Insights into the Molecular Mechanisms and Signaling Pathways of Epithelial to Mesenchymal Transition (EMT) in the Pathophysiology of Endometriosis
Abstract
1. Introduction
2. Review Methods
3. From Discovery to Classification: Understanding EMT Subtypes
4. Molecular Drivers and Mechanisms of EMT in Endometriosis
4.1. Factors That Trigger EMT in Endometriosis
4.1.1. Growth Factors
4.1.2. Hormonal Regulation
4.1.3. Environmental and Metabolic Factors
4.1.4. Lipid Signaling
4.1.5. Genetic and Epigenetic Modulators
4.2. EMT-Related Transcription Factors in Endometriosis
4.3. Molecular Alteration in EMT in Endometriosis
4.3.1. Cadherin Switch
4.3.2. Loss of Cytokeratin
4.3.3. Upregulation of Vimentin
4.3.4. Suppression of Claudins
5. Fibrosis
6. Lesional Differences
6.1. Lesional Patterns of EMT Expression
6.2. Microenvironmental Influences on EMT Dynamics
6.3. Molecular Feedback Loops and Lesion-Specific Regulation
6.4. Intra-Lesional Heterogeneity
7. Biomarkers
7.1. EMT-Associated Serum microRNAs
7.1.1. miR-17-5p, miR-20a, and miR-22
7.1.2. miR-200 Family
7.1.3. Combined Serum miRNA Panels
7.2. EMT-Related Serum Protein Markers
8. Emerging Interventions That Target EMT
8.1. Isoflavonoids
8.2. Plant Alkaloids
8.3. Terpenes
8.4. Polysaccharides
8.5. Biguanides
8.6. S1P Receptor Modulators
9. Conclusions
10. Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
αSMA | Alpha smooth muscle actin |
Akt | Protein kinase B |
ARID1A | AT-rich interaction domain-containing protein 1A |
BMPs | Bone morphogenetic proteins |
CK | Cytokeratin |
circRNA | Circular RNA |
CXCL12 | Chemokine ligand 12 |
CXCR4 | Chemokine receptor 4 |
DIE | Deeply infiltrating endometriosis |
ECM | Extracellular matrix |
EMT | Epithelial-to-mesenchymal transition |
EpCAM | Epithelial cell adhesion molecule |
E2 | 17Î2 estradiol |
FGFs | Fibroblast growth factors |
FOXC2 | Forkhead box protein C2 |
FMT | Fibroblast-to-myofibroblast transition |
GSK3β | Glycogen synthase kinase 3 beta |
HGF | Hepatocyte growth factor |
HIF | Hypoxia inducible factor |
HMGA2 | High mobility group AT hook 2 |
IGF1 | Insulin-like growth factor 1 |
IL | Interleukin |
lncRNA | Long non-coding RNA |
MALAT1 | Metastasis-associated lung adenocarcinoma transcript 1 |
MAPK | Mitogen-activated protein kinase |
MET | Mesenchymal-to-epithelial transition |
miRNA | MicroRNA |
MMT | Mesothelial-to-mesenchymal transition |
mTOR | Mechanistic target of rapamycin |
NFκB | Nuclear factor kappa B |
NICD | Notch intracellular domain |
OMA | Ovarian endometrioma |
PDGF | Platelet-derived growth factor |
PI3K | Phosphoinositide 3 kinase |
PR | Progesterone receptor |
PTEN | Phosphatase and tensin homolog |
ROCK | Rho-associated coiled-coil containing protein kinase |
S1P | Sphingosine 1 phosphate |
S1PR | Sphingosine 1 phosphate receptor |
SCID | Severe combined immunodeficient |
SMAD | Mothers against decapentaplegic homolog |
Snail SNAI1 | Zinc-finger protein SNAI1 |
Slug SNAI2 | Zinc-finger protein SNAI2 |
SP | Superficial peritoneal endometriosis |
TGF-β | Transforming growth factor beta |
TWIST | Twist-related protein |
VEGF | Vascular endothelial growth factor |
vWF | von Willebrand factor |
ZEB1 ZEB2 | Zinc-finger E-box-binding homeobox 1 Zinc-finger E-box-binding homeobox 2 |
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Category | Molecule/Factor | Change in Endometriosis | Function in EMT | Reference |
---|---|---|---|---|
Key Triggers | TGF-β | ↑ Active in lesions | Master EMT inducer by upregulated EMT-TFs (Snail, ZEB1); involved in fibrosis. | [27,28,29,30] |
PDGF | ↑ At lesion sites | Platelet-derived signaling promotes invasion under hypoxia. | [36,37] | |
Estradiol | ↑ Estrogen-rich environment | Upregulates ZEB1, activates RhoA/ROCK and HGF pathways, and promotes EMTEMT gene regulator under stress by activating VEGF, Wnt/β-catenin, and TGF-β1 pathways. | [40,41,42] | |
Hypoxia (HIF-1α/2α) | ↑ Elevated in ectopic tissue | EMT gene regulator under stress by activating VEGF, Wnt/β-catenin, and TGF-β1 pathways. | [46,47,50] | |
S1P | ↑ At lesion sites | Cross-talk with factors such as TGF-β. | [60,62] | |
Genetic mutations in PTEN, KRAS, ARID1A | Frequently mutated in DIE | Promote EMT via loss of suppression or gain of oncogenic signals. | [65,66,67,69] | |
Transcription Factors | Snail (SNAI1), Slug (SNAI2) | ↑ Upregulated | Induced by TGF-β, hypoxia, estrogen, and repressed by E-cadherin. | [81] |
ZEB1/ZEB2 | ↑ Upregulated | Targeted by miR-200 family and promotes EMT. | [24] | |
Twist | ↑ Upregulated | Associated with initiation and invasion of EMT. | [78] | |
FOXC2 | Likely ↑ | Enhance cell motility. | [83] | |
Epithelial Markers | E-cadherin | ↓ Downregulated | Repressed by Snail, Slug, ZEB1/2 and weakening of cell–cell adhesion. | [85,86] |
Cytokeratin | ↓ Downregulated | Reduced expression in ectopic epithelial cells leads to a loss of epithelial structure. | [81,87] | |
Claudins (e.g., -3, -4, -7) | ↓ Downregulated | Disruption of tight junction proteins in peritoneal lesions contributes to compromised epithelial integrity. | [20] | |
Mesenchymal Markers | N-cadherin | ↑ Upregulated | Cadherin switches from E- to N-cadherin and promotes cell motility. | [81,87] |
Vimentin | ↑ Upregulated | Associated with enhanced invasion and fibrosis. | [88,92] |
Biomarker | Relative Change | AUC (95%CI) | Sensitivity | Specificity | Reference |
---|---|---|---|---|---|
miR-17-5p | Decreased | 0.74 (0.58–0.90) | NR | NR | [110] |
miR-20a | Decreased | 0.79 (0.65–0.93) | NR | NR | [110] |
miR-22 | Decreased | 0.85 (0.71–0.98) | NR | NR | [110] |
miR-200a | Decreased | 0.75 (0.62–0.86) | 90.6% | 62.5% | [71,72] |
miR-200b | Decreased | 0.67 (0.53–0.79) | 90.6% | 45.8% | [71,72] |
miR-141 | Decreased | 0.71 (0.57–0.82) | 71.9% | 70.8% | [71,72] |
Decreased | 0.59 (0.51–0.67) | 81.1% | 37.5% | [111] | |
miR-199a | Increased | 0.83 (0.73–0.92) | 78.3% | 76.0% | [112] |
Increased | 0.62 (0.55–0.71) | 54.6% | 98.6% | [111] | |
Increased | 1.00 (no range) | 91.4% | 100% | [113] | |
miR-122 | Increased | 0.84 (0.75–0.92) | 80.0% | 76.0% | [112] |
Increased | 0.72 (0.61–0.82) | 45.8% | 97.4% | [111] | |
Increased | 0.96 (no range) | 95.6% | 100% | [106] | |
miR-145 | Decreased | 0.88 (0.81–0.95) | 70.0% | 96.0% | [112] |
Decreased | 0.76 (0.68–0.85) | 85.3% | 38.1% | [111] | |
miR-141 | Decreased | 0.85 (0.77–0.93) | 71.7% | 96.0% | [112] |
miR-542-3p | Decreased | 0.85 (0.77–0.94) | 79.7% | 92.0% | [112] |
E-cadherin | Decreased | 0.63 (0.33–0.81) | NR | NR | [107] |
N-Cadherin | Increased | 0.71 (0.45–0.86) | NR | NR | [107] |
HIF-1α | Increased | 0.74 (0.48–0.88) | NR | NR | [107] |
Biomarker Panel | Relative Change | AUC (95%CI) | Sensitivity | Specificity | Reference |
---|---|---|---|---|---|
miR-200a miR-200b miR-141 | Decreased Decreased Decreased | 0.76 (0.63–0.87) | 84.4% | 66.7% | [72] |
miR-199a miR-122 miR-145 miR-542-3p | Increased Increased Decreased Decreased | 0.99 (0.98-1.00) | 93.2% | 96.0% | [112] |
miR-141 miR-199a miR-122 miR-145 CA-125 | Decreased Increased Increased Decreased Increased | 0.94 (0.90–0.98) | 81.8% | 92.6% | [111] |
Class | Molecule | Model | Findings | Reference |
---|---|---|---|---|
Isoflavonoids | Isoliquiritigenin 3,6-ihydroxyflavone | End1/E6E7 cells; mouse endometriosis model OMA stromal cells; SCID/rat models | ↑ E-cadherin; ↓ N-cadherin, Snail, Slug; ↓ lesion size; ↑ BAX, caspase-3; ↑ E-cadherin, ↓ Twist, Slug; Notch pathway inhibition. | [121,122] |
Plant Alkaloids | Tetramethylpyrazine | 11Z cells, OMA stromal cells; mouse model | ↑ E-cadherin; inhibited FMT; ↓ TGF-β1, α-SMA; ↓ p-Smad2/3; ↓ weight/fibrosis. | [123] |
Terpenes | Parthenolide | Wistar albino rat model | ↓ Lesion area; ↑ E-cadherin, ↓ vimentin; inhibited PI3K/AKT and β-catenin. | [124] |
Polysaccharides | Fucoidan | End1/E6E7, Vk2/E6E7 cells; mouse model | ↑ Proliferation/migration; ↑ E-cadherin; ↓ N-cadherin, Slug, Snail. | [92] |
Biguanides | Metformin | OMA stromal cells; Wistar albino rat model | ↓ β-catenin translocation; ↓ proliferation/invasion; ↑ apoptosis. | [125] |
S1P Receptor Modulators | SEW2871, FTY720, JTE013 | Mouse endometriosis model; Wistar rat model; Primary OMA stromal cells | ↓ Lesion growth and fibrosis; ↓ collagen type I; ↑ E-cadherin; ↓ S1P1 signaling. | [126] |
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Hosseinirad, H.; Jeong, J.-W.; Barrier, B.F. Insights into the Molecular Mechanisms and Signaling Pathways of Epithelial to Mesenchymal Transition (EMT) in the Pathophysiology of Endometriosis. Int. J. Mol. Sci. 2025, 26, 7460. https://doi.org/10.3390/ijms26157460
Hosseinirad H, Jeong J-W, Barrier BF. Insights into the Molecular Mechanisms and Signaling Pathways of Epithelial to Mesenchymal Transition (EMT) in the Pathophysiology of Endometriosis. International Journal of Molecular Sciences. 2025; 26(15):7460. https://doi.org/10.3390/ijms26157460
Chicago/Turabian StyleHosseinirad, Hossein, Jae-Wook Jeong, and Breton F. Barrier. 2025. "Insights into the Molecular Mechanisms and Signaling Pathways of Epithelial to Mesenchymal Transition (EMT) in the Pathophysiology of Endometriosis" International Journal of Molecular Sciences 26, no. 15: 7460. https://doi.org/10.3390/ijms26157460
APA StyleHosseinirad, H., Jeong, J.-W., & Barrier, B. F. (2025). Insights into the Molecular Mechanisms and Signaling Pathways of Epithelial to Mesenchymal Transition (EMT) in the Pathophysiology of Endometriosis. International Journal of Molecular Sciences, 26(15), 7460. https://doi.org/10.3390/ijms26157460