Excessive oxidative stress in cumulus granulosa cells induced cell senescence contributes to endometriosis-associated infertility

Lin, Xiang; Dai, Yongdong; Tong, Xiaomei; Xu, Weifeng; Huang, Qianmeng; Jin, Xiaoying; Li, Chao; Zhou, Feng; Zhou, Hanjin; Lin, Xiaona; Huang, Dong; Zhang, Songying

doi:10.1016/j.redox.2020.101431

Cited by 108 publications

(98 citation statements)

References 42 publications

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“…1B ). In addition, as a GC tumor-derived cell line, KGN is commonly used to study the molecular mechanism underlying endometriosis ( 18 , 32 , 33 ); thus, MALAT1 expression was compared between KGN cells and normal GCs. MALAT1 expression was significantly upregulated in KGN cells compared with normal GCs ( Fig.…”

Section: Resultsmentioning

confidence: 99%

The AMPK‑mTOR axis requires increased MALAT1 expression for promoting granulosa cell proliferation in endometriosis

Liu

Zhang

et al. 2020

Exp Ther Med

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Endometriosis is a common reproductive disorder in women, with a global prevalence of 10-15%. Long noncoding RNAs (lncRNAs) are critical to gene transcription, cell cycle modulation and immune response. The lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) reportedly mediates autophagy of endometrial stromal cells in endometriosis. The present study aimed to evaluate the role and mechanism of MALAT1 in granulosa cells (GCs) in endometriosis. Consequently, MALAT1 expression was upregulated in GCs obtained from patients with endometriosis and in the steroidogenic human granulosa-like tumor cell line KGN. However, MALAT1 knockdown consequently decreased the proliferation and viability of these cells, as determined by MTT and 5-ethynyl-2'-deoxyuridine staining assays. Both Annexin V-fluorescein isothiocyanate/propidium iodide flow cytometry and western blotting performed to detect proapoptotic factors indicated that MALAT1 depletion might promote KGN cell apoptosis. Furthermore, MALAT1 knockdown increased GC autophagy, as evidenced by microtubule-associated protein 1A/1B-light chain 3 (LC3) cleavage upregulation and p62 degradation. In addition, although 5'-AMP-activated protein kinase (AMPK) mRNA expression and protein levels decreased in GCs obtained from patients with endometriosis and KGN cells, MALAT1 knockdown restored AMPK levels. However, addition of BML-275 (MALAT1 inhibitor) to MALAT1-knockdown KGN cells recovered their viability and proliferative capacity and simultaneously reduced their apoptotic and autophagic capacity. Therefore, MALAT1 may regulate GC proliferation via AMPK-mTOR-mediated cell apoptosis and autophagy.

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Section: Resultsmentioning

confidence: 99%

The AMPK‑mTOR axis requires increased MALAT1 expression for promoting granulosa cell proliferation in endometriosis

Liu

Zhang

et al. 2020

Exp Ther Med

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“…In our ovarian endometriosis model, oxidative stress caused FSHR suppression and reduced follicular growth, resulting eventually in the reduced number of pups. An association between oxidative stress and infertility has been reported both from the clinical and basic points of view [ 11 ]. Although no medicine for oxidative stress-associated infertility has been developed yet, our mouse model may contribute to screening new drugs to recover infertility due to oxidative stress induced by ovarian endometriosis.…”

Section: Discussionmentioning

confidence: 99%

“…Endometriosis with ovarian lesion may cause infertility [ 4 ] and ovarian cancer in addition to dysmenorrhea [ [5] , [6] , [7] , [8] , [9] ]. Endometriosis leads to infertility presumably via iron overload and oxidative stress [ 10 ] on follicular growth [ 11 ]. However, the molecular mechanisms how ovarian endometriosis suppresses folliculogenesis is still not elucidated yet.…”

Section: Introductionmentioning

confidence: 99%

Novel ovarian endometriosis model causes infertility via iron-mediated oxidative stress in mice

et al. 2020

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Ovarian endometriosis (OE) provides women of reproductive age with not only severe menstrual pain but also infertility and an increased risk for ovarian carcinogenesis. Whereas peritoneal endometriosis models have been developed with syngeneic implantation of minced uterine tissue and oncogenic K-ras allele with conditional Pten deletion within ovarian surface epithelium generated preneoplastic endometrial glandular morphology, followed by endometrioid adenocarcinoma, there has been no mouse model of OE similar to human counterparts, applicable to preclinical studies. Here we for the first time established a murine OE model that reveals infertility, and evaluated the involvement of iron catalyzed oxidative stress in the pathogenesis. Minced uterine tissue from female mice was implanted on ovarian surface of syngeneic mice after bursectomy to induce OE. Ectopic growth of endometrium was observed in association with ovary 4 weeks after implantation in 85.7% (12/14) of the operated mice with our protocol. Endometriotic lesions involved intestine, pancreas and peritoneal wall. Fibrosis around the ovary was prominent and increased time-dependently in the OE group. Iron accumulation was significantly increased in the OE group, leading to oxidative stress in each stage of the follicles as evaluated by 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-2′-deoxyguanosine. Expression of follicle stimulating hormone receptor in the follicles revealed a significant decrease during pre-antral, antral and pre-ovulatory phases in the OE group. Finally, the number of pups was significantly reduced in the OE group in comparison to the controls. This model affords an opportunity to evaluate agents or procedures to counteract ovarian endometriosis in the preclinical settings.

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“…There are many evidences about increased oxidative stress in the granulosa cells of women with endometriosis, who when compared to women with normal ovaries showed higher 8‐hydroxydeoxyguanosine and lipid peroxidation (4‐hydroxy‐2‐nonenal) 74‐76 . Lin et al reported that the granulosa cells from women with endometriosis had excessive reactive oxygen species, which provoked senescence through endoplasmic reticulum (ER) stress, decrease in mitochondrial membrane potential, and reduction in ATP production 77 . ER stress is significantly associated with oxidative stress.…”

Section: Granulosa Cells In Women With Endometriosismentioning

confidence: 99%

The impact of phthalate on reproductive function in women with endometriosis

Chou

Tzeng

2021

Reprod Medicine & Biology

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Background Endometriosis is a common gynecological condition in which stromal or glandular epithelium is implanted in extrauterine locations. Endometriosis causes detrimental effects on the granulosa cells, and phthalate interferes with the biological and reproductive function of endometrial cells at a molecular level. Methods This article retrospectively reviewed the studies on phthalate exposure and its relationship with endometriosis. A literature search was performed for scientific articles using the keywords “phthalate and endometriosis,” “endometriosis and granulosa cells,” “phthalate and granulosa cells,” and “phthalates and endometrial cells.” Results Endometriosis can affect cytokine production, steroidogenesis, cell cycle progression, expression of estrogen receptor‐α (ER‐α)/progesterone receptor (PR), and cause endoplasmic reticulum stress, senescence, apoptosis, autophagy, and oxidative stress in the granulosa cells. Mono‐n‐butyl phthalate (MnBP) alters the expression of cytokines, cell cycle‐associated genes, ovarian stimulation, steroidogenesis, and progesterone production. Several in vitro studies have demonstrated that phthalate caused inflammation, invasion, change in cytokines, increased oxidative stress, viability, resistance to hydrogen peroxide, and proliferation of endometrial cells. Conclusion This might provide new insights about the impact of phthalate on the pathogenesis of endometriosis and its consequences on the ovarian function.

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Excessive oxidative stress in cumulus granulosa cells induced cell senescence contributes to endometriosis-associated infertility

Cited by 108 publications

References 42 publications

The AMPK‑mTOR axis requires increased MALAT1 expression for promoting granulosa cell proliferation in endometriosis

The AMPK‑mTOR axis requires increased MALAT1 expression for promoting granulosa cell proliferation in endometriosis

Novel ovarian endometriosis model causes infertility via iron-mediated oxidative stress in mice

The impact of phthalate on reproductive function in women with endometriosis

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