Page 67 - GTM-3-2

Global Translational Medicine Genes and blood cells in Ph-negative MPNs

stimulation of several intracellular signaling pathways, activator (tPA):PAI-1 complex. Consequently, elevated
apoptosis, inflammation, proliferation, adhesion, cell plasma levels of suPAR in patients with MPNs may indicate
growth and migration, and oncogenesis. uPA initiates an increase in uPAR production in the bone marrow,
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the processes executed by the uPA system by activating resulting in enhanced bone marrow remodeling. 15
plasminogen and converting it to plasmin. In addition PAI-1 is not only a significant inhibitor of plasmin
to regulating fibrinolysis, plasmin is involved in the but also an important regulator of the uPA fibrinolytic
activation of matrix metalloproteinases, which can
hydrolyze all the main components of the extracellular system. PAI-1 is subject to modulation by a multitude
matrix, thereby playing a key role in the development of of regulatory factors, including hormones, cytokines,
invasion, metastasis, cell mobility, and the activation of and growth factors. Among these, transforming growth
and release of biologically active regulatory molecules factor-β (TGF-β) acts as a potent inducer of PAI-1
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from the extracellular matrix. uPAR, PAI-1, and PAI-2 are expression. PAI-1 represents a pivotal downstream
responsible for regulating uPA activity. target of the TGF-β pathway, which is the primary driver
of the fibrotic response. TGF-β positively regulates PAI-1
A comprehensive literature review by Santibanez gene expression via two main pathways, including Smad-
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indicates that the uPA system plays a pivotal role in mediated canonical and non-canonical pathways. The
numerous stages of cancer progression, including overexpression of PAI-1 has been demonstrated to reduce
extracellular matrix degradation, tumor cell growth the degradation of the extracellular matrix by perturbating
and migration, tumor angiogenesis, and epithelial– the plasminogen activation system. Elevated PAI-1 levels
mesenchymal transition. The overexpression of uPA and inhibit the proteolytic activity of tissue plasminogen
uPAR is frequently observed in a multitude of cancer types activator and uPA, which could contribute to excessive
and is often associated with a poor prognosis. The uPAR matrix deposition. 17
receptor serves to localize and enhance the action of uPA
and is expressed on the surface of malignant and tumor PAI-1 is involved in the processes of invasion and
stromal cells, including fibroblasts. metastasis by inhibiting uPA and the proteolytic cascade,
which includes the activation of plasminogen and matrix
Degradation and remodeling of surrounding tissues are
critical processes in the early stages of tumor progression. metalloproteinases. However, PAI-1 can also inhibit
tumor-destroying proteinases and protect the tumor from
These processes contribute to tumor mass expansion, the proteolysis. Consequently, a high level of PAI-1 expression
release of tumor growth factors, cytokine activation, and
the induction of tumor cell proliferation, migration, and may serve as a predictor of an unfavorable prognosis
invasion. The role of proteolytic enzymes of the uPA system and indicate an increased risk of metastasis and tumor
in the degradation of the extracellular matrix and tissue recurrence. In contrast to PAI-1, high expression of PAI-2
remodeling, which are typical of malignant neoplasms, is is associated with an increase in life expectancy, a decrease
of pivotal importance. in the number of metastases, and a decrease in the rate of
tumor growth in various types of cancer. It is important to
PAI-1 is also significant in the context of cancer note that the uPA system is regarded as a promising target
progression. Elevated levels of PAI-1 and soluble uPAR for anticancer therapy.
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(suPAR) have been observed in late-stage malignancies.
Furthermore, the activation of the PAI-1 gene by the action Elevated levels of PAI-1 may contribute to the
of the p53 gene is of great importance for the development formation of cancerous cells, possibly due to the fact that
of cancer. PAI-1 plays a pivotal role in the pathogenesis of the reactions caused by PAI-1 can result in mutations in
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carcinogenesis, angiogenesis, the occurrence of thrombotic genes that regulate cell growth and division. Furthermore,
complications, and myelofibrosis. PAI-1 has been demonstrated to stimulate inflammation,
which in turn can contribute to the development of cancer.
Ph-negative MPNs are characterized by progressive
remodeling of the bone marrow stroma, namely the PAI-1 is a direct target for the microRNA miR-145-5p,
overproduction and deposition of extracellular matrix which is a direct target of NKX2-1 antisense RNA 1
proteins, neoangiogenesis, and displacement of normal (NKX2-1-AS1). Its overexpression has been demonstrated
hematopoietic cells by fibrous tissue. SuPAR may serve as to promote cell proliferation, metastasis, invasion, and
a marker of significant tissue remodeling, particularly of angiogenesis. Furthermore, the NKX2-1-AS1/miR-145-5p
the bone marrow in MPNs. In a previous study, patients axis induces the translation of PAI-1, thereby activating the
with MPNs exhibited significantly elevated suPAR levels vascular endothelial growth factor receptor 2 (VEGFR-2)
compared to controls, and suPAR concentration was signaling pathway, which promotes tumor progression and
significantly correlated with the tissue plasminogen angiogenesis. 18

Volume 3 Issue 2 (2024) 3 doi: 10.36922/gtm.2559