Up-regulation of DNA2 results in cell proliferation and migration in endometriosis

Xinyan Wang,Yucheng Lai,Yan Yu,Sheng Xu,Wenjie Zeng,Jingya Nie,Lu Huang

doi:10.1007/s10735-021-09983-z

Abstract

Accumulating evidence has suggests that women with advanced endometriosis exhibit alterations in the expression of genes in the endometrium compared to healthy controls. Furthermore, replication stress is a characteristic feature of cancer cells, which results from sustained proliferative signaling induced by either the activation of oncogenes or the loss of tumor suppressors. In the present study, we propose that DNA replication ATP-dependent helicase/nuclease 2 (DNA2) might be upregulated in endometriosis. Immunohistochemical staining results confirmed the hypothesis that DNA2 is overexpressed in the eutopic/ectopic endometrium compared to that in a control endometrium from a healthy donor. Subsequently, ectopic endometrium-derived endometrial mesenchymal stem cells (EMSCs) showed the highest level of DNA2 and checkpoint kinase 1 (CHK1), as well as the strongest proliferation and migration capabilities, followed by eutopic endometrium-derived EMSCs, and then control EMSCs. To further analyze the function of DNA2, we knocked-down DNA2 expression in KLE cells. As expected, proliferation and migration declined when cells were transfected with DNA2 small interfering RNA. Taken together, our study demonstrated the overexpression of DNA2 in human endometriosis, which might be responsible for the upregulated cell proliferation and migration. This study provides insights into the mechanisms underlying human endometriosis.

Highlights

Endometriosis (EM) is an estrogen-dependent benign inflammatory response disease and refers to the appearance of endometrial interstitials and glands outside the uterine cavity (Burney and Giudice 2012; Giudice 2010)
To clarify the role of dependent helicase/nuclease 2 (DNA2) in endometriosis, we first assessed the levels of DNA2 in tissue samples obtained from patients with endometriosis
Migration of endometrial mesenchymal stem cells (EMSCs) isolated from ectopic endometrium was significantly reduced by DNA2 knockdown using siRNA (Supplementary Fig. 2). These results suggest a potential function of DNA2 in EMSC migration and endometriosis

Summary

Introduction

Endometriosis (EM) is an estrogen-dependent benign inflammatory response disease and refers to the appearance of endometrial interstitials and glands outside the uterine cavity (Burney and Giudice 2012; Giudice 2010). Common ectopic endometrial tissue invasion sites include the ovary, peritoneum, uterosacral ligament, and recto-uterine pouch (Keckstein and Wiesinger 2005; Kinkel et al 1999; Ness 2003; Young et al 2013). The incidence of this disease has shown an upward trend in recent years. There are many theories for the pathogenesis of endometriosis (Koninckx et al 2019; Sourial et al 2014). The anabolic or regulatory imbalance of estrogen can cause pathological changes in the endometrium (Gibson et al 2015; Skarzynski et al 2020; Xu et al 2019; Yang et al 2018)

Methods

Results

Conclusion