Molecular Insight into Gastric Cancer Invasion—Current Status and Future Directions
Abstract
:Simple Summary
Abstract
1. Introduction
2. Methods
3. Overview of Invasion and Metastasis
4. Genetic Alteration in Invasion-Associated Genes
5. Signaling Pathways Involved in GC Invasion and Metastasis
5.1. RHO/ROCK Signaling Pathway
5.2. Wnt/β-Catenin Signaling Pathway
5.3. PI3K/AKT/mTOR Signaling Pathway
5.4. JAK/STAT Signaling Pathway
5.5. NF-κB Signaling Pathway
5.6. Transforming Growth Factor-β Signaling Pathway
5.7. RAS/RAF/ERK/MAPK Signaling Pathway
5.8. Another Signaling Pathway
6. Tumor Microenvironment and GC Invasion
7. The Role of Non-Coding RNA Invasion of GC
7.1. ncRNAs Promoting GC Invasion
7.2. ncRNAs Inhibiting GC Invasion
8. Therapeutic Implications for Targeting the Invasion of GC
9. Discussion and Future Directions
10. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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ncRNAs | Dysregulations | Target | Comments | Ref |
---|---|---|---|---|
ncRNA prompting invasion | ||||
miRNA | ||||
miR-21 | ↑ | PDCD4, PTEN | Stimulates invasion by attenuating PDCD4 and PTEN expression. | [143] |
miR-30c-5p | ↓ | MTA1 | Activates M2 macrophages and, in turn, EMT through TGF-β/Smad2 signaling. | [159] |
miR-93 | ↑ | TIMP2 | Prompts invasion and EMT by targeting TIMP2, | [141] |
miR-192-5p | ↑ | RB1 | Induces EMT and Treg cell differentiation by modulating IL-10 secretion. | [142] |
miR-214 | ↑ | PTEN | Post-transcriptionally downregulates PTEN expression and prompts invasion. | [144] |
lnc RNAs | ||||
NEAT1 | ↑ | ALKBH5 | ALKBH5 prompts invasion and metastasis by reducing methylation of the NEAT1. | [146] |
PCGEM1 | ↑ | SNAI1 | Hypoxia-cultured GC-derived PCGEM enhances invasion. | [160] |
DIAPH2-AS1 | ↑ | NSUN2 NTN1 | Enhances the neural invasion via the DIAPH2-AS1-NSUN2-NTN1 axis. | [148] |
NSLT-1 | ↑ | NOTCH1 | Enhances invasion and metastasis by regulating NOTCH1. | [160] |
LINC00511 | ↑ | N.A. | Promotes invasion by modulating miR-515-5p. | [145] |
SNHG8 | ↑ | PDGFRA. | Enhances invasion by regulating the miR-491/PDGFRA. | [161] |
SNHG7 | ↑ | Snail | Increases invasion via repressing the miR-34a-Snail-EMT axis. | [162] |
ZFAS1 | ↑ | LIN28 CAPRIN1 | Enhances invasion by targeting LIN28 and CAPRIN1. | [163] |
circ RNAs | ||||
circ-RanGAP1 | ↑ | VAGFA | Increases GC invasion via miR-877-3p/VEGFA axis. | [153] |
circBGN | ↑ | IL6/STAT3 | Prompts invasion through miR-149-5p/IL6. | [164] |
circDUSP6 | ↑ | IVNS1ABP | Promotes invasion by sponging miR-145-5p. | [165] |
hsa-circ-0052001 | ↑ | MAPK signal pathway. | Facilitates invasion of GC cells through the MAPK signal pathway. | [166] |
circNRIP1 | ↑ | AKT1 | Sponges miR-149-5p to increase the AKT1 expression. | [150] |
circSHKBP1 | ↑ | HUR VEGF HSP90 | Exosomal circSHKBP1 modulates the miR-582-3p/HUR/VEGF pathway and inhibits HSP90 degradation. | [167] |
circUBE2Q2 | ↑ | STAT3 | Promotes GC invasion via the circUBE2Q2-miR-370-3p-STAT3 axis. | [168] |
circ-CEP85L | ↓ | NFKBIA | Increases NFKBIA expression by targeting miR-942-5p and impairs invasion. | [157] |
hsa_circ_0005230 | ↑ | RHOT1 | Induces the EMT by regulating RHOT1 expression via sponging miR-1299, thus promoting invasion. | [169] |
circPDIA4 | ↑ | MAPK | Enhances invasion and metastasis by bounding the ERK/MAPK pathway. | [151] |
ncRNA inhibiting invasion | ||||
miRNA | ||||
miR-9 | ↓ | cyclin D1, Ets1 | Represses invasion and metastasis of GC. | [170] |
miR-140-5p | ↓ | WNT1 YES | Inhibits cell invasion via Wnt/β-catenin signaling. | [171] |
miR-181a | ↑ | Caprin-1 | Inhibits caprin-1 and enhances GC invasion. | [172] |
miR-181-5p | ↓ | ZFP91. | Serves as a tumor suppressor by targeting ZFP91. | [173] |
miR-200b-3p | ↓ | CXCL12 CXCR7 | Suppresses invasion by modulating the CXCL12/CXCR7 axis. | [155] |
miR-214 | ↓ | FGF9 | Suppressed invasion via targeting FGF9 in CAFs and regulating the EMT. | [156] |
miR-330-3p | ↑ | PRRX1 | Repressed EMT and invasion via inhibiting PRRX1-regulated Wnt/β-catenin signaling. | [174] |
miR-505 | ↓ | HMGB1 | Suppresses invasion by targeting HMGB1. | [175] |
miR-520a-3p | ↑ | SKA2 | Suppresses invasion using invasion assay. | [176] |
miR-1254 | ↓ | Smurf1 | Suppresses invasion and EMT, and reduces the PI3K/AKT signaling via downregulating Smurf1. | [177] |
miR-3648 | ↓ | FRAT1, FRAT2 | Suppresses invasion by targeting FRAT-1 and-2 via the Wnt/β-catenin signaling. | [154] |
miR-3664-5p | ↓ | MTDH | Inhibits invasion through the NF-κB signaling by targeting MTDH. | [178] |
lnc RNAs | ||||
CA3-AS1 | ↓ | BTG3 | Increases the expression of BTG3 and inhibits invasion by targeting miR-93-5p. | [179] |
LINC00473 | ↑ | MMP2, MMP9 | Restores invasion via regulating MMP2 and MMP9 expression. | [149] |
circ RNAs | ||||
circ-ITCH | ↓ | Wnt/β-catenin pathway | Suppresses by sponging miR-17via Wnt/β-catenin pathway. | [180] |
circRELL1 | ↓ | EPHB3 | Represses invasion via the circRELL1/miR-637/EPHB3 axis. | [181] |
circ_0026344 | ↓ | PDCD4 | Increases PDCD4 expression by targeting miR-590-5p, thus impairing invasion. | [182] |
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] |
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Matsuoka, T.; Yashiro, M. Molecular Insight into Gastric Cancer Invasion—Current Status and Future Directions. Cancers 2024, 16, 54. https://doi.org/10.3390/cancers16010054
Matsuoka T, Yashiro M. Molecular Insight into Gastric Cancer Invasion—Current Status and Future Directions. Cancers. 2024; 16(1):54. https://doi.org/10.3390/cancers16010054
Chicago/Turabian StyleMatsuoka, Tasuku, and Masakazu Yashiro. 2024. "Molecular Insight into Gastric Cancer Invasion—Current Status and Future Directions" Cancers 16, no. 1: 54. https://doi.org/10.3390/cancers16010054
APA StyleMatsuoka, T., & Yashiro, M. (2024). Molecular Insight into Gastric Cancer Invasion—Current Status and Future Directions. Cancers, 16(1), 54. https://doi.org/10.3390/cancers16010054