Apoptosis In Endometrial Cells Research Articles

Nicotinamide Mononucleotide Improves Endometrial Homeostasis in a Rat Model of Polycystic Ovary Syndrome by Decreasing Insulin Resistance and Regulating the Glylytic Pathway.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that can lead to insulin resistance (IR) and dysregulation of glucose metabolism, resulting in an imbalance in the endometrial environment, which is unfavorable for embryo implantation of PCOS. This study aims to investigate whether nicotinamide mononucleotide (NMN) improves the stability of the endometrium in a rat model of PCOS and identifies whether it is related to reduce IR and increase glycolysis levels and its potential signaling pathway. Female Sprague-Dawley (SD) rats are fed letrozole and a high-fat diet (HFD) to form the PCOS model, then the model rats are treated with or without NMN. It randomly divided into control, PCOS, and PCOS-NMN groups according to the feeding and treating method. Compared with the PCOS group, the regular estrous cycles are restored, the serum androgen (p<0.01) and fasting insulin levels (p<0.05) are reduced, and endometrial morphology (p<0.05) is improved in NMN-PCOS group. Furthermore, NMN inhibits endometrial cell apoptosis, improves endometrial decidualization transition, reduces IR, restores the expression of glycolysis rate-limiting enzymes, and activates the PI3K/AKT pathway in the uterus. These results suggest that NMN enhances endometrial tissue homeostasis by decreasing uterine IR and regulating the glycolysis through the PI3K/AKT pathway.

Retracted] Zearalenone regulates endometrial stromal cell apoptosis and migration via the promotion of mitochondrial fission by activation of the JNK/Drp1 pathway.

Following the publication of this article, a concerned reader drew to the Editor's attention that the experimental design of the western blot assay experiments portrayed in Fig. 5A on p. 7804, and the overall organization of this figure, may have been flawed, as mitochondrial and cytosolic proteins were featured in the figure with only one set of supporting control western blot data; in this scenario, the proteins would necessarily have needed to have been obtained from two separate cell samples in different experiments, and blotted on to separate gels. Moreover, there was also a concern that certain of the gels featured possible breaks in their continuity/splicing events, such that the protein bands in the figure were not shown consecutively, as they would have appeared, in the affected slices. After having conducted an internal investigation, the Editor of Molecular Medicine Reports agrees with the reader that there were anomalies associated with the presentation of Fig. 5. Therefore, on the grounds of a lack of confidence in the presented data, the Editor has decided that the article should be retracted from the publication. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused, and we also thank the reader for bringing this matter to our attention. [Molecular Medicine Reports 17: 7797‑7806, 2018; DOI: 10.3892/mmr.2018.8823].

Evaluation of morphology, apoptosis, and cell proliferation of the uterus in postmenopausal women.

The aim of this study was to evaluate the morphology (atrophy and fibrosis), apopto-sis, and cell proliferation in the uterine wall. The research material came from postmenopausal women who had undergone hysterectomy due to uterine myomas or prolapse of the reproductive organ and were not taking menopausal hormone therapy (MTH). The collected material was divided into three groups. Group I (n=18) con-sisted of uterine sections taken 1 to 5 years after the last menstruation, Group II (n=17) 6 to 10 years after the last menstruation, and Group III (n=15) over 11 years after the last menstruation. To assess morphology and fibrosis, the uterine sections were subjected to hematoxylin and eosin (HE) staining and to Mallory's staining. In addition, we performed a histochemical examination to identify apopto-sis in endometrial and myometrial cells using the TUNEL method. An immunohistochemical analysis of endometrial and myometrial cells was also performed to detect the location of the proliferating cell nuclear antigen (PCNA). Differences in apoptosis were only found in the myometrium between Group I and Group III, and were strongest in Group I myometrial cells, and weakest in Group III. Neither the endome-trium nor the myometrium showed statistically significant differences in the overall percentage of PCNA(+) cells between groups. Morphological changes in the endometrial and myometrial layers of postmenopausal uteri increased with time since the last menstruation.

The Potential Role of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists as a Type of Conservative Treatment of Endometrial Cancer in Women of Reproductive Age: A Review of the Literature and a Call for Study.

Endometrial cancer (EC) is among the most common gynecological malignancies in developed countries and its occurrence has been increasing dramatically in the past few years. An in-depth knowledge of the causes of endometrial cancer, such as unopposed estrogen, insulin resistance, and chronic inflammation, has resulted in the suggestion of numerous interventions to decrease the occurrence of this cancer. Recent research has established a connection between obesity and type 2 diabetes mellitus (T2DM) with a higher chance of developing endometrial cancer, suggesting that insulin resistance is a key factor in its onset. Moreover, evidence from both epidemiological and clinical studies indicates that metformin, a drug used to treat diabetes, could possibly help in the prevention of specific types of cancer such as endometrial cancer. The aim of this study is to explore the possible impact of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) in the non-surgical management of endometrial cancer. GLP-1 has various functions and is produced when nutrients are consumed. Besides promoting the release of insulin, GLP-1 also suppresses the secretion of glucagon and reduces appetite. Moreover, the fact that GLP-1 receptors are found in different organs and tissues such as the brain, lung, pancreas, stomach, heart, and endometrium indicates that GLP-1RAs have multiple functions. Prior research has shown that it triggers apoptosis in endometrial cancer cells. Nevertheless, the precise physiological function of GLP-1 receptors in endometrial cancer still needs to be fully understood.

Endoplasmic reticulum stress is involved in mycotoxin zearalenone induced inflammatory response, proliferation, and apoptosis in goat endometrial stromal cells

Zearalenone (ZEA) is an estrogen-like mycotoxin and is considered a secondary metabolite produced by Fusarium fungi, which are widely found in the surrounding environment. ZEA has been found to cause reproductive dysfunction in female and male animals, but the underlying mechanism remains unclear. Therefore, this study examined cell proliferation, cell apoptosis, autophagy protein expression, and some inflammatory cytokines such as IL-1β and IL-8 of goat endometrial stromal cells (ESCs) induced by different concentrations (0, 15, 30, 60, and 90 µM) of ZEA. The apoptosis rate was detected by flow cytometry. Western Blot and ELISA assay were used to identify the ER stress signaling pathway and some inflammatory cytokines. Our results revealed that ZEA induced cell proliferation and inhibited cell apoptosis at low and middle concentrations, while at high concentrations of ZEA, cell apoptosis was induced in ESCs. Additionally, ZEA induced the ER stress protein markers such as ATF6, IRE1α, EIF2α, and ATF4. LC3 as a marker of autophagy was up-regulated at all concentrations of ZEA. Moreover, IL-1β and IL-8 showed down-regulation at a low concentration of ZEA, but middle and high concentrations showed up-regulation. In the present study, Knockdown ERN1 can inhibit autophagy and the main markers of ER stress. These results suggest that the IRE1 pathway can reduce apoptosis protein markers, down activate IRE1, and unfolded protein response branches such as ATF6 and LC3 in ESCs. Additionally, IL-1β and IL-8 achieve up-regulation under knockdown IRE1, which can block ER stress markers.

Impacts of tolylfluanid on implantation and placental development: Disruption of mitochondrial function and implantation-related gene expression in vitro and in vivo

Tolylfluanid is a widely used pesticide and antifouling agent in agricultural and marine industries and is recognized as a potential endocrine disruptor. However, the toxicological effects of tolylfluanid on the placenta development was not elucidated. This study used trophoblastic cell (HTR-8/SVneo cell) and endometrial cell (T HESCs) lines as in vitro model and mouse models as in vivo model to investigate the toxic effects of tolylfluanid on implantation-associated cell and placenta development during early pregnancy. Experimental results indicated that both cell lines exhibited reduced viability upon tolylfluanid exposure. Various in vitro experiments were conducted at <1 mg/L concentration. The results indicate that tolylfluanid can arrest cell cycle and induce apoptosis in endometrial and trophoblastic cells, abnormally regulate Ca2+ homeostasis and MAPK signaling pathways, and disrupt mitochondrial function. In vivo experiments, subchronic tolylfluanid exposure to mouse during puberty and pregnancy period impaired placenta development, resulting in reduced fetal and placental weight, abnormal placental structures, and altered gene expression. Specifically, a decrease in the ratio of labyrinth/junctional zones and changes in placenta gene expression patterns after tolylfluanid exposure were similar to characters of adverse pregnancy outcomes such as preeclampsia and fetal growth restriction (FGR). This study suggests that tolylfluanid exposure may have negative outcomes on female reproduction, and highlights the need for stricter regulation and monitoring of tolylfluanid use to protect women's reproductive health. This is the first study indicating the adverse effects of tolylfluanid on implantation and placental development during pregnancy.

Calcium ascorbate loaded ultrathin ferrous sulfide nanosheets thermo-sensitive hydrogels for near-infrared light activation of synergistic endometriosis therapy

Endometriosis can cause endometrial inflammation and affect women’s reproductive health. However, it’s still challenging to develop efficient endometriosis treatment strategies until now. Herein, a novel near-infrared light (NIR)-activated hydrogel nanostructure (Vc-Ca/UFNs@Gel) with ultrathin ferrous sulfide nanosheets (UFNs) and calcium ascorbate (Vc-Ca) was developed for in situ photothermal/ferroptosis/immune synergistic endometriosis therapy. UFNs with high photothermal conversion efficiency can convert NIR into heat to achieve efficient photothermal therapy (PTT) of endometrial cells, and simultaneously melt the hydrogels to achieve the release of Vc-Ca and UFNs. Vc-Ca can greatly prevent UFNs with ultrathin nanostructure from oxidation and keep their photothermal capacity, as well as directly inhibit the proliferation of endometrial cells. UFNs with dose-dependent internalization decomposed into H2S and Fe2+ ions in endometrial cell, catalyzing the self-oxidation process of Vc-Ca to generate H2O2 and enhancing Fe2+-triggered ferroptosis of endometriosis. Interestingly, ferroptosis and PTT-triggered endometrial cell apoptosis could also induce immunogenic cell death and enhance subsequent immunotherapy. Importantly, our hydrogels can be degradable in vivo with high safety. Overall, our work proposed a novel in situ photothermal/ferroptosis/immune synergistic endometriosis therapy strategy and may have significantly potential clinical application prospects.

The association between endometrial polyps and insulin resistance from the expression of PI3K and AKT proteins perspective

BackgroundInsulin resistance (IR) induces hyperinsulinemia, which activates downstream signaling pathways such as the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway, ultimately leading to abnormal proliferation and apoptosis of endometrial cells. This is thought to be a key pathogenic mechanism underlying the development of endometrial polyps (EP). This study aims to investigate the relationship between IR and the development of EP, the expression levels of downstream signaling molecules, including PI3K and AKT, and related laboratory parameters were examined.MethodsA total of 100 patients who visited the gynecology outpatient clinic of Zhongda Hospital affiliated with Southeast University from May 2021 to March 2023 and were diagnosed with abnormal endometrial echoes by vaginal ultrasound and underwent hysteroscopic diagnostic curettage were enrolled in this study. General data and relevant hematological indicators were compared, and intraoperative specimens were obtained for pathological examination. Possible factors influencing the development of endometrial polyps were analyzed using Pearson correlation analysis and logistic regression analysis.ResultsIn terms of body mass index, waist circumference, fasting insulin, insulin resistance index, serum total testosterone, and free testosterone index, women of childbearing age in the endometrial polyp group had higher values than those in the non-polyp group, while sex hormone-binding globulin in the endometrial polyp group was lower than that in the non-polyp group, and the differences were statistically significant (P < 0.05). The expression scores and mRNA expression levels of PI3K and AKT proteins were higher in the EP group than in the non-EP group (p < 0.05). Pearson correlation analysis showed a positive correlation between HOMA-IR and the expression scores of PI3K and AKT proteins (p < 0.01).ConclusionsInsulin resistance and abnormal activation of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway may be potential pathogenic mechanisms for the development of endometrial polyps.

Particulate matter exposure induces adverse effects on endometrium and fertility via aberrant inflammatory and apoptotic pathways in vitro and in vivo

This study aimed to evaluate the adverse effects of particulate matter (PM) exposure on endometrial cells and fertility and to identify possible underlying mechanisms. Thirteen women (aged 15–52 years) were included in this study. Enrolled patients underwent laparoscopic surgery at Gangnam Severance Hospital between 1 January and 31 December 2021. For in vivo experiments, 36 female and nine male C57BL/6 mice were randomly divided into control(vehicle), low-dose(10 mg/kg/d), and high-dose exposure groups(20 mg/kg/d). PM was inhaled nasally for four weeks and natural mating was performed. NIST® SRM® 1648a was used for PM exposure. qRT-PCR, western blotting and Masson's trichrome staining were performed. PM treatment in human endometrial stromal cells induced inflammation with significant upregulation of IL-1β, p–NF–kB, and p-c-Jun compared to those of controls. Additionally, PM treatment significantly increased apoptosis in human endometrial stromal cells by downregulating p-AKT and upregulating p-p53/p53, Cas-3, BAX/Bcl-2, p-AMPK, and p-ERK. After PM treatment, the relative expression of IL-1β, IL-6, TNF-α, p–NF–κB, p-c-Jun, and p-Nrf2/Nrf2 significantly increased in murine endometrium compared to those of the controls. Expression of apoptotic proteins p53, p27, and Cas-3, was also significantly elevated in murine endometrium of the PM exposure group compared to that of the controls. A significant increase in expression of procollagen Ⅰ, and Masson's trichrome staining scores in the murine endometrium was noted after PM treatment. PM treatment significantly decreased ERα expression. After natural mating, all 3 female mice in the control group gave birth to 25 offspring (mean 8.1), whereas in the low-dose PM treatment group, two of three female mice gave birth to nine offspring (mean 4.5). No pregnant mice or offspring was present in the high-dose PM treatment group. PM exposure induces adverse effects on the endometrium through aberrant activation of inflammatory and apoptotic pathways and is associated with detrimental effects on murine fertility.

The Downregulation of MMP23B Facilitates the Suppression of Vitality and Induction of Apoptosis in Endometrial Cancer Cells

Endometrial cancer is a malignant tumor that commonly occurs in the female reproductive system and its incidence is still increasing. The mechanism of the development of endometrial cancer has not yet been fully clarified, so we need to continuously study the relevant mechanisms of endometrial cancer and continue to explore its biomarkers in order to discover more precise and effective treatment methods for endometrial cancer. RT-qPCR (Real-Time quantitative Polymerase Chain Reaction) experiments were used to detect the expression level of MMP23B (Matrix Metalloproteinase 23B) in endometrial cancer cells; the clinical data of the TCGA (The Cancer Genome Atlas) database were downloaded, and gene expression profiles were analyzed to investigate the correlation between MMP23B (Matrix Metalloproteinase 23B) and the survival prognosis of endometrial cancer, and functional enrichment analysis was performed on MMP23B (Matrix Metalloproteinase 23B) related genes. After silencing MMP23B (Matrix Metalloproteinase 23B), CCK8 (Cell Counting Kit-8), RT-qPCR (Real-Time quantitative Polymerase Chain Reaction), scratch assay, and transwell assay were used to detect cell viability, levels of apoptotic factors, migration rate, and invasion number of endometrial cancer, respectively. MMP23B (Matrix Metalloproteinase 23B) was highly expressed in endometrial cancer, which is closely related to a poor survival prognosis for endometrial cancer, and may act on endometrial cancer through apoptosis-related functions. The downregulation of MMP23B (Matrix Metalloproteinase 23B) reduced the cell viability of endometrial cancer cells, upregulated the expression levels of CASP3 (Caspase-3), CASP8 (Caspase-8) and CASP9 (Caspase-9) in cells, and inhibited cell migration and invasion.

Palmitic Acid Exerts Anti-Tumorigenic Activities by Modulating Cellular Stress and Lipid Droplet Formation in Endometrial Cancer.

Epidemiological and clinical evidence have extensively documented the role of obesity in the development of endometrial cancer. However, the effect of fatty acids on cell growth in endometrial cancer has not been widely studied. Here, we reported that palmitic acid significantly inhibited cell proliferation of endometrial cancer cells and primary cultures of endometrial cancer and reduced tumor growth in a transgenic mouse model of endometrial cancer, in parallel with increased cellular stress and apoptosis and decreased cellular adhesion and invasion. Inhibition of cellular stress by N-acetyl-L-cysteine effectively reversed the effects of palmitic acid on cell proliferation, apoptosis, and invasive capacity in endometrial cancer cells. Palmitic acid increased the intracellular formation of lipid droplets in a time- and dose-dependent manner. Depletion of lipid droplets by blocking DGAT1 and DGAT2 effectively increased the ability of palmitic acid to inhibit cell proliferation and induce cleaved caspase 3 activity. Collectively, this study provides new insight into the effect of palmitic acid on cell proliferation and invasion and the formation of lipid droplets that may have potential clinical relevance in the treatment of obesity-driven endometrial cancer.

17β-estradiol Inhibits Oxidative Stress-Induced Apoptosis in Endometrial Cancer Cells by Promoting FOXM1 Expression.

The steroid hormone 17β-estradiol (E2) has a significant impact on the development and progression of tumors. E2 stimulates tumor cell growth and metabolism, leading to an increase in reactive oxygen species (ROS) production. However, the rise in ROS levels is not sufficient to cause severe harm to cancer cells. and the mechanisms that regulate ROS are not well understood. Since FOXM1 plays a crucial role in the production of ROS, we aimed to investigate the impact of E2 on oxidative stress and the involvement of FOXM1 in the Ishikawa endometrial cancer cell line. Our research revealed that E2 controls the levels of ROS inside cells and safeguards them from apoptosis by promoting the expression of FOXM1. We observed a decrease in the expression of FOXM1 alongside an increase in oxidative damage. Moreover, cells demonstrated elevated levels of FOXM1 and ERα upon E2 treatment. Overall, our findings suggest that E2 prevents apoptosis induced by oxidative stress in endometrial cancer cells by encouraging the expression of FOXM1, potentially affecting ERα.

P,p'-DDT induces apoptosis in human endometrial stromal cells via the PI3K/AKT pathway and oxidative stress.

Bis-[4-chlorophenyl]-1,1,1-trichloroethane (DDT), one of the most widely used synthetic pesticides, is an endocrine-disrupting chemical with the potential to interfere with the human reproductive system. The effects of DDT and one of its metabolites, p,p'-DDT, on human endometrial stromal cells (ESCs) and health outcomes remain unknown. In this study, we investigated whether p,p'-DDT induces an imbalance in cell proliferation and apoptosis in human ESCs via oxidative stress. We assessed apoptosis in ESCs by quantifying the expression of markers associated with both intrinsic and extrinsic pathways. Additionally, we measured levels of reactive oxygen species (ROS), antioxidant enzyme activity, and estrogen receptors (ERs). We also examined changes in signaling involving nuclear factor kappa-light-chain-enhancer of activated B cells. Following treatment with 1,000 pg/mL of p,p'-DDT, we observed an increase in Bax expression, a decrease in Bcl-2 expression, and increases in the expression of caspases 3, 6, and 8. We also noted a rise in the generation of ROS and a reduction in glutathione peroxidase expression after treatment with p,p'-DDT. Additionally, p,p'-DDT treatment led to changes in ER expression and increases in the protein levels of phosphatidylinositol 3-kinase (PI3K), phospho-protein kinase B (phospho-AKT), and phospho-extracellular signal-regulated kinase (phospho-ERK). p,p'-DDT was found to induce apoptosis in human ESCs through oxidative stress and an ER-mediated pathway. The activation of the PI3K/AKT and ERK pathways could represent potential mechanisms by which p,p'-DDT prompts apoptosis in human ESCs and may be linked to endometrial pathologies.

Inhibition of IGF2BP1 attenuates the progression of endometriosis through PTBP1.

Endometriosis (EMs), manifested by pain and infertility, is a chronic inflammatory disease. The precise pathophysiology of this disease remains uncertain. Insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) and polypyrimidine tract-binding protein 1 (PTBP1) have both been found to regulate proliferation, apoptosis, and invasion. This study aimed to investigate the effects of IGF2BP1/PTBP1 in treating EMs. qRT-PCR and western blotting were employed to quantify IGF2BP1 and PTBP1 expression in six patients with EMs (mean age 33.83 years). The correlation analysis, STRING database prediction, and RNA immunoprecipitation were utilized to identify the relationship between IGF2BP1 and PTBP1. Ectopic endometrial volume, weight, HE staining, and IGF2BP1 silencing were utilized to estimate the effects of IGF2BP1 in EMs model rats. qRT-PCR, CCK-8, 5-ethynyl-2'-deoxyuridine (EDU) labeling, Transwell assay, and flow cytometry were utilized to assess the effects of IGF2BP1/PTBP1 on the proliferation, migration, invasion, and apoptosis of ectopic endometrial stromal cells (eESCs). Furthermore, western blotting was employed to evaluate expressions of PCNA, VEGF, and E-cadherin in EMs rats and eESCs. The mRNA and protein levels of IGF2BP1 and PTBP1 in the ectopic and eutopic endometrium of EMs patients were significantly increased. RNA immunoprecipitation revealed a close interaction of IGF2BP1 with PTBP1. Additionally, the endometrial volume, weight, and histopathologic scores in rats were significantly reduced after IGF2BP1 silencing. IGF2BP1 silencing also decreased the expression of PCNA and VEGF, and increased E-cadherin expression in endometrial tissues of EMs rats. Moreover, IGF2BP1 silencing inhibited proliferation, migration, and invasion and promoted apoptosis through PTBP1 in eESCs. IGF2BP1 exhibits potential beneficial properties in the management of EMs by interacting with PTBP1, thereby highlighting IGF2BP1 as a promising therapeutic target for EMs.

KAT2A changes the function of endometrial stromal cells via regulating the succinylation of ENO1.

Endometriosis is increasingly affecting women worldwide and research is focusing on identifying key targets in its pathogenesis. Changes in succinylation genes regulate the function of this protein and further influence the development of the disease. However, the role of succinylation genes in endometriosis is not clear from current studies. The expression of succinylation genes was determined in ectopic endometrium (EC) and ectopic patients with uterine fibroids (EN) by real-time quantitative PCR (qRT-PCR) and Western blot. Cell Counting Kit-8, transwell assays, and flow cytometry were used to assess endometrial stromal cells (ESCs) proliferation, apoptosis, migration, and invasion. KAT2A and ENO1 association was detected by qRT-PCR, immunofluorescence, and CoIP. We found that gene and protein levels of KAT2A were significantly increased in the EC group compared to EN group tissues. KAT2A silencing inhibited cell proliferation, migration, and invasion and promoted apoptosis. Western blot results showed that the expression of ENO1 and its succinylation was significantly upregulated in ECSc after KAT2A overexpression. CoIP results showed that KAT2A is positively bound to ENO1. Immunofluorescence also showed co-localized expression of KAT2A with ENO1. Furthermore, ENO1 overexpression reversed the effects of KAT2A silencing on the malignant behavior of ESCs. In summary, we found that succinylation of ENO1 mediated by KAT2A played a role in promoting the progression of endometriosis.

Mechanism of regulation of KIF23 on endometrial cancer cell growth and apoptosis

ObjectiveThe global incidence of endometrial cancer, a malignant tumor in females, is on the rise. It is one of the most common gynecological cancers. Early-stage endometrial cancers can often be treated successfully with uterine extirpation. However, those diagnosed at a later stage have a poor prognosis and encounter treatment challenges. Therefore, additional research is necessary to develop primary prevention strategies for high-risk women and improve survival rates among patients with endometrial cancer. Hence, gene therapy targeting KIF23 shows promise as an advanced strategy for the treatment of endometrial cancer.MethodsImmunohistochemistry, Western blotting, and PCR were used to examine the expression of KIF23 and its associated pathway factors in endometrial cancer tissue (specifically Ishikawa and SNGM cells, respectively). We investigated the functional roles of KIF23 using CCK-8, colony-forming proliferation assays, Transwell migration assays, and xenotransplantation in mice.ResultsImmunohistochemistry analysis showed variations in the expression levels of KIF23 between endometrial cancer tissue and normal endometrium tissue. KIF23 downregulated BAX and caspase-3 protein expression while upregulating BCL-2 protein expression. Additionally, knocking out KIF23 inhibits endometrial cancer cell proliferation and migration while promoting cell death. Mechanistically, our study provides evidence that KIF23 promotes endometrial cancer cell proliferation by activating the ERK and AKT/PI3K pathways, while simultaneously inhibiting programmed cell death in endometrial cancer.ConclusionOur study provides evidence to support the inhibition of endometrial cancer by KIF23 knockdown. This offers valuable insights for future research on potential therapeutic strategies for this type of cancer.Graphical

DOCK1 regulates the malignant biological behavior of endometrial cancer through c-Raf/ERK pathway

BackgroundThe effect of DOCK1 gene on the biological behavior of endometrial carcinoma cells and its related pathway has not been reported.MethodsThe immunohistochemical method and western blot were utilized to analyze DOCK1 protein expression in endometrial tissues and cells, respectively. CCK-8, BrdU, transwell and flow cytometry were performed to analyze the effect of DOCK1 expression changes on the viability, proliferation, invasion, migration and apoptosis of endometrial cancer cells, respectively. The effects of DOCK1 gene on Bcl-2, MMP9, Ezrin, E-cadherin and c-RAF/ERK1/2 signaling pathway were evaluated by western blot. The xenograft models were constructed to analyze the effect of DOCK1 in vivo.ResultsDOCK1 expression was increased in endometrial cancer tissues and cells compared with those in normal adjacent tissues and cells. DOCK1 knockout could inhibit the malignant biological behavior of endometrial cancer cells, while DOCK1 overexpression played the opposite effect. The expression of E-cadherin was upregulated and those of MMP9, Ezrin, Bcl-2, p-c-RAF (S338) and p-ERK1/2 (T202/Y204) were downregulated after DOCK1 knockout, while DOCK1 overexpression played the opposite effect. Additionally, Raf inhibitor LY3009120 reversed the function of DOCK1 on malignant biological behavior. In vivo experiment results showed that the growth and weight of transplanted tumors in nude mice were inhibited after DOCK1 knockout. The changes of E-cadherin, MMP9, Ezrin and Bcl-2 expressions in the transplanted tumors were consistent with those in vitro.ConclusionDOCK1 could enhance the malignant biological behavior of endometrial cancer cells, which might be through c-RAF/ERK1/2 signaling pathways in vitro and in vivo.

Licochalcone A induces endoplasmic reticulum stress-mediated apoptosis of endometrial cancer cells via upregulation of GRP78 expression.

Licochalcone A (LicA), a natural compound extracted from licorice root, has been shown to exert a variety of anticancer activities. Whether LicA has such effects on endometrial cancer (EMC) is unclear. This study aims to investigate the antitumor effects of LicA on EMC. Our results show that LicA significantly reduced the viability and induced apoptosis of EMC cells and EMC-7 cells from EMC patients. LicA was also found to induce endoplasmic reticulum (ER) stress, leading to increased expression of ER-related proteins (GRP78/PERK/IRE1α/CHOP) in EMC cell lines. Suppression of GRP78 expression in human EMC cells treated with LicA significantly attenuated the effects of LicA, resulting in reduced ER-stress mediated cell apoptosis and decreased expression of ER- and apoptosis-related proteins. Our findings demonstrate that LicA induces apoptosis in EMC cells through the GRP78-mediated ER-stress pathway, emphasizing the potential of LicA as an anticancer therapy for EMC.

Inhibition of protein arginine methyltransferase 6 activates interferon signaling and induces the apoptosis of endometrial cancer cells via histone modification.

Histone modification, a major epigenetic mechanism regulating gene expression through chromatin remodeling, introduces dynamic changes in chromatin architecture. Protein arginine methyltransferase6 (PRMT6) is overexpressed in various types of cancer, including prostate, lung and endometrial cancer (EC). Epigenome regulates the expression of endogenous retrovirus (ERV), which activates interferon signaling related to cancer. The antitumor effects of PRMT6 inhibition and the role of PRMT6 in EC were investigated, using epigenome multi‑omics analysis, including an assay for chromatin immunoprecipitation sequencing (ChIP‑seq) and RNA sequencing (RNA‑seq). The expression of PRMT6 in EC was analyzed using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and immunohistochemistry (IHC). The prognostic impact of PRMT6 expression was evaluated using IHC. The effects of PRMT6‑knockdown (KD) were investigated using cell viability and apoptosis assays, as well as its effects on the epigenome, using ChIP‑seq of H3K27ac antibodies and RNA‑seq. Finally, the downstream targets identified by multi‑omics analysis were evaluated. PRMT6 was overexpressed in EC and associated with a poor prognosis. PRMT6‑KD induced histone hypomethylation, while suppressing cell growth and apoptosis. ChIP‑seq revealed that PRMT6 regulated genomic regions related to interferons and apoptosis through histone modifications. The RNA‑seq data demonstrated altered interferon‑related pathways and increased expression of tumor suppressor genes, including NK6 homeobox 1 and phosphoinositide‑3‑kinase regulatory subunit 1, following PRMT6‑KD. RT‑qPCR revealed that eight ERV genes which activated interferon signaling were upregulated by PRMT6‑KD. The data of the present study suggested that PRMT6 inhibition induced apoptosis through interferon signaling activated by ERV. PRMT6 regulated tumor suppressor genes and may be a novel therapeutic target, to the best of our knowledge, in EC.

RING1 Inhibition Has a Cell-Specific Antitumoral Role by Promoting Autophagy in Endometrial Cancer Cells.

Factors influencing gene expression through chemical modifications of histones may play an important role in the regulation of the autophagy process in cancers. RING1A or RING1B are responsible for the catalytical activity of Polycomb repressive complex 1 (PRC1) which monoubiquitylate histone H2A. The aim of the study was to determine the effect of the RING1A/B protein inhibition on the autophagy process in endometrial cancer cells and the anticancer effectiveness of RING1 inhibitor PRT4165 in combination with autophagy inhibitors. The expression of autophagy genes and proteins were analyzed in endometrial cancer cells HEC-1A and Ishikawa grown in different glucose concentrations and treated with PRT4165. To assess the effectiveness of PRT4165 used alone or in combination with HCQ or Lys05, IC50 and the combination index (CI) were calculated. Flow cytometry method was used to estimate apoptotic cells after treatment. The results confirm the impact of RINGs on autophagy and apoptosis in endometrial cancer cells. PRT4165 inhibitor causes changes in the expression of ATG genes and autophagy markers and the effect depends on glucose concentration and cell types. However, the anticancer effectiveness of PRT4165 was lower when it was used in combination with autophagy inhibitors, suggesting that such a combination is not a promising anticancer strategy. The results indicate the importance of the RINGs in the process of autophagy and apoptosis. Further potentially more effective combinations of PRT4165 with autophagy modulators should be sought.