Reassessing the Role of Tissue Factor Pathway Inhibitor 2 in Neoplastic and Non-Neoplastic Lesions
Simple Summary
Abstract
1. Introduction
2. Materials and Methods
Search Strategy and Selection Criteria
3. Results
3.1. Localization and Function of the TFPI2 Molecule
3.2. Molecules and Signaling Pathways Regulated by TFPI2
3.2.1. MMP-2 Regulation by TFPI2
3.2.2. Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) and Its Regulation by TFPI2
3.2.3. Nuclear Factor Kappa B (NF-κB) and Its Regulation by TFPI2
3.2.4. Regulation of TFPI2-Dependent NF-κB Activation by CAP-Gly Domain-Containing Linker Protein 1 (CLIP1)
3.2.5. Regulation of the Mitogen-Activated Protein Kinase (MAPK)/ERK Pathway by TFPI2
3.2.6. Regulation of Transforming Growth Factor Beta (TGF-β) Signaling by TFPI2
3.2.7. TFPI2 and Integrin-Mediated Focal Adhesion Dynamics
3.2.8. Cytoskeletal Regulation by TFPI2
3.2.9. TFPI2-Mediated Regulatory Role of Transmembrane Protease Serine 4 (TMPRSS4)
3.2.10. TFPI2-Mediated Regulatory Role of Prosaposin (PSAP)
3.2.11. TFPI2-Mediated Suppression of Melanocyte-Induced Transcription Factor (MITF)
3.3. Regulation of TFPI2 Expression: Molecular Mechanisms and Signaling Pathways
3.3.1. Factors Contributing to TFPI2 Upregulation (Figure 4, Left)
Signaling Pathway
Inflammatory Cytokines
Transcription Factors
miRNA/lncRNA
Others
3.3.2. Factors That Downregulate TFPI2 Expression (Figure 4, Right)
miRNA
Epigenetic Regulation of TFPI2 Expression
3.4. Role of TFPI2 in Non-Neoplastic Diseases
3.5. Effects of TFPI2 on Cancer Malignancy
3.5.1. Tumor Suppressive Function of TFPI2
3.5.2. Tumor-Promoting Role of TFPI2
3.6. Impact of TFPI2 on Prognosis
3.6.1. Tissue TFPI2 Levels and Prognostic Significance
TFPI2 Expression in Ovarian, Endometrial, and Renal Cell Carcinomas
3.6.2. Serum TFPI2 Levels and Prognostic Significance
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Search Mode | The Keyword and Search Term Combinations |
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Search term 1 | Tissue factor pathway inhibitor 2 OR TFPI2 |
Search term 2 | Ovarian cancer OR Gynecological cancer |
Search term 3 | Clear cell carcinoma |
Search term 4 | Tumor suppression OR Suppressor |
Search term 5 | Tumor promotion OR Promoter |
Search term 6 | Hyperglycemia |
Search term 7 | Atherosclerosis |
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Type of Cancer | Ref. | Number of Patients | Tissue | Serum | Prognosis |
---|---|---|---|---|---|
Ovarian cancer | [17] | 142 | Fifty-two of seventy-seven ovarian clear cell carcinoma (OCCC) tumors (67.5%) exhibited TFPI2 protein expression in at least one of the nuclear, cytoplasmic, or extracellular matrix compartments, whereas all other histological subtypes (n = 65) were TFPI2-negative. | No significant correlation was observed between immunohistochemical findings and five-year survival rates. | |
Among 11 OCCC cell lines, four demonstrated TFPI2 expression in the nuclear, cytoplasmic, or extracellular matrix fractions; four were positive exclusively in the extracellular matrix; and three were entirely negative. | |||||
[18] | 256 | Serum TFPI2 levels were quantified in 109 serous carcinomas, 66 clear cell carcinomas, and 81 cases of other histological subtypes. | In clear cell carcinoma, patients with serum TFPI2 levels ≥ 255 pg/mL exhibited significantly poorer progression-free survival (PFS) compared to those with lower levels. Among non-clear cell carcinoma cases, patients with serum TFPI2 levels ≥201 pg/mL had significantly reduced overall survival (OS) relative to those with levels below this threshold. | ||
Endometrial cancer | [21] | 207 | A serum TFPI2 concentration ≥ 177 pg/mL was identified as an adverse prognostic marker. | ||
[22] | 328 | Immunohistochemical analysis of 105 endometrial carcinoma cases revealed TFPI2 positivity in 39 cases (37.1%), with no significant variation in expression across histological subtypes. | Serum TFPI2 levels increased in parallel with disease progression and were significantly elevated in high-risk histological variants compared to low-risk types. | A serum TFPI2 level ≥ 191 pg/mL was associated with poor prognosis. | |
[174] | 55 | TFPI2 expression was evaluated via immunohistochemistry in 13 endometrial clear cell carcinoma cases and 42 cases of other histological subtypes. All 13 clear cell carcinoma cases exhibited TFPI2 positivity, whereas 11 cases (26.2%) among the other histological subtypes showed expression. | |||
Renal cell carcinoma | [19] | No significant difference was detected in TFPI2 mRNA expression between malignant and normal tissues. | Serum TFPI2 levels were assessed in 42 patients with localized disease, 12 with metastatic disease, and 241 healthy controls using a cutoff value of 170 pg/mL. TFPI2 levels were significantly higher in patients with metastatic disease compared to those with localized disease and correlated with tumor grade but not with tumor size. |
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Kobayashi, H.; Shigetomi, H.; Imanaka, S. Reassessing the Role of Tissue Factor Pathway Inhibitor 2 in Neoplastic and Non-Neoplastic Lesions. Cancers 2025, 17, 1447. https://doi.org/10.3390/cancers17091447
Kobayashi H, Shigetomi H, Imanaka S. Reassessing the Role of Tissue Factor Pathway Inhibitor 2 in Neoplastic and Non-Neoplastic Lesions. Cancers. 2025; 17(9):1447. https://doi.org/10.3390/cancers17091447
Chicago/Turabian StyleKobayashi, Hiroshi, Hiroshi Shigetomi, and Shogo Imanaka. 2025. "Reassessing the Role of Tissue Factor Pathway Inhibitor 2 in Neoplastic and Non-Neoplastic Lesions" Cancers 17, no. 9: 1447. https://doi.org/10.3390/cancers17091447
APA StyleKobayashi, H., Shigetomi, H., & Imanaka, S. (2025). Reassessing the Role of Tissue Factor Pathway Inhibitor 2 in Neoplastic and Non-Neoplastic Lesions. Cancers, 17(9), 1447. https://doi.org/10.3390/cancers17091447