Abstract
The role of the extracellular matrix (ECM) in uterine fibroids (UF) has recently been appreciated. Overhydroxylation of lysine residues and the subsequent formation of hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) cross-links underlie the ECM stiffness and profoundly affect tumor progression. The aim of the current study was to investigate the relationship between ECM of UF, collagen and collagen cross-linking enzymes [lysyl hydroxylases (LH) and lysyl oxidases (LOX)], and the development and progression of UF. Our results indicated that hydroxyl lysine (Hyl) and HP cross-links are significantly higher in UF compared to the normal myometrial tissues accompanied by increased expression of LH (LH2b) and LOX. Also, increased resistance to matrix metalloproteinases (MMP) proteolytic degradation activity was observed. Furthermore, the extent of collagen cross-links was positively correlated with the expression of myofibroblast marker (α-SMA), growth-promoting markers (PCNA; pERK1/2; FAKpY397; Ki-67; and Cyclin D1), and the size of UF. In conclusion, our study defines the role of overhydroxylation of collagen and collagen cross-linking enzymes in modulating UF cell proliferation, differentiation, and resistance to MMP. These effects can establish microenvironment conducive for UF progression and thus represent potential target treatment options of UF.
Highlights
Uterine fibroids (UF), known as uterine leiomyomas, are benign smooth muscle neoplasms of the uterus found in almost 20–40% of women of reproductive age [1]
Our data indicated that total collagen is significantly higher in UF compared to the normal myometrial tissues
Estrogen and progesterone are considered the most important regulators of leiomyoma growth but the current understanding is that stem cells, genetic and epigenetic factors, sex steroids, growth factors, cytokines, chemokines, and extracellular matrix (ECM) components are important factors involved in the development and growth of leiomyomas [30,31,32,33,34,35]
Summary
Uterine fibroids (UF), known as uterine leiomyomas, are benign smooth muscle neoplasms of the uterus found in almost 20–40% of women of reproductive age [1]. The annual public cost for fibroids is estimated to be up to 34 billion dollars, calculated through combined expenses for management of symptomatic fibroids, diagnosis, and dealing with obstetrical complications of fibroids [3]. Finding effective therapeutic options is crucial for overcoming this major public health problem. An important step towards this goal is to explore the molecular basis of fibroids to understand and target the underlying specific pathophysiological pathways. Future research can identify potential targets which may help the development of new nonsurgical noninvasive treatments
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