HOX cluster and their cofactors showed an altered expression pattern in eutopic and ectopic endometriosis tissues

Esfandiari, Fereshteh; Chitsazian, Fereshteh; Jahromi, Masoumeh Golestan; Favaedi, Raha; Bazrgar, Masood; Aflatoonian, Reza; Afsharian, Parvaneh; Aflatoonian, Abbas; Shahhoseini, Maryam

doi:10.1186/s12958-021-00816-y

Cited by 6 publications

(7 citation statements)

References 44 publications

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“…The Lactate concentrations were as well in the long run selected in the peritoneal fluid of patients with EM [38]. At the same time, the related proteomic analysis found that ectopic endometrial stromal cells have extensive metabolic reprogramming and cancer-like changes, which have striking similarities with tumorigenesis [35,39,40]. Interestingly, the glycolysis inhibitor reduces the mouse peritoneal fluid lactate concentration and the size of endometriotic lesions in the mouse model of EM [37].…”

Section: Discussionmentioning

confidence: 91%

Phosphorylation of PFKFB4 by PIM2 promotes anaerobic glycolysis and cell proliferation in endometriosis

Lü

Qiao

et al. 2022

Cell Death Dis

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Endometriosis (EM) is one of the vanquished wonted causes of chronic pelvic sting in women and is closely associated with infertility. The long-term, complex, systemic, and post-treatment recurrence of EM wreaks havoc on women's quality of life. Extensive metabolic reprogramming (aerobic glycolysis, glucose overweening intake, and high lactate production) and cancer-like changes have been found in EM, which bears striking similarities to tumorigenesis. The key glycolysis regulator PFKFB4 is overexpressed in EM. However, the mechanism of PFKFB4 in EM remains unknown. We found that PFKFB4 was upregulated and was closely related to the progression of EM. We identified focus PIM2 as a new pioneering adjoin protein of PFKFB4. Vigorous biochemical methods were used to confirm that PIM2 phosphorylated site Thr140 of PFKFB4. PIM2 also could enhance PFKFB4 protein expression through the ubiquitin-proteasome pathway. Moreover, PIM2 expression was really corresponding prevalent with PFKFB4 in endometriosis in vivo. Importantly, phosphorylation of PFKFB4 on Thr140 by PIM2 promoted EM glycolysis and cell growth. Our study demonstrates that PIM2 mediates PFKFB4 Thr140 phosphorylation thus regulating glycolysis and EM progression. We illustrated a new mechanism that PIM2 simulated a central upstream partnership in the regulation of PFKFB4, and reveal a novel means of PIM2-PFKFB4 setting EM growth. Our research provided new theoretical support for further clarifying the reprogramming of EM glucose metabolism, and provided new clues for exploring non-contraceptive treatments for EM.

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Section: Discussionmentioning

confidence: 91%

Phosphorylation of PFKFB4 by PIM2 promotes anaerobic glycolysis and cell proliferation in endometriosis

Lü

Qiao

et al. 2022

Cell Death Dis

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“…Initially, the analysis of general data and clinic characteristics of EMT patients and healthy women unraveled the elevated proportions of dysmenorrhea, infertility, and pelvic pain in EMT patients. EMT individuals usually have a prolonged history of dysmenorrhea [31], and 30-50% of women with EMT also suffer from pelvic pain and infertility [32]. These clinical parameters could assist the diagnosis of EMT.…”

Section: Discussionmentioning

confidence: 99%

miR-424-5p combined with miR-17-5p has high diagnostic efficacy for endometriosis

Lin¹,

Zeng

2022

Arch Gynecol Obstet

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Purpose: Endometriosis (EMT) is a chronic benign disease with high prevalence. This study investigated the diagnostic value of serum miR-17-5p, miR-424-5p, and their combined expressions for EMT.Methods: A total of 80 EMT patients of reproductive age were included as the study subjects, and another 80 healthy women of reproductive age were selected as the control group. The whole blood samples of enrolled subjects were collected and clinical characteristics were recorded. The miR-17-5p, miR-424-5p, VEGFA, IL-4, and IL-6 levels in the serum were measured. ROC curve was used to evaluate the diagnostic e cacy of miR-17-5p and miR-424-5p expressions for EMT. Pearson correlation was performed to analyze the correlation of miR-17-5p and miR-424-5p with clinical indexes in EMT patients.Results: miR-17-5p and miR-424-5p were signi cantly downregulated in EMT patients. For the diagnosis of EMT, the AUC of miR-17-5p was 0.865 and cutoff value was 0.890 (91.3% sensitivity and 85% speci city), the AUC of miR-424-5p was 0.737 and cutoff value was 0.915 (98.8% sensitivity and 61.2% speci city), the AUC of miR-424-5p combined with miR-17-5p was 0.938 and cutoff value was 2.205 (93.8% sensitivity and 88.7% speci city), with the diagnostic e cacy higher than miR-424-5p or miR-17-5p alone. The expressions of miR-17-5p and miR-424-5p were negatively correlated with dysmenorrhea, infertility, pelvic pain, and rASRM stage, but not with age, BMI, menstrual disorder, and nulliparity. VEGFA, IL-4, and IL-6 were remarkably increased in EMT patients, and both were inversely associated with miR-17-5p and miR-424-5p.Conclusion: miR-424-5p combined with miR-17-5p has high diagnostic e cacy for EMT.

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“…Altered expression of the HOXC cluster has been found in ectopic and eutopic tissues from endometriosis patients vs. control 71-73 , as well as in gastrointestinal disorders such as ulcerative colitis, colorectal cancer and gastric cancer 74-77 . Even though RERG , and nearby PTPRO , were not implicated in any GWAS studies of the separate traits, P-values for the lead SNP were close to genome-wide significance ( P Endometriosis = 9.24E-06, P GPM = 8.80E-07) suggesting the increased power from combining the traits was able to identify a novel risk locus for both diseases.…”

Section: Discussionmentioning

confidence: 99%

Evidence of shared genetic factors in the aetiology of gastrointestinal disorders and endometriosis and clinical implications for disease management

Hockey

Doust

et al. 2022

Preprint

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In clinical practice, the co-existence of endometriosis and gastrointestinal symptoms is often observed; however, the factors driving this link remain largely unknown. Here, using large-scale multifaceted data including observational, genetic, and pharmaceutical datasets, we report a positive phenotypic and genetic association of endometriosis with peptic ulcer disease (PUD), gastro-oesophageal reflux disease (GORD), a combined GORD/PUD Medicated (GPM) phenotype and irritable bowel syndrome (IBS), but not with inflammatory bowel disease (IBD). Mendelian randomization analysis identified a causal effect of the GPM phenotype on endometriosis and a bidirectional causal association between endometriosis and IBS. Cross-trait meta-analysis and colocalization along with comprehensive functional annotation confirmed two shared genetic loci (FN1, TACSTD2) for endometriosis with IBS and twelve loci (ETAA1, HOXC4, RERG, SEMA3F, SPAG16, HIST1H2BC, RAB5B, CCKBRandPDE4B) with GORD and PUD. Shared genetic loci may contribute to risk of both endometriosis and digestive disorders through the involvement of DNA damage, estrogen regulated cell-proliferation and inflammation, and barrier dysfunction. Analyses of medication usage identified a higher use of drugs for IBS, GORD and PUD in women diagnosed with endometriosis as well as a higher use of hormone therapies in women diagnosed with IBS, GORD and PUD but not for IBD, which strongly supports the co-occurrence of these conditions and highlights the potential for drug repositioning and caution around drug contraindications in clinical practice. Taken together, the combined evidence robustly suggests a shared disease aetiology and provides important clinical implications for diagnostic and treatment decisions for endometriosis and digestive disorders.WHAT IS ALREADY KNOWN ON THIS TOPIC?Both endometriosis and gastrointestinal disorders affect a large proportion of people worldwide and the co-existence of endometriosis and gastrointestinal symptoms (eg, abnormal pain, bloating, constipation) is often observed in clinical practice.The association of these two diseases was supported but also limited to previous observational evidence which highlights a three-fold increase in the prevalence of irritable bowel syndrome (IBS) in women with endometriosis.Observational study is easily subject to measurement error, confounding and reverse causation. Therefore, it is important to assess the association using multidimensional datasets and more accurate approaches, such as the use of genetic data in a mendelian randomisation framework as well as the analysis from a perspective of medication usage.WHAT THIS STUDY ADDSGenetic risk factors for endometriosis and gastrointestinal disorders, two leading causes of discomfort and chronic pelvic pain, are correlated.Mendelian randomisation analyses supported a causal relationship between genetic predisposition to gastrointestinal disorders (gastro-oesophageal reflux disease (GORD) and peptic ulcer diseases (PUD)) and endometriosis risk, and evidence for a bidirectional causal relationship between endometriosis and IBS, which might explain in part the co-occurrence of these diseases.The identification of shared risk loci highlighted biological pathways that may contribute to the pathogenesis of both diseases, including estrogen regulation and inflammation, as well as potential therapeutic drug targets such asCCKBRandPDE4B.The higher use of drugs for IBS, GORD and PUD in women diagnosed with endometriosis as well as the higher use of hormone therapies in women diagnosed with IBS, GORD and PUD, support the co-occurrence of these conditions and shared disease aetiology but also highlights the potential for drug repositioning and caution around drug contraindications.Graphical abstract

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HOX cluster and their cofactors showed an altered expression pattern in eutopic and ectopic endometriosis tissues

Cited by 6 publications

References 44 publications

Phosphorylation of PFKFB4 by PIM2 promotes anaerobic glycolysis and cell proliferation in endometriosis

Phosphorylation of PFKFB4 by PIM2 promotes anaerobic glycolysis and cell proliferation in endometriosis

miR-424-5p combined with miR-17-5p has high diagnostic efficacy for endometriosis

Evidence of shared genetic factors in the aetiology of gastrointestinal disorders and endometriosis and clinical implications for disease management

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