Development Of Endometrial Carcinoma Research Articles

Abstract PR006: ARID1A/B mutations retarget mSWI/SNF chromatin remodeler activity and define a spectrum of dedifferentiation in endometrial carcinoma

Abstract Dedifferentiated/undifferentiated endometrial carcinoma (DEC/UEC) is a highly aggressive histologic subtype of uterine cancer with a higher incidence among non-Hispanic Black women. Recent exome-wide sequencing studies have revealed frequent and often concomitant mutations in the ARID1A and ARID1B genes in over 50% of DEC/UEC cases and 30% of all endometrial carcinomas. The mSWI/SNF family of chromatin remodelers are critical regulators of cell type-specific chromatin accessibility and gene expression, existing in three distinct forms: canonical BAF (cBAF), Poly bromodomain-associated BAF (PBAF), and non-canonical BAF (ncBAF). The paralog subunits, ARID1A and ARID1B, specifically nucleate the assembly of cBAF complexes. However, the precise role ARID1A/ARID1B mutations (cBAF loss) play in the development of dedifferentiated endometrial carcinoma remains unclear. In this study, we define an expression signature associated with endometrial “dedifferentiation” by profiling the well-differentiated and dedifferentiated components of cBAF loss DEC cases through laser capture microdissection followed by RNA sequencing. Introduction of ARID1A or ARID1B in cBAF loss DEC cell lines demonstrated the restoration of cBAF assembly, confirmed by glycerol gradient and IP mass spectrometry. Upon the expression of ARID1A or ARID1B, we observed widespread chromatin occupancy and DNA accessibility at distinct paralog-specific sites, along with common sites associated with epithelial lineage differentiation, estrogen receptor, and PI3K/AKT pathway signaling. These findings align with the differentiation signature, defined in DEC cases demonstrating downregulation of genes associated with Myc targets, cell cycle checkpoint pathways, and DNA repair, suggesting these pathways represent potential therapeutic avenues for targeting DEC/UEC. Collectively, these data establish that well-differentiated endometrial carcinoma and DEC/UEC with mSWI/SNF mutations represent a spectrum of cBAF loss, defining the unique roles of ARID1A and ARID1B in endometrial carcinoma development. Furthermore, these findings imply that cBAF loss drives the widespread changes in DEC morphology, gene expression, and clinical behavior, enhancing our understanding of the etiology and therapeutic options for these cancers. Citation Format: Jessica D. St. Laurent, Grace Xu, Kasey Cervantas, Ajinkya Patil, Akshay Sankar, Shary Chen, David Kolin, Yemin Wang, David G. Huntsman, Cigall Kadoch. ARID1A/B mutations retarget mSWI/SNF chromatin remodeler activity and define a spectrum of dedifferentiation in endometrial carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr PR006.

Impact of artificial intelligence on the diagnosis, treatment and prognosis of endometrial cancer.

Endometrial cancer is one of the most prevalent tumours in females and holds an 83% survival rate within 5 years of diagnosis. Hypoestrogenism is a major risk factor for the development of endometrial carcinoma (EC) therefore two major types are derived, type 1 being oestrogen-dependent and type 2 being oestrogen independent. Surgery, chemotherapeutic drugs, and radiation therapy are only a few of the treatment options for EC. Treatment of gynaecologic malignancies greatly depends on diagnosis or prognostic prediction. Diagnostic imaging data and clinical course prediction are the two core pillars of artificial intelligence (AI) applications. One of the most popular imaging techniques for spotting preoperative endometrial cancer is MRI, although this technique can only produce qualitative data. When used to classify patients, AI improves the effectiveness of visual feature extraction. In general, AI has the potential to enhance the precision and effectiveness of endometrial cancer diagnosis and therapy. This review aims to highlight the current status of applications of AI in endometrial cancer and provide a comprehensive understanding of how recent advancements in AI have assisted clinicians in making better diagnosis and improving prognosis of endometrial cancer. Still, additional study is required to comprehend its strengths and limits fully.

Bcl-2 May Contribute to Evolution of Endometrial Hyperplasia, but It Isn’t a Factor in Subsequent Carcinogenesis

Endometrial carcinoma is common in the western world and is increasing in frequency in developing countries as well. Endometrial hyperplasia is considered to be a precancerous lesion. Apoptosis plays an important role in the neoplastic transformation of cells, with Bcl-2 being an anti-apoptotic cellular marker. Bcl-2 may have an important contribution to the development of endometrial carcinoma. The aim was to evaluate and compare the expression of markers Bcl-2 through the spectrum of normal endometrium, endometrial hyperplasias and endometrial adenocarcinomas. 50 cases were included in this study, comprising of 10 cases of normal endometrium, 10 cases of endometrial hyperplasia without atypia, 10 cases of atypical endometrial hyperplasia and 20 cases of endometrial adenocarcinomas from January 2017 to June 2018. Immunohistochemical staining with Bcl-2 was performed and the results were analyzed. Bcl-2 staining showed an increase in cases with strong intensity of staining from normal endometrium (20% cases) to cases of endometrial hyperplasia (75% cases). There was, however a decrease in the number of cases with strong intensity Bcl-2 staining as the lesions progressed from endometrial hyperplasia to endometrial carcinoma (30% cases). The results were statistically significant (P =0.00309). However, there was no significant association of staining between atypical hyperplasia and endometrial carcinomas (p=0.429), as well as the degree of carcinoma (p=0.6903). Bcl-2 expression showed an increase from cases of normal endometrium to endometrial hyperplasia supporting the process of increased anti- apoptotic activity in endometrial hyperplastic lesions. Its decreased expression in endometrioid adenocarcinoma when compared to endometrial hyperplasias could point towards other mechanisms of carcinogenesis other than failure of apoptosis.

CDK1 promotes the phosphorylation of KIFC1 to regulate the tumorgenicity of endometrial carcinoma.

This study aims to clarify the mechanical action of cyclin-dependent protein kinase 1 (CDK1) in the development of endometrial carcinoma (EMCA), which may be associated with the phosphorylation of kinesin family member C1 (KIFC1) and further activate the PI3K/AKT pathway. The protein and gene expression of CDK1 in EMCA tissues and tumor cell lines were evaluated by western blot, quantitative polymerase chain reaction, and immunohistochemistry staining. Next, Cell Counting Kit-8 and colony formation assay detected cell survival and proliferation. Cell migration and invasion were measured by Transwell assay. Cell apoptosis and cell cycle were tested by flow cytometry. Immunofluorescence staining of γH2AX was used to evaluate DNA damage, respectively. Subsequently, a co-immunoprecipitation assay was used to detect the interaction between CDK1 and KIFC1. The phosphorylated protein of KIFC1 and PI3K/AKT was detected by western blot. Finally, the effect of CDK1 on the tumor formation of EMCA was evaluated in a nude mouse xenograft model. CDK1 was highly expressed in EMCA tumor cell lines and tissues, which contributed to cell survival, proliferation, invasion, and migration, inhibited cell apoptosis, and induced DNA damage of EMCA cells dependent on the phosphorylation of KIFC1. Moreover, the CDK1-KIFC1 axis further activated PI3K/AKT pathway. Finally, CDK1 knockdown repressed tumor formation of EMCA in vivo. We report that increased CDK1 promotes tumor progression and identified it as a potential prognostic marker and therapeutic target of EMCA.

Expression of DKK1 in Endometrial Endometrioid Carcinoma and Its Correlation with Wnt/β-catenin Signalling Pathway.

Endometrial cancer is the most prevalent form of cancer affecting female reproductive organs. The most common histologic type, endometrioid carcinoma, accounts for 75-80% of all endometrial cancer cases. Studies on DKK1 expression profiles and their inhibitory role in the Wnt signalling pathway in the genesis and development of endometrial carcinoma are scarce. This study aimed to investigate DKK1 expression in endometrial carcinoma and its correlation with the Wnt/β-catenin pathway. A total of 160 formalin-fixed paraffin-embedded samples were included in this study (50 cases of endometrial atypical hyperplasia, 50 cases of endometrioid endometrial carcinoma, 30 cases of proliferative endometrium and 30 cases of secretory endometrium). The expression patterns of DKK1, E-cadherin, β-catenin and c-Myc in endometrial atypical hyperplasia and carcinoma were investigated and compared with that of proliferative and secretory endometrium. Immunohistochemistry and analysis were performed from July 2018 to June 2020. A decreasing pattern of immunopositivity for DKK1, E-cadherin and β-catenin from proliferative/secretory endometrium to endometrial atypical hyperplasia and endometrioid carcinoma was found. Increasing c-Myc immunopositivity was noted from proliferative/secretory endometrium to endometrial atypical hyperplasia and endometrioid carcinoma. Moreover, decreasing DKK1 immunopositivity was well correlated with E-cadherin, β-catenin and c-Myc immunopositivity. Decreasing DKK1 positivity from benign endometrium to endometrioid carcinoma suggests a negative regulatory function of DKK1 in endometrioid carcinoma. DKK1 is downregulated in the Wnt signalling pathway in endometrioid endometrial carcinoma. Therefore, DKK1 is promising as a biomarker for screening endometrioid carcinoma. Future studies should examine the reactivation of the DKK1 gene, which may be a valuable strategy for antagonising the Wnt signalling pathway.

Casein kinase 1 controls the shuttling of epidermal growth factor receptor and estrogen receptor in endometrial carcinoma induced by breast cancer hormonal therapy: Relevance of GPER1/Src

Casein kinase 1 plays a crucial role in carcinogenesis. 4-Hydroxytamoxifen (4-OHT), which is widely used to treat breast cancer, often leads to the development of endometrial carcinoma with poor prognosis, particularly among women who receiving long-term treatment. This study was performed to elucidate whether specific inhibition of casein kinase 1 (CK1) controls 4-OHT-mediated Ishikawa cell carcinogenesis. 4-OHT significantly stimulated the activity of estrogen receptor alpha (ERα) and nuclear translocation and expression of epidermal growth factor receptor (EGFR) from the plasma membrane to perinuclear or nuclear regions, as well as the activities of G-protein-coupled estrogen receptor 1 (GPER1) and Src in Ishikawa cells. However, inhibition of EGFR by Gefitinib blocked all these events, and inhibition of GPER1 or Src produced a partial block. GPER1 and Src controlled Ishikawa cell carcinogenesis in different manners: GPER1 accelerated EGFR mobility without affecting ERα activity, while Src activated ERα and EGFR without any change in GPER1 expression. EGFR and GPER1 performed reciprocal regulation in endometrial cell carcinogenesis via direct interaction in 4-OHT-treated Ishikawa cells, implying a possible key role of GPER1 in these events. Inhibition of CK1 by CKI-7 and IC261, however, impeded all changes beginning with EGFR translocation and activity in 4-OHT-treated Ishikawa cells. These findings indicate that inhibition of CK1 could control 4-OHT-mediated activation and translocation of ER/EGFR and GPER1/Src expression, inhibiting 4-OHT-triggered endometrial carcinogenesis. Therefore, targeting of CK1 by CKI-7 and IC261 could be a prospective adjuvant therapy for breast cancer patients taking tamoxifen.

Mutation-specific Mismatch Repair-deficient Benign Endometrial Glands in Endometrial Biopsies and Curettings Are a Biomarker of Lynch Syndrome and Associate With Endometrial Carcinoma Development.

Endometrial carcinoma is the most common extraintestinal cancer in Lynch syndrome (LS). Recent studies have demonstrated mismatch repair (MMR) deficiency can be detected in benign endometrial glands in LS. We performed MMR immunohistochemistry in benign endometrium from endometrial biopsies and curettings (EMCs) from a study group of 34 confirmed LS patients and a control group of 38 patients without LS who subsequently developed sporadic MLH1-deficient or MMR-proficient endometrial carcinoma. MMR-deficient benign glands were only identified in patients with LS (19/34, 56%) and were not identified in any control group patient (0/38, 0%) ( P < 0.001). MMR-deficient benign glands were identified as large, contiguous groups in 18 of 19 cases (95%). MMR-deficient benign glands were identified in patients with germline pathogenic variants in MLH1 (6/8, 75%), MSH6 (7/10, 70%), and MSH2 (6/11, 55%) but not in patients with variants in PMS2 (0/4). MMR-deficient benign glands were seen in all EMC samples (100%) but in only 46% of endometrial biopsy samples ( P =0.02). Patients with MMR-deficient benign glands were significantly more likely to have endometrial carcinoma (53%) compared with LS patients with only MMR-proficient glands (13%) ( P =0.03). In conclusion, we demonstrated that MMR-deficient benign endometrial glands are frequently identified in EMB/EMC in women with LS and are a specific marker for LS. Women with LS with MMR-deficient benign glands were more likely to have endometrial carcinoma suggesting that MMR-deficient benign glands may be a biomarker of increased risk of endometrial carcinoma development in LS.

LncRNA XIST/miR‑129‑2‑3p axis targets CCP110 to regulate the proliferation, invasion and migration of endometrial cancer cells.

Centromere coiled-coil protein 110 (CCP110) plays a role in the development of several types of cancer; however, its regulatory mechanism and role in endometrial cancer is unclear. The present study revealed that CCP110 is regulated by a signaling pathway involving microRNA (miR/miRNA)-129-2-3p and the long non-coding RNA (lncRNA) X-inactive-specific transcript (XIST), and plays a role in controlling the proliferation, migration and invasion of endometrial cancer cells. CCP110 was upregulated in human endometrial cancer tissues, as revealed by immunohistochemistry, and high expression of the protein was related to reduced overall survival of the patients. Genetic knockdown of CCP110 by small interfering RNA promoted apoptosis and suppressed the proliferation, migration, invasion and colony formation of endometrial cancer cells significantly in the endometrial cancer Ishikawa and HEC-1B cell lines, as assessed by flow cytometry, and Cell Counting Kit-8, Transwell and colony formation assays. A bioinformatics analysis and luciferase reporter assay revealed that CCP110 is a target of miR-129-2-3p. Overexpression of miR-129-2-3p mimic fragments inhibited the proliferation, migration and invasion of endometrial cancer cells significantly, while co-overexpression of CCP110 counteracted these inhibitory effects. The expression level of the lncRNA XIST was upregulated significantly in endometrial cancer tissues, as assessed by reverse transcription-quantitative PCR assay, while that of miR-129-2-3p was downregulated significantly. A bioinformatics analysis and luciferase reporter assay showed that XIST could inhibit miR-129-2-3p via a miRNA sponge effect. Furthermore, co-overexpression of XIST antagonized the inhibitory effect of the miR-129-2-3p mimic on the luciferase reporter gene signal and protein expression of CCP110. Co-overexpression of XIST also abolished the inhibitory effect of the miR-129-2-3p mimic on the proliferation, migration and invasion of endometrial cancer cells. Overall, these data identified a novel regulatory mechanism of CCP110 involving XIST and miR-129-2-3p, which affected the development of endometrial carcinoma. CCP110, XIST and miR-129-2-3p could represent novel targets for the clinical treatment of endometrial cancer.

Development and validation of two redox-related genes associated with prognosis and immune microenvironment in endometrial carcinoma.

In recent studies, the tumourigenesis and development of endometrial carcinoma (EC) have been correlated significantly with redox. We aimed to develop and validate a redox-related prognostic model of patients with EC to predict the prognosis and the efficacy of immunotherapy. We downloaded gene expression profiles and clinical information of patients with EC from the Cancer Genome Atlas (TCGA) and the Gene Ontology (GO) dataset. We identified two key differentially expressed redox genes (CYBA and SMPD3) by univariate Cox regression and utilised them to calculate the risk score of all samples. Based on the median of risk scores, we composed low-and high-risk groups and performed correlation analysis with immune cell infiltration and immune checkpoints. Finally, we constructed a nomogram of the prognostic model based on clinical factors and the risk score. We verified the predictive performance using receiver operating characteristic (ROC) and calibration curves. CYBA and SMPD3 were significantly related to the prognosis of patients with EC and used to construct a risk model. There were significant differences in survival, immune cell infiltration and immune checkpoints between the low-and high-risk groups. The nomogram developed with clinical indicators and the risk scores was effective in predicting the prognosis of patients with EC. In this study, a prognostic model constructed based on two redox-related genes (CYBA and SMPD3) were proved to be independent prognostic factors of EC and associated with tumour immune microenvironment. The redox signature genes have the potential to predict the prognosis and the immunotherapy efficacy of patients with EC.

Potential serum metabolites and long‐chain noncoding RNA biomarkers for endometrial cancer tissue

Endometrial carcinoma (EC) is one of the most common tumors in the female reproductive system. There are nearly 200 000 new cases every year. It is the third most common gynecological malignant tumor leading to female death. The incidence rate is closely related to lifestyle, and the incidence rate varies in different regions. The incidence rate of EC is ranking the first in the female reproductive system cancer just second only to breast, lung, and colorectal cancer in North America and Europe and the incidence rate of EC is only second, followed by breast cancer and cervical cancer in China. The potential metabolic markers of endometrial cancer were screened by liquid chromatograph mass spectrometer (LC-MS), and the tissues of patients with hysteromyoma and endometrial cancer were sequenced to explore the relationship between the disease and change in the content of long-chain noncoding RNA (lncRNA). Serum and tissue samples were collected from patients with endometrial dysplasia, endometrial cancer stage I, and endometrial cancer stage III. The metabolites in all serum samples were extracted, and the metabolites in all samples were detected by LC-MS/MS technology. The Pareto-scaling method was used for normalization, and the MetaboAnalyst 4.0 software was used for different analyses. The T test between groups showed that p ≤ 0.05 was regarded as the metabolite with a difference. Further, the function of differential metabolites was determined by metabolite function enrichment and co-expression analysis. Meanwhile, the differentially expressed lncRNA was detected by Illumina second-generation high-throughput sequencing technology, and the expression was analyzed by DEGseq software. Different lncRNA were screened according to p < 0.05. LncRNA with significant differences were screened by p < 0.01, q < 0.001, fold change ≥2, and false discovery rate (FDR) ≤0.001. Through synthesis of T test, cluster heatmap, and ROC curve analysis, five biomarkers with potential diagnostic ability were obtained, including 2,3-Pyridinedicarboxylic acid (area under the curve (AUC)=0.69), Hematommic acid, ethyl ester (AUC=0.69), Maltitol (AUC=0.69), 13(S)-HODE (AUC=0.88), and D-Mannitol (AUC=0.69) had potential diagnostic ability between EC phase I versus EC phase III. At the same time, lncRNA sequencing results showed that when endometrial atypical hyperplasia continued to change, including LINC00511, PVT1, and IQCH-AS1 (downregulated), and only changed significantly in the endometrial dysplasia group, including MALAT1, CARMN (downregulated) and LINC00648, BISPR, LINC01534, and LINC00930 (upregulated). Moreover, both differential metabolites and differential lncRNA were annotated to the lipid metabolism pathway, suggesting that this pathway played an important role in the occurrence and development of endometrial carcinoma. It can combine the results of metabolomics and lncRNA sequencing to assist in the early diagnosis of endometrial precancerous lesions and endometrial cancer patients, to enhance the sensitivity and specificity of diagnosis, which has a certain clinical application prospect.

The Expression and Clinical Significance of Sphingosine Kinase 1 and Vascular Endothelial Growth Factor in Endometrial Carcinoma.

The aim of the study is to investigate the expression of sphingosine kinase 1 (SPHK1) and vascular endothelial growth factor (VEGF) in patients with endometrial carcinoma and its clinical significance. The tissues of 86 cases of patients with endometrial carcinoma and 54 cases of patients with endometrial atypical hyperplasia were collected. The expression of SPHK1 and VEGF in the tissue was detected by immunohistochemistry. The expression of SPHK1 in patients with endometrial carcinoma was compared with the clinicopathological data. Results. 69 cases (82.1%) of endometrial carcinoma were positive for SPHK1, which was higher than 2 cases (3.7%) of endometrial atypical hyperplasia (P < 0.05). The VEGF expression in 54 patients (62.8%) with endometrial carcinoma was higher than that in 12 patients with endometrial atypical hyperplasia (22.2%) (P < 0.05). There was a positive correlation between SPHK1 and VEGF expressions in endometrial carcinoma (c = 0.595). The expression of SPHK1 in endometrial cancer patients was different in different pathological types, FIGO stages, lymph node metastasis, ER, and PR positive or not, and the difference between the two groups was significant (P < 0.05). There was no difference in age, degree of differentiation, and depth of myometrial infiltration (P < 0.05). The expression of SPHK1 in patients with endometrial carcinoma is increased, which is helpful for early detection of patients with endometrial carcinoma, and may play a synergistic role with VEGF in the pathogenesis and development of endometrial carcinoma.

Depleting TMED3 alleviates the development of endometrial carcinoma

BackgroundAs one of gynecologic tumors, endometrial carcinoma (EC) has been characterized by high incidence rate, but its molecular pathogenesis has remained unclear. TMED3 is a membrane protein and has been indicated to implicate several tumor-related diseases. In the current study, we aimed to explore the physiological function of TMED3 in EC progression.MethodsThrough bioinformatic analysis using The Cancer Genome Atlas database and immunohistochemistry assay on tissue microarray, we examined whether TMED3 was upregulated in EC tissues. After constructing TMED3-knockdown cell models via lentiviral transfection, qPCR and western blot were employed to determine the expression levels of TMED3 mRNA and protein. Then, Celigo cell counting assay, CCK8 assay, flow cytometry, wound-healing assay and Transwell assay were used to detect cell proliferation, cell cycle, cell apoptosis and cell migration, respectively.ResultsAs a result, it was found that TMED3 was upregulated in EC cells, which was also verified in clinical samples. We then found that downregulation of TMED3 considerably restrained cell cycle, cell growth and migration but promoted apoptosis of EC cells. The following in-vivo experiments also verified that tumor growth was inhibited after TMED3 knockdown. The exploration in molecular mechanisms showed that TMED3 deletion may weaken cellular viability through upregulating pro-apoptotic proteins and targeting PI3K/AKT signaling pathways.ConclusionsThis study suggested that knocking down TMED3 affected the malignant phenotype of EC cells and thus limited tumor progression, which provided insights to the development of targeted drugs for EC treatment.

Hsa_circ_0000437 Inhibits the Development of Endometrial Carcinoma through miR-626/CDKN1B Axis.

Circular RNAs (circRNAs) are pivotal in cancer biology. Nevertheless, the biological functions of circular RNA hsa_circ_0000437 (circ_0000437) have not yet been elucidated. In the present study, we studied the expression characteristics of circ_0000437 in endometrial carcinoma (EC) and explored the roles and potential mechanisms of circ_0000437 in EC progression. Quantitative real-time polymerase chain reaction (qRT-PCR) was adopted to detect the expressions of circ_0000437, microRNA-626 (miR-626) and cyclin-dependent kinase inhibitor 1B (CDKN1B) in EC tissues and cells. 5-Ethynyl-2'-deoxyuridine (EdU), cell counting kit-8 (CCK-8) and Transwell assays were performed to evaluate EC cell proliferation and invasion. The expressions of CDKN1B and epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin and N-cadherin) were detected by Western blot. Moreover, the targeted relationship between miR- 626 and circ_0000437 or CDKN1B was determined by a dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Circ_0000437 expression was reduced in EC tissues, and the low expression of circ_0000437 was positively correlated with the lymph node metastasis and high TNM stage of EC patients. Knocking down circ_0000437 promoted the proliferation, invasion and EMT of EC cells. Circ_0000437 directly targeted miR-626 and negatively modulated miR-626 expression in EC cells. CDKN1B was identified as the downstream target of miR-626 in EC cells. Besides, CDKN1B overexpression of miR-626 knockdown reversed the effects of knocking down circ_0000437 on EC cells. Circ_0000437 regulates the miR-626/CDKN1B pathway to suppress the proliferation, invasion and EMT of EC cells. This indicates that circ_0000437 may be a promising biomarker and therapy target for EC.

Long noncoding RNA EIF1AX-AS1 promotes endometrial cancer cell apoptosis by affecting EIF1AX mRNA stabilization.

Long noncoding RNAs (lncRNAs) have been found to play an important role in the occurrence and development of endometrial carcinoma (EC). Here, using RNA sequencing analysis, we systemically screened and identified the lncRNA eukaryotic translation initiation factor 1A, X‐linked (EIF1AX)‐AS1, which is aberrantly downregulated in clinical EC tissues and closely correlated with tumor type. EIF1AX‐AS1 markedly inhibited EC cell proliferation and promoted apoptosis in vitro and in vivo. Mechanistically, EIF1AX‐AS1 interacts with EIF1AX mRNA and poly C binding protein 1 (PCBP1), which promote EIF1AX mRNA degradation. Intriguingly, by interacting with internal ribosome entry site‐related protein Y‐box binding protein 1 (YBX‐1), EIF1AX promotes c‐Myc translation through the internal ribosome entry site pathway. c‐Myc promotes EIF1AX transcription and thus forms a feed‐forward loop to regulate EC cell proliferation. Taken together, these data reveal new insights into the biology driving EC proliferation and highlights the potential of lncRNAs as biomarkers for prognosis and future therapeutic targets for cancer.

Hsa_circ_0039569 facilitates the progression of endometrial carcinoma by targeting the miR-197/high mobility group protein A1 axis

ABSTRACT Circular RNAs are novel regulators in endometrial carcinoma. Hsa_circ_0039569 was reportedly upregulated in endometrial carcinoma; however, the functional roles and mechanisms of hsa_circ_0039569 need further investigation. Therefore, we used quantitative real-time PCR (qRT–PCR) to determine the mRNA levels of hsa_circ_0039569, miR-197 and high mobility group protein A1 (HMGA1). The protein level of HMGA1 was determined by Western blot. Cell Counting Kit-8 and colony formation assays were used to assess cell proliferation. Cell migration was measured via wound healing and Transwell assays. Transwell assay was also performed to determine cell invasion ability. Direct binding of the indicated molecules were verified by RNA binding protein immunoprecipitation (RIP) assay and dual luciferase reporter assay. The results revealed that hsa_circ_0039569 and HMGA1 were elevated, while miR-197 was downregulated in endometrial carcinoma. Moreover, hsa_circ_0039569 was positively correlated with the expression of HMGA1 and was negatively correlated with the level of miR-197. In addition, hsa_circ_0039569 facilitated the proliferation, migration and invasion of endometrial carcinoma cells. The underlying mechanism is that hsa_circ_0039569 serves as a sponge of miR-197 to repress the inhibitory effect of miR-197 on HMGA1. Furthermore, the miR-197/HMGA1 axis was implicated in endometrial carcinoma progression accelerated by hsa_circ_0039569. Collectively, hsa_circ_0039569 may promote the development of endometrial carcinoma by serving as an endogenous sponge of miR-197, increasing HMGA1 expression and identifying a novel target for endometrial carcinoma treatment.

Components of NOTCH Signaling for Uterine Cancer Patients' Prognosis.

New molecular biomarkers that could have an independent prognostic value in endometrial cancer are currently under investigation. Recently, it was suggested that genetic changes in the Notch signaling pathway could be associated with the development of endometrial carcinoma. This study aimed to determine the expression of the Notch signaling pathway components in tumour and adjacent normal uterine tissue and to evaluate their importance for the survival of uterine cancer patients. The present study was performed on uterine body samples collected from 109 patients and paired adjacent noncancerous endometrial tissue samples. Kaplan–Meier curves and Cox regression were used for survival analyses. Expression alterations of NOTCH2, NOTCH3, NOTCH4, JAG2, and HES1 were evaluated as independent and significant prognostic factors for uterine cancer patients.

Construction and Comprehensive Analysis of a Special Competitive Endogenous RNAs Network to Reveal Potential Prognostic Biomarkers for Endometrial Carcinoma

Background: Endometrial carcinoma (EC) is one of the most common malignancies in women worldwide. For EC patients discovered at an early stage, the prognosis is good. However, the advanced EC patients (stage III-IV) have very poor prognoses. The competitive endogenous RNAs (ceRNA) regulatory network in EC remains unclear, and the relationship between hub RNAs and important clinical characters (clinical stage) has not been strictly studied yet. Objective: In order to study the development of endometrial carcinoma and the identification of early diagnostic markers, the relationship between hub RNAs and important clinical traits (clinical stage) was strictly studied. Methods: The co-expression networks of mRNA, lncRNA, and miRNA were constructed by weighted gene co-expression network analysis. Gene ontology (GO) biological process terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were carried out for DEmRNA. AceRNA regulated network was constructed based on miRcode, miRDB, TargetScan, and miRTarBase. Furthermore, survival analysis, regression analysis of mRNA-lncRNA pairs, and gene set enrichment analysis were carried out. Results: A ceRNA network containing 11 mRNAs, 4 miRNAs, and 18 lncRNAs was constructed based on aberrantly expressed RNAs in the co-expression modules. In this network, 7 mRNAs, 4 lncRNAs, and 1 miRNA were found closely related to the overall survival of EC. The positive correlations of 35 pairs of mRNA and lncRNA in the ceRNA network were obtained. Notably, 5 mRNAs, 3 lncRNAs, and 1 miRNA were identified as potential prognostic biomarkers for EC. Single gene GSEA analysis revealed that the signal pathways related to cell cycle and cancer were highly enriched. Conclusion: Identification of five mRNAs (CBX6, PIM1, RIMS3, SOX11, and XKR7), three lncRNA (WT1-AS, LINC00494, and LINC00501), and one miRNA (miR-195) as potential prognostic biomarkers for EC was helpful for the early diagnosis, prognosis, and development of new treatment strategies of EC patients.

Histone Deacetylase Inhibitors: A Promising Therapeutic Alternative for Endometrial Carcinoma.

Endometrial carcinoma is the most common malignant tumor of the female genital tract in the United States. Epigenetic alterations are implicated in endometrial cancer development and progression. Histone deacetylase inhibitors are a novel class of anticancer drugs that increase the level of histone acetylation in many cell types, thereby inducing cell cycle arrest, differentiation, and apoptotic cell death. This review is aimed at determining the role of histone acetylation and examining the therapeutic potential of histone deacetylase inhibitors in endometrial cancer. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The search terms histone deacetylase, histone deacetylase inhibitor, and endometrial cancer were employed, and we were able to identify fifty-two studies focused on endometrial carcinoma and published between 2001 and 2021. Deregulation of histone acetylation is involved in the tumorigenesis of both endometrial carcinoma histological types and accounts for high-grade, aggressive carcinomas with worse prognosis and decreased overall survival. Histone deacetylase inhibitors inhibit tumor growth, enhance the transcription of silenced physiologic genes, and induce cell cycle arrest and apoptosis in endometrial carcinoma cells both in vitro and in vivo. The combination of histone deacetylase inhibitors with traditional chemotherapeutic agents shows synergistic cytotoxic effects in endometrial carcinoma cells. Histone acetylation plays an important role in endometrial carcinoma development and progression. Histone deacetylase inhibitors show potent antitumor effects in various endometrial cancer cell lines as well as tumor xenograft models. Additional clinical trials are however needed to verify the clinical utility and safety of these promising therapeutic agents in the treatment of patients with endometrial cancer.

Management of Atypical Endometrial Hyperplasia with a Focus on Conservative Treatment

Study Objective To compare local management of women diagnosed with atypical endometrial hyperplasia (AH) against RCOG Greentop Guideline No. 67 “Management of endometrial hyperplasia,” with specific emphasis on conservative treatment. Design An existing database of patients with endometrial pathology from 2012 to 2019 was used to identify 118 cases of AH. Patient demographics, management, and follow up were interrogated. Setting NHS Lanarkshire, Scotland (population 655,000). Patients or Participants Patient age ranged from 26-83 years with 50% over the age of fifty. 75% of patients were postmenopausal and 90% were overweight (BMI >25). Interventions Seventy-eight women (66%) had immediate hysterectomy. Thirty-five women (30%) underwent conservative management and five (4%) were lost to follow up. Conservative treatment comprised of levonorgestrel-releasing intrauterine system (LNG-IUS) (67%), oral progestogens (18%), GnRH analogues (9%), weight loss alone or no management (6%). Measurements and Main Results Follow up biopsy results in the conservative treatment group showed regression in fourteen patients (67%), persistence in five (23%) and progression to endometrial cancer in two (10%). Low rates of progression (12% overall) and persistence were observed overtime alongside continued regression rates. Eight women (23%) managed conservatively subsequently progressed to hysterectomy. Four of which required surgery due to the development of endometrial carcinoma. Conclusion Local management is consistent with current RCOG guidelines with more than half of women proceeding immediately to hysterectomy. The majority of patients managed conservatively had the LNG-IUS, consistent with guidelines. Follow up was appropriate in terms of monitoring and tissue sampling with four cases of endometrial cancer detected. This emphasises the importance of regular monitoring. Over 90% had an elevated BMI, a known risk factor for developing AH. Literature supports weight loss in improving regression rates in this demographic. In some cases, an initial conservative approach may allow peri-operative optimisation and risk factor modification which has a role in improving surgical outcomes. To compare local management of women diagnosed with atypical endometrial hyperplasia (AH) against RCOG Greentop Guideline No. 67 “Management of endometrial hyperplasia,” with specific emphasis on conservative treatment. An existing database of patients with endometrial pathology from 2012 to 2019 was used to identify 118 cases of AH. Patient demographics, management, and follow up were interrogated. NHS Lanarkshire, Scotland (population 655,000). Patient age ranged from 26-83 years with 50% over the age of fifty. 75% of patients were postmenopausal and 90% were overweight (BMI >25). Seventy-eight women (66%) had immediate hysterectomy. Thirty-five women (30%) underwent conservative management and five (4%) were lost to follow up. Conservative treatment comprised of levonorgestrel-releasing intrauterine system (LNG-IUS) (67%), oral progestogens (18%), GnRH analogues (9%), weight loss alone or no management (6%). Follow up biopsy results in the conservative treatment group showed regression in fourteen patients (67%), persistence in five (23%) and progression to endometrial cancer in two (10%). Low rates of progression (12% overall) and persistence were observed overtime alongside continued regression rates. Eight women (23%) managed conservatively subsequently progressed to hysterectomy. Four of which required surgery due to the development of endometrial carcinoma. Local management is consistent with current RCOG guidelines with more than half of women proceeding immediately to hysterectomy. The majority of patients managed conservatively had the LNG-IUS, consistent with guidelines. Follow up was appropriate in terms of monitoring and tissue sampling with four cases of endometrial cancer detected. This emphasises the importance of regular monitoring.

CD3D has the Potential to be a Prognostic Factor for Endometrial Carcinoma and an Indicator of Tumor Immune Microenvironment Regulation: a Study based on TCGA Data Mining

Accumulating evidence shows that tumor immune microenvironment infiltration plays a crucial role in the occurrence and development of endometrial carcinoma (EC). At present, studying the regulation mechanism of the immune microenvironment in EC remains a challenge. We calculated the amount of immune and stromal components and the proportion of tumor-infiltrating immune lymphocytes via ESTIMATE, single-sample gene enrichment analysis (ssGSEA), and CIBERSORT computational methods. Differentially expressed genes were analyzed by protein–protein interaction network construction and univariate survival analysis. CD3D expression was negatively correlated with clinicopathological features, such as age, histological type, clinical grade, and pathological stage, but positively correlated with the survival of patients with EC. Logistic regression analysis suggested that CD3D expression could be used as a biomarker to predict EC occurrence. Gene set enrichment analysis revealed that CD3D was upregulated in the immune effect pathway. Interestingly, CD3D was downregulated in the EC pathway. EC was divided into three immune cell subsets by ssGSEA. Correlation analysis between ssGSEA and CIBERSORT showed that the infiltration level of CD8 + T cells and plasma cells in tumor-infiltrating lymphocytes was lower than that in the high-immune-score group (Immunity_H). Moreover, CD3D expression in Immunity_H was low, and the prognosis was even worse. This study demonstrated that low CD3D expression is an index of poor prognosis in patients with EC. Levels of CD3D in tumor microenvironment (TME) might be a useful indicator for predicting the prognosis of patients with EC patients.