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

ABSTRACT: Endometriosis is major gynecological disease that affects over 10% of women worldwide and 30%-50% of these women have pelvic pain, abnormal uterine bleeding and infertility. The cause of endometriosis is unknown and there is no definite cure mainly because of our limited knowledge about its pathophysiology at the cellular and molecular levels. Therefore, demystifying the molecular mechanisms that underlie endometriosis is essential to develop advanced therapies for this disease. In this regard, HOX genes are remarkable because of their critical role in endometrial development and receptivity during implantation, which is attributed to their ability to mediate some of the sex steroid functions during the reproductive period. Access to the expression profiles of these genes would provide the necessary information to uncover new genes for endometriosis and assist with disease diagnosis and treatment. In this study we demonstrate an altered expression pattern for the HOX clusters (A-D) and their cofactors in both eutopic and ectopic conditions compared to control tissue biopsies. Remarkably, most of the intensive changes occurred in eutopic samples from endometriosis patients compared to control tissue biopsies. Pathway analysis revealed the involvement of differentially expressed genes in cancer that correlate with an association between endometriosis and cancer. Our results suggest critical roles for the HOX cluster and their cofactors in endometriosis pathophysiology.

SUBMITTER: Esfandiari F

PROVIDER: S-EPMC8409001 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIn order to obtain a lead of the pathophysiology of endometriosis, genome-wide expressional analyses of eutopic and ectopic endometrium have earlier been reported, however, the effects of stages of severity and phases of menstrual cycle on expressional profiles have not been examined. The effect of genetic heterogeneity and fertility history on transcriptional activity was also not considered. In the present study, a genome-wide expression analysis of autologous, paired eutopic and ectopic endometrial samples obtained from fertile women (n=18) suffering from moderate (stage 3; n=8) or severe (stage 4; n=10) ovarian endometriosis during proliferative (n=13) and secretory (n=5) phases of menstrual cycle was performed.MethodsIndividual pure RNA samples were subjected to Agilent's Whole Human Genome 44K microarray experiments. Microarray data were validated (P<0.01) by estimating transcript copy numbers by performing real time RT-PCR of seven (7) arbitrarily selected genes in all samples. The data obtained were subjected to differential expression (DE) and differential co-expression (DC) analyses followed by networks and enrichment analysis, and gene set enrichment analysis (GSEA). The reproducibility of prediction based on GSEA implementation of DC results was assessed by examining the relative expressions of twenty eight (28) selected genes in RNA samples obtained from fresh pool of eutopic and ectopic samples from confirmed ovarian endometriosis patients with stages 3 and 4 (n=4/each) during proliferative and secretory (n=4/each) phases.ResultsHigher clustering effect of pairing (cluster distance, cd=0.1) in samples from same individuals on expressional arrays among eutopic and ectopic samples was observed as compared to that of clinical stages of severity (cd=0.5) and phases of menstrual cycle (cd=0.6). Post hoc analysis revealed anomaly in the expressional profiles of several genes associated with immunological, neuracrine and endocrine functions and gynecological cancers however with no overt oncogenic potential in endometriotic tissue. Dys-regulation of three (CLOCK, ESR1, and MYC) major transcription factors appeared to be significant causative factors in the pathogenesis of ovarian endometriosis. A novel cohort of twenty-eight (28) genes representing potential marker for ovarian endometriosis in fertile women was discovered.ConclusionsDysfunctional expression of immuno-neuro-endocrine behaviour in endometrium appeared critical to endometriosis. Although no overt oncogenic potential was evident, several genes associated with gynecological cancers were observed to be high in the expressional profiles in endometriotic tissue.

Project description:Are microRNAs (miRs) altered in the eutopic endometrium (EuE) of baboons following the induction of endometriosis?Induction of endometriosis causes significant changes in the expression of eight miRs, including miR-451, in the baboon endometrium as early as 3 months following induction of the disease.Endometriosis is one of the most common gynecological disorders and causes chronic pelvic pain and infertility in women of reproductive age. Altered expression of miRs has been reported in women and has been suggested to play an important role in the pathophysiology of several gynecological disorders including endometriosis.EuE was obtained from the same group of baboons before and 3 months after the induction of endometriosis. The altered expression of miR-451 was validated in the eutopic and ectopic endometrium of additional baboons between 3 and 15 months following disease induction. Timed endometrial biopsies from women with and without endometriosis were also used to validate the expression of miR-451.Total RNA was extracted from EuE samples before and after the induction of endometriosis, and miRNA expression was analyzed using a 8 × 15 K miR microarray. Microarray signal data were preprocessed by AgiMiRna software, and an empirical Bayes model was used to estimate the changes. The present study focused on quantitative RT-PCR validation of the microarray data, specifically on miR-451 and its target genes in both baboons (n = 3) and women [control (n = 7) and endometriosis (n = 19)]. Descriptive and correlative analysis of miR-451 and target gene expression was conducted using in situ hybridization and immunohistochemistry, while functional analysis utilized an in vitro 3' untranslated region (UTR) luciferase assay and overexpression of miR-451 in human endometrial and endometriotic cell lines.Induction of endometriosis results in the altered expression of miR-451, -141, -29c, -21, -424, -19b, -200a and -181a in the baboon endometrium. In the baboon, induction of endometriosis significantly decreased the expression of miR-451 at 3 months (P < 0.001), which was also associated with increased expression of its target gene YWHAZ (14.3.3?). A similar significant (P < 0.0001) decrease in miR-451 expression was observed in women with endometriosis. The 3' UTR luciferase assay confirmed the regulation of YWHAZ expression by miR-451. Furthermore, overexpression of miR-451 in 12Z cells (immortalized human endometriotic epithelial cell line) led to the decreased expression of its target YWHAZ and this was correlated with decreased cell proliferation.The study focused only on miR-451 and one of its targets, namely YWHAZ. A single miR could target number of genes and a single gene could also be regulated by number of miRs; hence, it is possible that other miRs and their regulated genes may contribute to the pathophysiology of endometriosis.Our data suggest that the presence of ectopic lesions in baboon causes changes in EuE miR expression as early as 3 months postinduction of the disease, and some of these changes may persist throughout the course of the disease. We propose that the marked down-regulation of miR-451 in both baboons and women with endometriosis increases the expression of multiple target genes. Increased expression of one of the target genes, YWHAZ, increases proliferation, likely contributing to the pathophysiology of the disease.

Project description:BackgroundEndometriosis is a common gynecological disease among women in their reproductive years. Although much effort has been made, the pathogenesis of this disease and the detailed differences between eutopic endometrial cells and ectopic endometrial cells are still unclear.MethodsIn this study, eutopic and ectopic endometrial cells were collected from patients with and without endometriosis and RNA sequencing was performed. The gene expression patterns and differentially expressed genes (DEGs) in eutopic and ectopic endometrial cells, as well as control endometrial cells, were analyzed using a weighted gene co-expression network analysis (WGCNA) and the DESeq2 package. The functions of significant genes were detected using Gene ontology (GO) enrichment analysis, and qRT-PCR validation was performed.ResultsThe results indicated that eight gene modules were found among these three groups. They also indicated that the gene module, which is highly related to eutopic endometrial cells, was mainly enriched in cell adhesion, embryo implantation, etc., while the gene module related to ectopic endometrial cells was mainly enriched in cell migration, etc. The results of differential expression analysis were generally consistent with the WGCNA results through identified significant DEGs between different groups. These DEGs may play an important role in the occurrence of endometriosis, including the infertility associated gene ARNTL and PIWIL2, tissue remodeling gene MMP11, cell survival and migration gene FLT1, inflammatory response gene GNLY, the tumor suppressor genes PLCD1, etc. Further analysis suggested the function of adhesion is stronger in ectopic endometrial cells than in eutopic endometrial cells, while the ectopic endometrium may have a higher potential risk of malignant transformation than eutopic endometrium.ConclusionsOverall, these data provide a reference for understanding the pathogenesis of endometriosis and its relationship with malignant transformation.

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

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