Molecular characterization of Wdr13 knockout female mice uteri: a model for human endometrial hyperplasia

Abstract

endometrial hyperplasia (eH) is a condition where uterine endometrial glands show excessive proliferation of epithelial cells that may subsequently progress into endometrial cancer (ec). Modern lifestyle disorders such as obesity, hormonal changes and hyperinsulinemia are known risk factors for eH. A mouse strain that mimics most of these risk factors would be an ideal model to study the stagewise progression of eH disease and develop suitable treatment strategies. Wdr13, an X-linked gene, is evolutionarily conserved and expressed in several tissues including uteri. in the present study, Wdr13 knockout female mice developed benign proliferative epithelium that progressed into eH at around one year of age accompanied by an increase in body weight and elevated estradiol levels. Molecular characterization studies revealed increase in ERα, PI3K and a decrease in PAX2 and ERβ proteins in Wdr13 mutant mice uteri. Further, a decrease in the mRNA levels of cell cycle inhibitors, namely; p21 and cyclin G2 was seen. Leukocyte infiltration was observed in the uterine tissue of knockout mice at around 12 months of age. These physiological, molecular and pathological patterns were similar to those routinely seen in human EH disease and demonstrated the importance of WDR13 in mice uterine tissue. thus, the genetic loss of Wdr13 in these mice led to mimicking of the human eH associated metabolic disorders making Wdr13 knockout female mice a potential animal model to study human endometrial hyperplasia. Endometrial hyperplasia (EH) is a precancerous condition for endometrial carcinoma (EC) marked with abnormal proliferation of endometrial cells 1,2. EC is one of the most common reproductive cancers in females 3,4 accounting for 90% of uterine cancers 5. Although EH is a common gynecologic disease, information on the progression of EH to EC and its pathogenesis is scanty. It is now increasingly understood that modern lifestyle metabolic syndromes involving obesity, elevated estradiol, hyperinsulinemia are known risk factors for EH which generally advances to EC 4,6. Hence, it is critical to understand the underlying mechanisms and the pathophysiology of EH. Mouse models are important tools in identifying the mechanisms underlying the development of EH as well as to test the drugs for EH treatment 7. Some of the genetically modified mouse models available to study EH include Beta-catenin and Transforming growth factor-β knockout mice 2,5. Genetic mouse models implicate the importance of the specific gene in the development of EH disease. However, these mice do not replicate the human EH condition that developed due to metabolic disorders such as obesity, elevated estradiol, hyperinsulinemia etc. Thus, mice which may mimic the human risk factors for EH without forcible induction would be an appropriate model to study EH and to develop drugs for EH treatment. WDR13 protein belongs to WD-repeat containing family of proteins with diverse functions 8,9. Wdr13 gene is X-linked and conserved across vertebrates with 87% homology between h...

Natural products modulate cell apoptosis: a promising way for treating endometrial cancer

“…The type-I EC is derived from a precancerous condition called endometrial hyperplasia, whereas the type-II is hormone-independent pathogenesis without known precursor lesions ( Huvila et al, 2013 ). Hyperplasia is a significant problem, and the associated risk factors include hyperinsulinemia, obesity, high estradiol levels, and increasing age ( Singh et al, 2020 ). Endometrial hyperplasia without atypical has a low (5%) risk of progression to endometrial cancer over 20 years.…”

SOX9: Advances in Gynecological Malignancies

“…Although these findings suggest an important role for SOX9 in endometrial cell proliferation and carcinogenesis, it cannot explain why the expression of SOX9 in EC is higher than in normal endometrial tissue. Over-expression of SOX9 in a mouse model induced alterations in the tissue structure of the reproductive tract in female mice and played a role in the development of histological lesions similar to endometrial polyps and hyperplasia in humans ( 79 ); endometrial hyperplasia is a precancerous lesion of EC ( 80 ). This suggests that SOX9 is involved in the pathogenesis of endometrial diseases and may contribute to the formation of EC.…”

Absence of WDR13 in p53-Null Mice Increases Longevity

“…Earlier studies on WDR13 suggest its involvement in cell cycle regulation in different tissues like pancreas (7)(8)(9), liver (10) adipose (11), colon (12) and uterus (13). Wdr13 expression has also been reported in many human cancers like breast cancer, glioma, Ewing's sarcoma, lung cancer, melanoma, testes cancer, ovary teratocarcinoma, and urothelial cancer (Human protein atlas http://www.proteinatlas.org/ENSG00000101940-WDR13/cancer).…”