaling | CCT5 | ↑ | Enhances GC cell invasion and lymph node metastasis by activating Wnt/β-catenin signaling activity and EMT. | [54] |
| Capn4 | ↑ | Induces invasion by promoting MMP9 expression via Wnt/β-catenin signaling. | [55] | |
| ADMA | ↑ | Promotes the expression of β-catenin and activates the Wnt/β-catenin pathway, thereby enhancing invasion and EMT. | [56] | |
| HIF-1α | ↑ | HIF-1α regulates the Wnt/β-catenin pathway, activates uPA and MMP-7 expression, and contributes to the enhanced invasion. | [57] | |
| PI3K/AKT/mTOR signaling | PTEN | ↓ | Represses the PI3K/NF-κB pathway, which leads to the inhibition of invasion. | [60] |
| BAG4 | ↑ | Activates the PI3K/AKT/NF-κB/ZEB1 axis and enhances the invasion and metastasis. | [61] | |
| CEACAM6 | ↑ | Induces EMT and promotes the production of MMP-9 through PI3K/AKT pathway. | [63] | |
| CSNK2 | ↑ | Acts as an oncogene in invasion via EMT and the PI3K/Akt/mTOR signaling. | [64] | |
| JAK/STAT signaling | gastrokine2 | ↓ | Restores the invasion by suppressing JAK2/STAT3 signaling and downregulated MMP-2 and MMP-9 activity. | [68] |
| GDF15 | ↑ | Promotes the invasion and EMT via STAT3 activation in refractory GC cells. | [69] | |
| leptin | ↑ | Activates the invasion by targeting the MEK and JAK-STAT pathways, which led to the preservation of stemness. | [70] | |
| NF-κB signaling | ADAMTS16 | ↑ | Enhances the invasion by targeting IFI27 via the NF-κB pathway. | [72] |
| ADAMTS19 | ↓ | Restores cell invasion by targeting S100A16 through the NF-κB pathway. | [73] | |
| CRYABZ | ↑ | Promotes invasion by overexpression of CRYABZ via the NF-κB-regulated EMT. | [74] | |
| CHIP | ↓ | Restores invasion through NF-κB subunits, RelA/p65, and RelB signaling by reducing TRAF2 activity. | [75] | |
| ZBTB20 | ↑ | Overexpresses in GC cells by Helicobacter pylori activity and promotes invasion through MMP-2/-9. | [81] | |
| TGF-β signaling | TRPV2 | ↑ | Enhances invasion through the TGF-β signaling pathway. | [84] |
| S100A4 | ↑ | Enhances invasion by activation of the TGF-β/Smad signaling-mediated EMT. | [85] | |
| inhibin βA (TGF-β superfamily) | ↑ | Enhances invasion by activating the TGF-β signaling pathway. | [86] | |
| NNMT | ↑ | Increased the EMT markers and invasion via TGF-β signaling pathway. | [92] | |
| DACH1 | ↓ | Impairs GC invasion and EMT by suppressing TGF-β signaling. | [93] | |
| RAS/RAF/ERK/MAPK signaling | SIRT2 | ↑ | Enhances invasion through RAS/ERK/JNK/MMP-9. | [94] |
| TAF15 | ↑ | Promotes the migration and invasion through RAF1/MEK/ERK signaling | [95] | |
| MAGI1 | ↓ | Impairs invasion by affecting the expression of EMT-related molecules and MMP. | [96] | |
| Hippo pathway | GNB4, | ↑ | Prompts invasion through the Hippo-YAP1 pathway by Helicobacter pylori infection | [102] |
| FBXW5 | ↓ | Increases invasion by downregulating the Hippo signaling. | [103] | |
| Proteases | ||||
| MMP | MMP-1 | ↑ | MMP-1 expression at the leading edge of invasive tumors can predict lymph node metastasis. | [110] |
| MMP-2 | ↑ | The expression of MMP2 was correlated with invasion, metastasis, and microvessel density in GC | [112] | |
| MMP-7 | ↑ | Promotes levels of activator protein 1, gastrin which is closely associated with H. pylori infection. | [120] | |
| MMP-9 | ↑ | The level of MMP9 in serum enhanced progressively depending on the depth of tissue invasion. | [116] | |
| MT1-MMP | ↑ | Promotes invasion of cells by modulating the vimentin and E-cadherin expression | [122] | |
| uPA | uPAR | ↑ | uPAR modulates the proteolytic activity of the ECM to activate the plasminogen activation system. | [123] |
| Chemokines | CXCL12 | ↑ | CXCL12 derived from CAFs enhances invasion via stimulating the β1-integrin clustering | [127] |
| CXCL5 | ↑ | Induces EMT and pre-cancerous activation of neutrophils, which lead to facilitate invasion. | [131] | |
| CXCL10/CXCR3 | ↑ | Enhances invasion by stimulating MMP-2/9 secretion through PI3K/AKT pathway. | [132] | |
| Inflammatory cytokines | TNF-α and IL-1β | ↑ | Stimulates gastric cell MMP-1, 13 secretions through RAS/RAF/ERK/MAPK signaling. | [97] |
| IL-33 | ↑ | Facilitates invasion and EMT triggered by CAFs by the ERK1/2-SP1-ZEB2 signaling through ST2L. | [133] | |
| IL-23 | ↑ | IL-23 connecting to its receptor and thereby induced microtubules via the STAT3 signaling. | [134] | |
| Genes | DDOST, GNS, NEDD8, LOC51096, CCT3, CCT5, PPP2R1B, and two ESTs. | ↑ | Nine of the 12 genes are relatively upregulated and three are downregulated in GC patients with lymph node metastasis. | [38] |
| UBQLN1, AIM2, USP9X | ↓ | |||
| CDH17 and APOE | N.A. | Correlates with invasion depth of tumors by serial analysis of gene expression (SAGE) | [40] | |
| IQGAP1 | ↑ | Promotes cell invasion by targeting RhoC GTPase. | [42] | |
| IQGAP3 | N. A. | IQGAP3 acts as an essential mediator of invasion and EMT through TGF-beta signaling. | [43] | |
| ZYX | ↑ | Regulates EMT via the WNK1/SNAI1 signaling to increase invasion. | [44] | |
| DPP4, OLFM4, CLCA1, SI, MEP1A. | N.A. | These genes were enriched in protein digestion and absorption and carbohydrate digestion pathways. | [45] | |
| Cells | CAFs | N.A. | CAF-mediated TME remodeling promotes EMT and invasion, which is facilitated by the collagen-rich matrix. | [25] |
| CAFs | N.A. | CAFs may produce gaps in the BM and stromal components which are bound to cell–cell junctions to prompt collective cell invasion | [136] | |
| FAP (CAF marker) | ↑ | Stromal FAP secreted from CAFs facilitates invasion through EMT by targeting the Wnt/β-catenin pathway. | [210] | |
| Others | ATP5B | ↑ | ATP5B in the TME contributes to tumor invasion of GC via FAK/AKT/MMP2 pathway. | [114] |
| NDRG1 | ↑ | Enhances invasion cells by targeting MMP-9. | [117] | |
| semaphorin 5A | ↑ | Promotes invasion by increasing uPA expression through the PI3K/Akt signaling pathway. | [125] |