Assessing the prognostic value of PAX2 and PTEN in endometrial carcinogenesis

Rewcastle, Emma; Varhaugvik, Anne Elin; Gudlaugsson, Einar; Steinbakk, Anita; Skaland, Ivar; Diermen, Bianca van; Baak, Jan P. A.; Janssen, Emiel A. M.

doi:10.1530/erc-18-0106

Cited by 9 publications

(5 citation statements)

References 30 publications

(49 reference statements)

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“…In addition, the intercellular transfer of hsa-miR-4306 by platelet microparticles inhibits the migration of human monocyte-derived macrophages through the VEGFA/ERK1/2/NF-κB signaling pathway, which may influence the immunological environment at the maternal–fetal interface ( Yang et al, 2019 ). In addition, its target gene PAX2 acts as a tumor suppressor in endometrial carcinogenesis ( Raffone et al, 2019 ), which is an accurate marker of precancerous endometrial hyperplasia ( Rewcastle et al, 2018 ). The reduction of PAX2 expression in murine oviductal cells enhances estrogen receptor signaling ( Colina et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Endometrial MicroRNAs and Their Target Genes Associated With Pathogenesis of Recurrent Implantation Failure by Integrated Bioinformatics Analysis

Shang

Cheng

et al. 2022

Front. Genet.

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Purpose: Recurrent implantation failure (RIF) is an enormous challenge for in vitro fertilization (IVF) clinicians. An understanding of the molecular mechanisms of RIF helps to predict prognosis and develop new therapeutic strategies. The study is designed to identify diagnostic biomarkers for RIF as well as the potential mechanisms underlying RIF by utilizing public databases together with experimental validation.Methods: Two microarray datasets of RIF patients and the healthy control endometrium were downloaded from the Gene Expression Omnibus (GEO) database. First, differentially expressed microRNAs (miRNAs) (DEMs) were identified and their target genes were predicted. Then, we identified differentially expressed genes (DEGs) and selected hub genes through protein-protein interaction (PPI) analyses. Functional enrichment analyses of DEGs and DEMs were conducted. Furthermore, the key DEMs which targeted these hub genes were selected to obtain the key miRNA–target gene network. The key genes in the miRNA-target gene network were validated by a single-cell RNA-sequencing dataset of endometrium from GEO. Finally, we selected two miRNA–target gene pairs for further experimental validation using dual-luciferase assay and quantitative polymerase chain reaction (qPCR).Results: We identified 49 DEMs between RIF patients and the fertile group and found 136,678 target genes. Then, 325 DEGs were totally used to construct the PPI network, and 33 hub genes were selected. Also, 25 DEMs targeted 16 key DEGs were obtained to establish a key miRNA–target gene network, and 16 key DEGs were validated by a single-cell RNA-sequencing dataset. Finally, the target relationship of hsa-miR-199a-5p-PDPN and hsa-miR-4306-PAX2 was verified by dual-luciferase assay, and there were significant differences in the expression of those genes between the RIF and fertile group by PCR (p < 0.05).Conclusion: We constructed miRNA–target gene regulatory networks associated with RIF which provide new insights regarding the underlying pathogenesis of RIF; hsa-miR-199a-5p-PDPN and hsa-miR-4306-PAX2 could be further explored as potential biomarkers for RIF, and their detection in the endometrium could be applied in clinics to estimate the probability of successful embryo transfer.

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Section: Discussionmentioning

confidence: 99%

Identification of Key Endometrial MicroRNAs and Their Target Genes Associated With Pathogenesis of Recurrent Implantation Failure by Integrated Bioinformatics Analysis

Shang

Cheng

et al. 2022

Front. Genet.

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“…IHC staining of our clinical samples showed that PAX2 protein was absent in 90.91% of EEC and 75.68% of EIN cases, indicating that progression from EIN to ECC induces gradual loss of PAX2 protein expression. Rewcastle et al also found decreasing PAX2 expression from normal endometrium to EIN and EEC tissues during IHC analysis [23]. These findings suggest that PAX2 inactivity is involved in the early carcinogenesis of EEC.…”

Section: Discussionmentioning

confidence: 88%

PAX2 is regulated by estrogen/progesterone through promoter methylation in endometrioid adenocarcinoma and has an important role in carcinogenesis via the AKT/mTOR signaling pathway

Chen,

Li,

Liu

et al. 2024

The Journal of Pathology

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Endometrioid adenocarcinoma (EEC) is one of the most common cancers of the female reproductive system. In recent years, much emphasis has been placed on early diagnosis and treatment. PAX2 (Paired box 2) inactivation is reportedly an important biomarker for endometrioid intraepithelial neoplasia (EIN) and EEC. However, the role of PAX2 in EEC carcinogenesis remains unclear. PAX2 expression and associated clinical characteristics were analyzed via The Cancer Genome Atlas, Gene Expression Omnibus, and Cancer Cell Line Encyclopedia databases and clinical paired EIN/EEC tissue samples. Bioinformatic analysis was conducted to identify the putative molecular function and mechanism of PAX2. Cell proliferation, colony formation, cell migration, and invasion assays in vitro, and mouse xenograft models were utilized to study the biological functions of PAX2 in vivo. Pyrosequencing and the demethylating drug 5‐Aza‐dc were used to verify promoter methylation in clinical tissues and cell lines, respectively. The mechanism underlying the regulatory effect of estrogen (E2) and progesterone (P4) on PAX2 expression was investigated by receptor block assay and double luciferase reporter assay. PAX2 expression was found to be significantly downregulated in EIN and EEC tissues, its overexpression inhibited EEC cell malignant behaviors in vivo and in vitro and inhibited the AKT/mTOR signaling pathway. PAX2 inactivation in EEC was related to promoter methylation, and its expression was regulated by E2 and P4 through their receptors via promoter methylation. Our findings elucidated the expression and function of PAX2 in EEC and have provided hitherto undocumented evidence of the underlying molecular mechanisms. PAX2 expression is suppressed by estrogen prompting its methylation through estrogen receptor. Furthermore, PAX2 regulates the AKT/mTOR signaling pathway to influence EEC progression. © 2024 The Pathological Society of Great Britain and Ireland.

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“…(8) Other study done byRewcastle et al (2018)showed thata progressive decrease in PAX2 expression from proliferative endometrium to EIN to EEC were observed. (17) A study done by Trabzonlu et al (2019)showed that 73.3%of EIN cases had decreased PAX2 stainingas compare tonormalendometrial glands. (18) Only one study found todisagreed with this study done by Kahraman et al (2012) showed that PAX2 expression was detected in all of the endometrial samples: -80.8% in proliferative endometrium, 92.7% and 99.2% in atypical hyperplasia and endometrial adenocarcinoma respectively).…”

Section: Discussionmentioning

confidence: 97%

PAX2 Expression in Endometrial Intraepithelial Neoplasia

Fadhil¹,

Mirza²,

Ali³

2021

Indian Journal of Forensic Medicine & Toxicology

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Endometrial intraepithelial neoplasia (EIN) is a clonal growth of glands of the endometrium, regarded as a precancerous condition because of its highcorrelation with endometrioid adenocarcinoma of the endometrium of uterus.Objective: To evaluate the expression of PAX2 in EIN and to correlate the expression with clinical parameters. Materials and Methods:-This is a retrospective study for (57)totalcasesof D&C and endometrial pipple biopsies, (21) cases where diagnosed as hormonal imbalance, (26) cases where diagnosed as EIN and (10) cases where diagnosed as endometrioid endometrial adenocarcinoma.Results: -Total number of cases that showed completely loss of PAX2 expression in all this study groups 25/57 and cases that showed partial loss 10/57. In hormonal imbalance group: all the cases showed normal expression of PAX2. In EIN: (65.4%) of cases were with complete loss of PAX2, (30.4%) with partial loss. In endometrial endometrioid cancer group:80% of cases with complete PAX2 expression, while partial loss or decrease PAX2 expression did occur in only (20%) ofcases.The association between study groups and PAX2 expression:decrease and complete loss of PAX2 staining were significantly (P= 0.001) occurred in cases of EIN and endometrial endometroid adenocarcinoma, while there was insignificant association (P=0.635) between study groups (EIN and endometrial endometroid adenocarcinoma), and results of PAX2 expression. Conclusion:-Loss of PAX2 immunomarkerexpressionhappens early and during of EIN using the WHO diagnostic categories.

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Assessing the prognostic value of PAX2 and PTEN in endometrial carcinogenesis

Cited by 9 publications

References 30 publications

Identification of Key Endometrial MicroRNAs and Their Target Genes Associated With Pathogenesis of Recurrent Implantation Failure by Integrated Bioinformatics Analysis

Identification of Key Endometrial MicroRNAs and Their Target Genes Associated With Pathogenesis of Recurrent Implantation Failure by Integrated Bioinformatics Analysis

PAX2 is regulated by estrogen/progesterone through promoter methylation in endometrioid adenocarcinoma and has an important role in carcinogenesis via the AKT/mTOR signaling pathway

PAX2 Expression in Endometrial Intraepithelial Neoplasia

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