Research advances in endometriosis-related signaling pathways: A review

Zhang, Manlin; Xu, Tong; Tong, D.; Li, Siman; Yu, Xiaodan; Liu, Boya; Jiang, Lili; Liu, Kuiran

doi:10.1016/j.biopha.2023.114909

Cited by 26 publications

(11 citation statements)

References 273 publications

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“…Endometrial cells within endometriotic lesions can synthesize TGF-β1, accumulate in the surrounding ovarian tissue, disrupt ECM, and contribute to fibrosis around endometriotic cysts. Activation of TGF-β1/Smad, PI3K/AKT, MAPK/ERK, and Wnt/β-catenin pathways has been linked to the survival, proliferation, migration, and collagen contraction of interstitial cells in endometriosis [ 69 ]. Our investigation additionally unveiled the ubiquitination of key proteins in these signaling pathways in endometriosis.…”

Section: Discussionmentioning

confidence: 99%

Multi-omics integration highlights the role of ubiquitination in endometriosis fibrosis

Yang,

Jiang,

Ding

et al. 2024

J Transl Med

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Background Endometriosis, characterized by the presence of active endometrial-like tissues outside the uterus, causes symptoms like dysmenorrhea and infertility due to the fibrosis of endometrial cells, which involves excessive deposition of extracellular matrix (ECM) proteins. Ubiquitination, an important post-transcriptional modification, regulates various biological processes in human diseases. However, its role in the fibrosis process in endometriosis remains unclear. Methods We employed multi-omics approaches on two cohorts of endometriosis patients with 39 samples. GO terms and KEGG pathways enrichment analyses were used to investigate the functional changes involved in endometriosis. Pearson’s correlation coefficient analysis was conducted to explore the relationship between global proteome and ubiquitylome in endometriosis. The protein expression levels of ubiquitin-, fibrosis-related proteins, and E3 ubiquitin-protein ligase TRIM33 were validated via Western blot. Transfecting human endometrial stroma cells (hESCs) with TRIM33 small interfering RNA (siRNA) in vitro to explore how TRIM33 affects fibrosis-related proteins. Results Integration of proteomics and transcriptomics showed genes with concurrent change of both mRNA and protein level which involved in ECM production in ectopic endometria. Ubiquitylomics distinguished 1647 and 1698 ubiquitinated lysine sites in the ectopic (EC) group compared to the normal (NC) and eutopic (EU) groups, respectively. Further multi-omics integration highlighted the essential role of ubiquitination in key fibrosis regulators in endometriosis. Correlation analysis between proteome and ubiquitylome showed correlation coefficients of 0.32 and 0.36 for ubiquitinated fibrosis proteins in EC/NC and EC/EU groups, respectively, indicating positive regulation of fibrosis-related protein expression by ubiquitination in ectopic lesions. We identified ubiquitination in 41 pivotal proteins within the fibrosis-related pathway of endometriosis. Finally, the elevated expression of TGFBR1/α-SMA/FAP/FN1/Collagen1 proteins in EC tissues were validated across independent samples. More importantly, we demonstrated that both the mRNA and protein levels of TRIM33 were reduced in endometriotic tissues. Knockdown of TRIM33 promoted TGFBR1/p-SMAD2/α-SMA/FN1 protein expressions in hESCs but did not significantly affect Collagen1/FAP levels, suggesting its inhibitory effect on fibrosis in vitro. Conclusions This study, employing multi-omics approaches, provides novel insights into endometriosis ubiquitination profiles and reveals aberrant expression of the E3 ubiquitin ligase TRIM33 in endometriotic tissues, emphasizing their critical involvement in fibrosis pathogenesis and potential therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Multi-omics integration highlights the role of ubiquitination in endometriosis fibrosis

Yang,

Jiang,

Ding

et al. 2024

J Transl Med

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“…The mechanism of action by which RiDE reduces MMPs levels is yet to be elucidated. When various molecules and cytokines such as MMPs, VEGFs, hypoxia-inducible factor-1α (HIF-1α), IL-2, IL-27 are dysfunctional, they enhance both angiogenesis and the development of endometriotic lesions [ 55 , 56 ]. Also, the growth and progression of endometrial stromal cells are influenced by the alteration of different pathways, such as NF-κB, Wnt/β-catenin, JAK/STAT, COX2/PGE2, and TGF-β upregulation.…”

Section: Discussionmentioning

confidence: 99%

“…Also, the growth and progression of endometrial stromal cells are influenced by the alteration of different pathways, such as NF-κB, Wnt/β-catenin, JAK/STAT, COX2/PGE2, and TGF-β upregulation. These abnormalities can lead to the expression of tumor-like traits in endometrial stromal cells, such as the overproduction of ROS, inflammatory reactions, immune system activation, angiogenesis, proliferation, fibrosis, apoptosis, and autophagy [ 7 , 55 , 57 , 58 , 59 ]. Further, Tcf/β-catenin targets both MMP-9 and MMP-2 genes.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Rubus idaeus Polyphenols Extract in Induced Endometriosis in Rats

Jianu,

Pop,

Gherman

et al. 2024

Molecules

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Endometriosis is a common gynecological condition with a complex physio-pathological background. This study aimed to assess the role of Rubus idaeus leaf extract (RiDE) as a potential therapeutic agent in reducing the size of the endometriotic lesions and modulate the plasma expression of MMP-2, MMP-9, and TGF-β1. The endometriotic lesions were induced in a rat model by the autologous transplant of endometrium. Thirty-six female rats, Wistar breed, with induced endometriosis, were divided into four groups and underwent treatment for 28 days. The CTRL group received 0.5 mL/day of the vehicle; the DG group received 1 mg/kg b.w./day dienogest; the RiDG group received 0.25 mL/kg b.w./day RiDE and the D+RiDG group received 1 mg/kg b.w./day dienogest and 0.25 mL/kg b.w./day RiDE, respectively. Rats’ weight, endometriotic lesion diameter and grade, and plasma levels of MMP-2, MMP-9, and TGF-β1 were assessed before and after treatment. The administration of RiDE in association with dienogest vs. dienogest determined a lower weight gain and a reduction in diameter of the endometriotic lesions. RiDE administration restored MMP2 and MMP9 plasma levels to initial conditions. Rubus idaeus extract may help in reducing dienogest-associated weight gain, lower the size of endometriotic lesions, and have anti-inflammatory effects through MMP2 and MMP9 reduction.

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“…Nuclear factor-kappa B (NF-induced B) is a kind of nuclear transcription factor that widely exists in various cells of the body. It is closely related to immune and inflammatory reactions as well as the apoptosis, formation, and metastasis of tumors [ 31 ]. The activity of NF-κB on EM may regulate inflammatory response, adhesion, invasion, and angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Chronic Stress Blocks the Endometriosis Immune Response by Metabolic Reprogramming

Lu,

Xu,

et al. 2023

IJMS

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Studies have shown that the occurrence and development of endometriosis are closely linked to long-term psychological stress. The specific contribution of chronic stress to the metabolic adaptations in patients with endometriosis is still unknown. Lesions were removed from ten endometriosis patients during an operation, and the participants were divided into two groups using a psychological questionnaire. An mRNA Human Gene Expression Microarray analysis was applied to compare the mRNA expression profiles between the chronic stress group and the control group. In addition, the reliability of the mRNA Human Gene Expression Microarray analysis was verified by using research on metabolites based on both the liquid chromatography (LC-MS/MS) technique and quantitative reverse transcription polymerase chain reaction (RT–PCR). A microarray analysis of significantly up-regulated, differentially expressed genes between the chronic stress and the control groups showed genes that were principally related to metabolism-related processes and immune-related processes, such as the immune response process, negative regulation of T cell proliferation, the leucine metabolic process, and the L-cysteine metabolic process (p < 0.05). LC-MS showed that the differential metabolites were primarily concerned with arginine and proline metabolism, D-glutamine and D-glutamate metabolism, aspartate metabolism, glycine, serine metabolism, and tyrosine metabolism (p < 0.05). The possibility of chronic stress blocks the endometriosis immune response through metabolic reprogramming. Chronic stress reduces the supply of energy substrates such as arginine and serine, down-regulates T immune cell activation, and affects the anti-tumor immune response, thereby promoting the migration and invasion of endometriosis lesions in patients with chronic stress.

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Research advances in endometriosis-related signaling pathways: A review

Cited by 26 publications

References 273 publications

Multi-omics integration highlights the role of ubiquitination in endometriosis fibrosis

Multi-omics integration highlights the role of ubiquitination in endometriosis fibrosis

The Effect of Rubus idaeus Polyphenols Extract in Induced Endometriosis in Rats

Chronic Stress Blocks the Endometriosis Immune Response by Metabolic Reprogramming

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