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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 |
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| Authors: | Hui Chen Lingjun Li Huimin Liu Ping Qin Ruichao Chen Shaoyan Liu Hanzhen Xiong Yang Li Zhongfeng Yang Mingyu Xie Haili Yang Qingping Jiang |
| Affiliation: | 1. Department of Pathology, Guangdong Provincial Key Laboratory of Major Obstetric Disease, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, PR China;2. Department of Pathology, Guangdong Provincial Key Laboratory of Major Obstetric Disease, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, PR China Department of Pathology, Jingmen Central Hospital, Jingmen, PR China These authors contributed equally.;3. Department of Pathology, Guangdong Provincial Key Laboratory of Major Obstetric Disease, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, PR China These authors contributed equally. |
| Abstract: | 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. |
| Keywords: | PAX2 endometrioid adenocarcinoma promoter methylation estrogen progesterone |