Pathways of Hypoxia-Inducible Factor (HIF) in the Orchestration of Uterine Fibroids Development
Abstract
:1. Introduction
2. Methodology
3. UF in Terms of Hypoxia Response
4. Basic Biology of HIF
5. The Role of Hypoxia-Inducible Factor in Uterine Fibroids
6. HIF and GWAS-Identified Genes
7. Future Perspectives
8. Limitations
9. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
UF | uterine fibroids |
NM | normal myometrium |
HIF | hypoxia-inducible factor |
EPO | erythropoietin |
VHL | von Hippel–Lindau |
CUL2 | cullin 2 |
VEGF | vascular endothelial growing factor |
KEGG | Kyoto Encyclopedia of Genes and Genomes |
ANG-1 | angiopoietin-1 |
VEGFR-1 | vascular endothelial growing factor receptor 1 |
EGF | epidermal growing factor |
SERPINE1 (PAI1) | plasminogen activator inhibitor 1 |
TEK | endothelial tyrosine kinase |
TIMP1 | tissue inhibitor of metalloproteinases 1 |
HMOX1 | heme oxygenase 1 |
EDN1 | endothelin 1 |
iNOS | inducible nitrogen oxide synthase |
cNOS (eNOS) | constitutive (endothelial) nitric oxide synthase |
GLUT-1 | glucose transporter type 1 |
HK | hexokinase |
ALDOA | aldolase, fructose-bisphosphate A |
ENO1 | enolase 1 |
PGK1 | phosphoglycerate kinase 1 |
PFK/FBPase 3 | 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 |
LDHA | lactate dehydrogenase A |
HLRCC | hereditary leiomyomatosis and renal cell cancer |
FH | fumarate hydratase |
F2,6BP | fructose-2,6-bisphosphate |
GWAS | genome-wide association studies |
Bcl-2 | B-cell lymphoma 2 |
STRING | Search Tool for the Retrieval of Interacting Genes/Proteins |
ROS | reactive oxygen species |
PPI | protein–protein interactions |
ATM | ataxia telangiectasia mutated |
CDC42 | cell division control protein 42 homolog |
FOXO1 | forkhead box protein O1 |
IGF1 | insulin-like growth factor I |
RBMS1 | RNA-binding motif, single-stranded-interacting protein 1 |
SIM2 | single-minded homolog 2 |
SIRT3 | NAD-dependent protein deacetylase sirtuin-3, mitochondrial |
TERT | telomerase reverse transcriptase |
THRB | thyroid hormone receptor beta |
TP53 | tumor protein P53 |
WT1 | Wilms tumor 1 |
ZEB1 | zinc finger e-box binding homeobox 1 |
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Factor * | Function ** | Reference | Design of the Study | Main Findings in UF |
---|---|---|---|---|
VEGF-A | Promotes the PI3K/Akt pathway, endothelial cell growth, and neo-angiogenesis. | Hague et al. [41] | Comparison of VEGF-A protein levels between women with UF (n = 52) and women without UF (control group, n = 39). | Increased VEGF-A expression was detected in UF compared with controls (p < 0.05). |
Korompelis et al. [42] | Comparison of the blood levels of VEGF-A protein in women with UF (n = 46) and healthy controls (n = 39). | VEGF-A was significantly elevated in the blood of UF patients compared with controls (p < 0.001). | ||
Wei et al. [43] | Comparison of VEGF protein in UF tissue (n = 7) and normal myometrium from the same patients (n = 7) Measurements were performed in six zones of UF, from the periphery to the centre. | The level of hypoxia has a linear correlation to VEGF expression levels. VEGF concentrations in UF were gradually increasing from the periphery to the central UF zone (p < 0.05). | ||
Asano et al. [44] | Comparison of VEGF mRNA in MED12-mutated UF (n = 52) and MED12-wild-type UF (n = 56). | MED12-mutated UF expressed higher VEGF mRNA levels compared with wild-type tumors (p = 0.024). | ||
Joo et al. [45] | Comparison of VEGF-A mRNA levels in intramural (n = 19) and subserosal (n = 4) UF tissue and normal myometrium (n = 10). | VEGF-A mRNA was significantly higher in both UF types (p < 0.05). | ||
FLT-1 (VEGFR-1) | Encodes vascular endothelial growth factor receptor 1, which mediates VEGF signaling. | Sanci et al. [46] | Comparison of FLT-1 protein between cellular UF tissue (n = 20) and ordinary UF (n = 20). | Moderate FLT-1 immunostaining intensities in UF and its higher level in cellular UF compared with ordinary UF (p < 0.01). |
EGF | Induces angiogenesis, cell growth, and differentiation through binding with EGFR. | Tsiligiannis et al. [47] | The level of EGF mRNA was compared between UF (n = 11) and surrounding normal myometrial tissue (n = 11). | An increased level of EGF expression in UF than in NM (p = 0.01–0.05). |
Dixon et al. [48] | The level of EGF protein expression was studied in UF samples (n = 7) and matched myometrial samples (n = 7). | Lower EGF expression in UF than in myometrium (p < 0.05). | ||
Park et al. [49] | The level of EGF protein was compared between UF (n = 12) and surrounding normal myometrial tissue (n = 12). | There is no difference in EGF expression between UF and NM (p > 0.05). | ||
SERPINE1 | Inhibits two ferments: tissue plasminogen activator and urokinase, and hence fibrinolysis. | Sourla et al. [50] | Comparison of SERPINE1 mRNA between UF samples (n = 16) and adjacent myometrium (n = 16). | 11 UF showed higher expression of SERPINE1 mRNA compared with the adjacent myometrium, and 5 UF showed a lower level (p< 0.05). |
Cheng et al. [51] | Comparison of SERPINE1 mRNA and protein in UF samples (n = 30) and the adjacent myometrial tissue. | Higher expression of SERPINE1 mRNA and protein was investigated in UF compared with the adjacent myometrium (p < 0.05). | ||
TEK | Angiopoietin-1 receptor. Participates in angiogenesis. | Tsiligiannis et al. [9] | Comparison of TEK mRNA expression between UF (n = 11) and surrounding normal myometrial tissue (n = 11). | Decreased level of TEK expression in UF compared with NM (p < 0.01). |
TIMP1 | Inhibits proteins from the MMP family. It takes part in extracellular matrix restructuring and slows down endothelial cell migration. | Bogusiewicz et al. [52] | Comparison of TIMP1 protein in UF (n = 20) and the corresponding myometrium (n = 20) of hysterectomized women. | There are no differences between comparable groups (p > 0.05). |
Tsiligiannis et al. [47] | Comparison of TIMP1 mRNA between UF (n = 11) and surrounding normal myometrial tissue (n = 11). | Higher level of TIMP1 mRNA in UF and proximal myometrium compared with distal myometrium (p > 0.1–0.2). | ||
Korompelis et al. [42] | Comparison of blood TIMP1 protein level in women with UF (n = 46) and healthy controls (n = 39). | TIMP1 blood level was elevated in UF patients compared with healthy woman (p = 0.003). | ||
Governini et al. [53] | Comparison of TIMP1 mRNA in women with UF (n = 18) and control women (n = 18). | There were no differences in TIMP1 expression (p > 0.05). | ||
EDN1 | Strong activator of vasoconstriction. | Pekonen et al. [54] | Comparison of EDN1 mRNA levels in UF (n = 8) and adjacent myometrium (n = 8). | There is no difference between normal myometrium and UF in the abundance of EDN1 mRNA (p > 0.05). |
Wallace et al. [55] | Comparison of EDN1 protein blood levels in UF (n = 32) and the control group (n = 11). The secretion of ET-1 protein under hypoxia and normoxia was studied using UF samples (n = 32), samples from the adjacent myometrium (n = 32), and samples from control women (n = 11). EDN1 transcript-preproendothelin mRNA (PPET) was quantitated in UF (n = 7) and NM (n = 7) under normoxic and hypoxic conditions. | The circulating EDN1 level was greater in UF patients compared with controls (p < 0.005). Secretion of EDN1 was higher in UF compared with adjacent myometrium (p = 0.025). Hypoxia-induced ET-1 secretion from UF was higher compared to normoxic UF (p = 0.001). EDN1 secretion from UF cultured under normoxia was higher compared with adjacent myometrium (p = 0.02). EDN1 secretion was higher in UF exposed to 24 h of hypoxia (p = 0.005) compared with myometrium explants exposed to hypoxia. Under normoxia, PPET mRNA was increased in UF compared with NM (p = 0.01) and in hypoxic UF compared to hypoxic NM (p = 0.002). | ||
Miyashita-Ishiwata et al. [33] | Comparison of EDN1 in UF and myometrial cells cultured under normoxic and hypoxic conditions. | Hypoxia induced EDN1 expression in the culture media in leiomyoma but not in myometrial cells. | ||
iNOS | Inducible enzyme, which produces NO. | Plewka et al. [56] | Comparison of iNOS protein levels in the myometrium of six groups of women with different myoma sizes in perimenopausal and reproductive age. | Increased NO expression in both small and large UF compared to control in women of reproductive and perimenopausal age (p = 0.05). Higher iNOS expression in large myomas compared to small ones (p = 0.05). |
Fletcher et al. [39] | Comparison of expression of iNOS mRNA and nitrate/nitrite ratio (activity index of iNOS) in UF and NM cell lines exposed to normal (20% O2) and hypoxic (2% O2) conditions for 24 h. | Higher iNOS mRNA expression (p = 0.059) and total nitrate/nitrite ratio (p < 0.04) in UF than in NM under normoxic conditions. Hypoxic conditions led to a more significant increase in iNOS levels in NM (p < 0.001) than in UF (p = 0.268). Under hypoxia, the nitrate/nitrite ratio increased in UF (p = 0.091) and NM (p < 0.001). | ||
cNOS (eNOS) | Produces NO, the predominant isoform in endothelial cells. | Oh et al. [57] | Comparison of cNOS protein in two groups of perimenopausal women with UF (n = 24) and the control group of healthy patients (n = 8). | Higher level of cNOS expression in the UF women compared with the control (p = 0.05). Inside UF patients, cNOS expression was higher in symptomatic patients (menorrhagia and dysmenorrhea) compared to asymptomatic patients (endometrium p = 0.0029, myometrium p = 0.0276). |
Gokdeniz et al. [58] | Comparison of cNOS protein levels in UF tissue and normal myometrium (n = 8). | Higher level of cNOS in the smooth muscle cells of UF compared to NM (p < 0.005). | ||
Joo et al. [45] | Comparison of cNOS mRNA expression in UF patients (n = 23) and normal myometrium (n = 10). | Expressions of cNOS mRNA were higher in intramural and subserosal UF compared with normal myometrium (p < 0.05). Expression of cNOS mRNA was higher in large UF than small UF (p < 0.05). | ||
EPO | Activator of erythropoiesis in the bone marrow. Under hypoxic conditions, it increases the oxygen-carrying capacity of the blood. | Asano et al. [59] | Comparison of EPO mRNA expression in UF patients (n = 114) and NM from these patients (n = 17). | Higher mRNA expression of EPO in the UF than in the NM (p = 0.025). |
Asano et al. [44] | Comparison of EPO mRNA expression in MED12-mutated UF (n = 52) and MED12-wild-type UF (n = 56). | The EPO mRNA level was threefold higher in UF with wild-type MED12 genes compared to mutated ones (p = 0.01). | ||
GLUT-1 | One of the glucose transporter families. Activates glucose passing through the blood–brain barrier, the cell membranes of red blood cells, and tumors. | Ishikawa et al. [35] | Comparison of GLUT-1 mRNA expression in cell cultures of UF under hypoxia and normoxia. | Hypoxia induced the GLUT-1 mRNA expression (p < 0.05). |
Knapp et al. [60] | Comparison of GLUT-1 mRNA expression in NM specimens and UF women (n = 74). | Higher GLUT-1 mRNA expression in UF compared to NM (p < 0.05). | ||
HK1 | The first enzyme of glycolysis, phosphorylating glucose to glucose-6-phosphate. | Kwon et al. [61] | Comparison of HK1 mRNA derived from UF and corresponding NM were labeled with Cy5 and Cy3 fluorescein (n = 5). | HK1 mRNA was higher in UF compared to NM (p < 0.05). |
Catherino et al. [62] | Comparison of 3 UF and NM tissue pairs obtained from a patient with the HLRCC (hereditary leiomyomatosis and renal cell cancer) and patients with nonsyndromic or common UF (n = 11). | Similar expression of HK1 mRNA in nonsyndromic UF and HLRCC compared to NM (p > 0.05). | ||
ALDOA | Glycolytic enzyme which provides the reversible conversion of fructose-1,6-bisphosphate to dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. | Ishikawa et al. [35] | Comparison of mRNA expression of ALDOA in cells cultures of UF under hypoxia and normoxia. | Hypoxia induced the ALDOA mRNA expression (p < 0.05). |
Catherino et al. [62] | Comparison of 3 UF and NM tissue pairs obtained from a patient with the HLRCC (hereditary leiomyomatosis and renal cell cancer) and patients with nonsyndromic or common UF (n = 11). | HLRCC fibroids overexpressed ALDOA mRNA (p < 0.05). Expression of this gene was not changed in nonsyndromic UF (p < 0.01). | ||
ENO1 | Glycolytic enzyme, which provides the conversion of 2-phosphoglycerate to phosphoenolpyruvate. This protein involved in allergic reaction, growth and hypoxia tolerance | Vanharanta et al. [63] | Comparison of ENO1 mRNA levels in UF carrying FH mutations (n = 7) and wild-type FH (n = 15). | Overexpression of ENO1 mRNA in FH-mutated tumors compared to nonmutated UF (p < 0.05). |
Catherino et al. [62] | Comparison of 3 UF and NM tissue pairs obtained from a patient with HLRCC (hereditary leiomyomatosis and renal cell cancer) and patients with nonsyndromic UF (n = 11). | HLRCC fibroids overexpressed ENO1 mRNA (p < 0.01). Expression of this gene was not changed in nonsyndromic UF. | ||
Ishikawa et al. [35] | Comparison of ENO1 mRNA expression in cell cultures of UF under hypoxia and normoxia. | Hypoxia induced ENO1 mRNA expression (p < 0.05). | ||
PGK1 | Glycolytic enzyme catalysing the conversion of 1,3-diphosphoglycerate to 3-phosphoglycerate. | Catherino et al. [62] | Comparison of 3 UF and NM tissue pairs obtained from a patient with the HLRCC (hereditary leiomyomatosis and renal cell cancer) and patients with nonsyndromic or common UF (n = 11). | HLRCC fibroids overexpressed PGK1 mRNA (p < 0.01). Expression of this gene was not changed in nonsyndromic UF. |
PFK/FBPase 3 | Involved in the synthesis of fructose-2,6-bisphosphate (F2,6BP) and the degradation of F2,6BP. | Catherino et al. [62] | Comparison of 3 UF and NM tissue samples obtained from patients with hereditary leiomyomatosis and renal cell cancer and patients with nonsyndromic or common UF (n = 11). | HLRCC fibroids overexpressed PFK/FBPase 3 mRNA (p < 0.01). Expression of this gene was not changed in nonsyndromic UF. |
Ishikawa et al. [35] | A comparison of PFK/FBPase 3 mRNA expression was evaluated in cell cultures of UF under hypoxia and normoxia. | Hypoxia induced PFK/FBPase 3 mRNA expression (p < 0.05). | ||
LDHA | The final glycolytic enzyme that converts L-lactate to pyruvate. | Vanharanta et al. [63] | Comparison of LDHA mRNA expression in UF carrying FH mutations (n = 7) and UF with a wild-type FH (n = 15). | Overexpression of LDHA mRNA in FH-mutated tumors compared to nonmutated UF (p < 0.05). |
Ishikawa et al. [35] | Comparison of LDHA mRNA expression in cell cultures of UF under hypoxia and normoxia. | Hypoxia induced LDHA mRNA expression (p < 0.05). | ||
Bcl-2 | Antiapoptotic gene from the B-cell lymphoma gene family. | Zhang et al. [64] | Comparison of Bcl-2 protein expression in patients with UF (n = 34), uterine leiomyosarcoma (n = 34) and normal myometrial samples (n = 34). | Higher Bcl-2 expression in UF than in NM and in uterine leiomyosarcoma (p < 0.01). |
Wu et al. [65] | Comparison of Bcl-2 protein levels in UF tissue (n = 24) and correspondent NM (n = 22) in patients with UF. | Bcl-2 was overexpressed in UF compared to NM only in the proliferative phase of the menstrual cycle (p < 0.05). Bcl-2 was more expressed in UF from fertile women than from menopausal women (p < 0.05). | ||
Zhang et al. [64] | Comparison of Bcl-2 protein expression in UF and normal myometrium (n = 40). | Bcl-2 was highly expressed in UF during the whole menstrual cycle compared to NM (p < 0.01). The increase rate was higher in the secretory phase of the menstrual cycle than in the proliferative phase (p < 0.01). | ||
Kovács et al. [66] | Comparison of Bcl-2 protein in normal and UF specimens from cyclic (n = 16) and menopausal (n = 5) women. | The amount of Bcl-2 in the UF was higher than in the NM (p < 0.05) in the proliferative and secretory phases (p < 0.05). The rate of increase was higher in the secretory phase than in the proliferative phase. In menopausal women, no change was detected in UF relative to NM. | ||
Csatlós et al. [67] | Comparison of Bcl-2 mRNA in UF women (n = 101) and control women (n = 110). | Bcl-2 mRNA overexpression in UF compared to the control group (p = 0.02–0.04). Bcl-2 expression was positively correlated with the number of tumors. | ||
Fletcher et al. [39] | Comparison of Bcl-2/Bax RNA ratio in UF and NM cell lines exposed to normal (20% O2) and hypoxic (2% O2) conditions for 24 h. | Higher level of Bcl-2/Bax ratio in UF than in NM under normoxic conditions (p < 0.001). Hypoxia increased the Bcl-2/Bax ratio and decreased the level of apoptosis in UF; in contrast, changes in UF were opposite (decreased Bcl-2/Bax, p < 0.04). | ||
CDKN1A | Regulator of cell cycle progression at the G1 phase. | Salimi et al. [68] | Comparison of CDKN1A 98A allele frequency in genomic DNA extracted from blood samples of 154 women with UF and 197 matched controls. | The frequency of the CDKN1A 98A allele was significantly higher in the UF women compared to controls (p = 0.04). |
Biological Process | Fold Enrichment | FDR |
---|---|---|
Positive regulation of transcription from RNA polymerase II promoter in response to hypoxia | >100 | 2.04 × 10−3 |
Regulation of transcription from RNA polymerase II promoter in response to oxidative stress | >100 | 2.90 × 10−3 |
DNA damage response, signal transduction by P53 class mediator resulting in cell cycle arrest | >100 | 1.21 × 10−2 |
Positive regulation of nitric-oxide synthase activity | >100 | 1.37 × 10−2 |
Positive regulation of glycolytic process | >100 | 1.36 × 10−2 |
Regulation of DNA damage response, signal transduction by P53 class mediator | 93.16 | 1.02 × 10−3 |
Regulation of intrinsic apoptotic signaling pathway by P53 class mediator | 71.24 | 2.56 × 10−2 |
Positive regulation of vascular associated smooth muscle cell proliferation | 65.47 | 2.87 × 10−2 |
Positive regulation of smooth muscle cell migration | 65.47 | 2.86 × 10−2 |
Myoblast differentiation | 62.11 | 3.02 × 10−2 |
Negative regulation of reactive oxygen species metabolic process | 55.05 | 3.59 × 10−2 |
Positive regulation of cell growth | 22.15 | 2.23 × 10−2 |
Mesenchymal cell differentiation | 21.25 | 2.43 × 10−2 |
Negative regulation of apoptotic signaling pathway | 21.15 | 3.97 × 10−3 |
Positive regulation of apoptotic process | 9.50 | 3.83 × 10−2 |
Data were obtained using the bioinformatics tool Gene Ontology (http://geneontology.org/ (accessed on 4 June 2023)) |
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Fedotova, M.; Barysheva, E.; Bushueva, O. Pathways of Hypoxia-Inducible Factor (HIF) in the Orchestration of Uterine Fibroids Development. Life 2023, 13, 1740. https://doi.org/10.3390/life13081740
Fedotova M, Barysheva E, Bushueva O. Pathways of Hypoxia-Inducible Factor (HIF) in the Orchestration of Uterine Fibroids Development. Life. 2023; 13(8):1740. https://doi.org/10.3390/life13081740
Chicago/Turabian StyleFedotova, Maria, Ekaterina Barysheva, and Olga Bushueva. 2023. "Pathways of Hypoxia-Inducible Factor (HIF) in the Orchestration of Uterine Fibroids Development" Life 13, no. 8: 1740. https://doi.org/10.3390/life13081740
APA StyleFedotova, M., Barysheva, E., & Bushueva, O. (2023). Pathways of Hypoxia-Inducible Factor (HIF) in the Orchestration of Uterine Fibroids Development. Life, 13(8), 1740. https://doi.org/10.3390/life13081740