Occurrence Of Endometrial Cancer Research Articles

Integrative Analysis of Multi-Omic Data for the Characteristics of Endometrial Cancer.

Endometrial cancer (EC) is a frequently diagnosed gynecologic cancer. Identifying reliable prognostic genes for predicting EC onset is crucial for reducing patient morbidity and mortality. Here, a comprehensive strategy with transcriptomic and proteomic data was performed to measure EC's characteristics. Based on the publicly available RNA-seq data, death-associated protein kinase 3, recombination signal-binding protein for the immunoglobulin kappa J region, and myosin light chain 9 were screened out as potential biomarkers that affect the EC patients' prognosis. A linear model was further constructed by multivariate Cox regression for the prediction of the risk of being malignant. From further integrative analysis, exosomes were found to have a highly enriched role that might participate in EC occurrence. The findings were validated by qRT-polymerase chain reaction (PCR) and western blotting. Collectively, we constructed a prognostic-gene-based model for EC prediction and found that exosomes participate in EC incidents, revealing significantly promising support for the diagnosis of EC.

Study of Serum Copper and Zinc Levels and Serum Cu/Zn Ratio among Polish Women with Endometrial Cancer.

Micronutrients are important components for the homeostasis of the human body. The studies available in the literature of the subject on their impact on the risk of population diseases, including malignant neoplasms, are ambiguous. In this paper, the relationship between Cu and Zn serum levels and the occurrence of endometrial cancer have been analyzed. 306 patients (153 test group and 153 control group) matched for age were analyzed for Cu and Zn levels. Microelements levels were determined for sera collected during the hospitalization of patients by means of an inductively coupled plasma mass spectrometry. In addition, the Cu/Zn ratio in the population included in the study was analyzed. Univariable and multivariable analyzes were used to examine the relationship between the factors under study and the incidence of endometrial cancer. Lower levels of elements were observed in the study group compared with the control group (Cu: 959.39 μg/L vs. 1176.42 μg/L, p < 0.001; Zn: 707.05 μg/L vs. 901.67 μg/L, p < 0.001). A statistically significant relationship with the occurrence of endometrial cancer was observed for Cu and Zn. The patients with the lowest Cu level had a significantly higher occurrence of endometrial cancer compared with reference tertile (OR 8.54; p < 0.001). Similarly, compared with the reference tertile, the patients with the lowest Zn levels had a significantly greater incidence of endometrial cancer (OR 15.0; p < 0.001). The results of the study suggest an association of endometrial cancer occurrence with lower Cu and Zn serum levels.

Endometrial cancer (EC) derived G3BP1 overexpression and mutant promote EC tumorigenesis and metastasis via SPOP/ERα axis

BackgroundRas-GTPase-activating protein binding protein 1 (G3BP1) is an oncogenic factor, which highly expressed in a variety of cancers. In recent years, G3BP1 has been reported to promote the development of prostate cancer by inhibiting the degradation of AR through inhibiting SPOP. However, whether G3BP1 contributes in a similar manner to the abnormal accumulation of ERα, which is also an important target for hormone therapy, remains unknown. This article addresses this issue and explores potential mechanisms.MethodsBioinformatics tools were used for G3BP1 expression analysis, survival analysis, and clinical association analysis. Immunohistochemical staining was used to examine the correlation between G3BP1 and ERα in EC patients. In addition, western blot and co-immunoprecipitation were used to detect the half-life of G3BP1 and mutant, and the effect of G3BP1 and mutant on the ubiquitination and degradation of ERα mediated by SPOP. Then, the oncogenic functions of G3BP1 dependent on the SPOP/ERα axis were determined by CCK8 cell proliferation assay, colony formation assay and cell migration assay. Finally, we established the EC cells treated or untreated with fulvestrant, exploring the possibility of fulvestrant combined with the reduction of G3BP1 to improve the efficacy of fulvestrant.ResultsG3BP1 is abnormally high expressed and characterized by high-frequency mutation in EC. In addition, there is a positive correlation between G3BP1 protein and ERα protein. Mechanistically, both G3BP1 and mutant, the latter is displaying the longer half-life, competitively bind SPOP with ERα, thereby inhibiting SPOP-mediated ubiquitination and degradation of ERα. Functionally, G3BP1 and mutant promote the proliferation and migration of EC cells by regulating the G3BP1/SPOP/ERα axis. However, fulvestrant can reverse the cancer-promoting effects of G3BP1 and mutant.ConclusionsG3BP1 and its mutant positively regulate ERα signaling pathway by inhibiting SPOP-mediated ubiquitination and degradation of ERα, indicating the promising effect of fulvestrant on the suppression the occurrence and development of EC with high expressed G3BP1 and G3BP1 mutants.7zf14ZtBi1KWa6qjVt88ZxVideo

Bioinformatic analysis of differentially expressed profiles of lncRNAs and miRNAs with their related ceRNA network in endometrial cancer.

Increasing evidence suggests that long non-coding riboneucleic acids (lncRNAs), as competing endogenous RNA (ceRNA), play a key role in the initiation, invasion, and metastasis of cancer. As a new hypothesis, the lncRNA-micro RNA (miRNA)-messenger RNA (mRNA), ceRNA regulatory network has been successfully constructed in a variety of cancers. However, lncRNA, which plays a ceRNA function in endometrial cancer (EC), is still poorly understood. In this study, we downloaded EC expression profiling from The Cancer Genome Atlas database and used the R software "edgeR" package to analyze the differentially expressed genes between EC and normal endometrium samples. Then, differentially expressed (DE) lncRNAs, miRNAs and mRNAs were selected to construct a lncRNA-miRNA-mRNA prognosis-related regulatory network based on interaction information. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed on the genes in the network to predict the potential underlying mechanisms and functions of lncRNAs in EC. Kaplan-Meier method and the log-rank test were used for survival analysis. Based on the "ceRNA hypothesis," we constructed a co-expression network of mRNA and lncRNA genes mediated by miRNA in the process of tumor genesis. Furthermore, we successfully constructed a dysregulated lncRNA-associated ceRNA network containing 96 DElncRNAs, 27 DEmiRNAs, and 74 DEmRNAs. Through Kaplan-Meier curve analysis, we found that 9 lncRNAs, 3 miRNAs, and 12 mRNAs were significantly correlated with the overall survival rate of patients among all lncRNAs, miRNAs, and mRNAs involved in ceRNA (P < .05). Our research provides a new perspective for the interaction among lncRNAs, miRNAs, and mRNA and lays the foundation for further research on the mechanism of lncRNAs in the occurrence of EC.

Obesity alters the mouse endometrial transcriptome in a cell context-dependent manner

Obesity impacts fertility and is positively correlated with endometrial hyperplasia and endometrial cancer occurrence. Endometrial epithelia often harbor disease driver-mutations, while endometrial stroma are highly regulative of neighboring epithelia. Here, we sought to determine distinct transcriptome changes occurring in individual cell types in the obese mouse uterus. Outbred CD-1 mice were fed high-fat or control diets for 18 weeks, estrous cycle staged, and endometrial epithelia, macrophages, and stroma isolated for transcriptomic analysis. High-fat diet mice displayed increased body mass and developed glucose intolerance, hyperinsulinemia, and fatty liver. Obese mouse epithelia displayed differential gene expression for genes related to innate immunity and leukocyte chemotaxis. The obese mouse stroma differentially expressed factors related to circadian rhythm, and expression of these genes correlated with glucose tolerance or body mass. We observed correlations between F4/80 + macrophage numbers, Cleaved Caspase 3 (CC3) apoptosis marker staining and glucose intolerance among obese mice, including a subgroup of obese mice with high CC3 + luminal epithelia. This subgroup displayed differential gene expression among all cell types, with pathways related to immune escape in epithelia and macrophages, while the stroma dysregulated pathways related to regulation of epithelia. These results suggest an important role for differential response of both the epithelia and stroma in their response to obesity, while macrophages are dysregulated in the context of apoptotic epithelia. The obesity-related gene expression programs in cells within the uterine microenvironment may influence the ability of the endometrium to function during pregnancy and influence disease pathogenesis.

Follicle-Stimulating Hormone Promotes the Development of Endometrial Cancer In Vitro and In Vivo.

Endocrine disruptors as risk factors for endometrial cancer (EC) are positively correlated with serum follicle-stimulating hormone (FSH) levels. Additionally, increased FSH is associated with EC. However, its exact mechanism is not yet clear. Therefore, this study investigated how FSH affects the occurrence of EC. Using immunohistochemistry (IHC), immunofluorescence (IF), and Western blot (WB), we found that FSH receptor (FSHR) was expressed in both EC tissues and cell lines. To explore the effect of FSH on EC in vitro, Ishikawa (ISK) cells were cultured in different doses of FSH, and it was found that FSH could promote the proliferation and migration of ISK cells. Furthermore, the detection of key molecules of migration and apoptosis by WB showed that FSH promoted cell migration and inhibited apoptosis. Additionally, FSH decreased AMPK activation. To clarify the effect of FSH on EC in vivo, we subcutaneously planted ISK cells into ovariectomized mice and then gave two of the groups oestradiol (E2). In comparison with the OE (ovariectomy plus E2) and sham groups, the growth rates and weights of the tumors in the OE plus FSH group were significantly higher. The findings above suggest that FSH promotes the proliferation and metastasis of EC, providing a new strategy for the treatment of EC.

M6A mRNA methylation regulates the ERK/NF-κB/AKT signaling pathway through the PAPPA/IGFBP4 axis to promote proliferation and tumor formation in endometrial cancer.

N6-methyladenosine (m6A) mRNA methylation has been considered a gene modulatory mechanism involved in disease progression and carcinogenesis. Herein, we aimed to explore the specific mechanism of m6A mRNA methylation in endometrial cancer. RT-qPCR was implemented to test the clinical correlation between m6A methylation and endometrial cancer. Bioinformatics analysis was performed to screen the genes related to endometrial cancer, and SRAMP was utilized for the prediction of m6A targets. Western blot assay and MeRIP-qPCR experiments were conducted to verify the effect of m6A methylation on the candidate genes and the signaling pathways involved in the occurrence of endometrial cancer. m6A-seq, RT-qPCR, and polysome profiling were used to confirm the mechanisms of m6A methylation in modulating related genes and pathways. The levels of m6A methylation, METTL3, and IGFBP4 were reduced in tumor tissues of patients with endometrial cancer, and SRAMP analysis confirmed that IGFBP4 and PAPPA had m6A methylation sites. Reduced m6A methylation promoted endometrial cancer cell progression and tumor formation in vivo. m6A methylation of RNA in endometrial cancer cells directly modulated IGFBP4 and PAPPA expression. m6A methylation regulated the PAPPA/IGFBP4 axis, thereby influencing endometrial cancer through the NF-κB and ERK signaling pathways. Knockdown of PAPPA or overexpression of IGFBP4 in endometrial cancer cells partially reduced disease progression caused by reduced m6A methylation. This research suggests that m6A mRNA methylation modulates the ERK/NF-κB/AKT signaling pathway through the PAPPA/IGFBP4 axis to induce cell proliferation and tumor formation in endometrial cancer. 1. METTL3 expressed modestly and m6A methylation of IGFBP4 and PAPPA mRNAs decreased in endometrial cancer; 2. YTHDF1-mediated IGFBP4 translation was reduced in HEC-1-A and AN3CA cells, and YTHDF2-mediated PAPPA mRNA degradation was blunted but its protein expression increased; 3. Increased PAPPA and reduced IGFBP4 activated IGF1-induced ERK, AKT, and NF-κB pathways by binding IGFR, thereby promoting cancer cell malignancy.

Box C/D snoRNA SNORD89 influences the occurrence and development of endometrial cancer through 2’-O-methylation modification of Bim

The small nucleolar RNA (snoRNA) is a type of small non-coding RNA widely distributed in the nucleoli of eukaryotic cells, promoting cancer development. The aim of this study was to assess box C/D snoRNA 89 (SNORD89) dysregulations in endometrial cancer. According to the TCGA database as well as the International Federation of Gynecology and Obstetrics (FIGO), higher SNORD89 expression is found in endometrial cancer tissues. In addition, the SNORD89 expression level was higher in endometrial carcinoma with lymph node metastasis than in endometrial carcinoma without lymph node metastasis. By interacting with the conservative chaperone protein methylase fibrillarin (Fbl), SNORD89 inhibits the translation process of the Bim gene, leading to a decrease in Bim protein. Cancer-promoting effect of SNORD89 can be reversed by Fbl knockdown or Bim overexpressing. What’s more, ASO-mediated silencing of SNORD89 could inhibit endometrial cancer cell proliferation and migration ability. Taken together, SNORD89 can modify Bim through 2′-O-methylation and affect downstream signaling pathways to promote endometrial cancer occurrence and development. The role of methylation modification in the prevention and treatment of endometrial cancer provides a new understanding and SNORD89 may be a new diagnostic and therapeutic target for endometrial cancer.

β-Klotho inhibits CSF-1 secretion and delays the development of endometrial cancer

ABSTRACT Senescent cells can drive tumors development by promoting chronic inflammation. There is a significant correlation between β-Klotho expression profiles and endometrial cancer (EC). However, how β-Klotho regulates the occurrence and development of uterine EC remains to be further studied. Our research found that compared with normal endometrial tissues, β-Klotho expression levels in EC tissues were significantly reduced; overexpression of β-Klotho significantly inhibited aging, proliferation and migration but promoted apoptosis of EC cells cultured in vitro. In normal endometrial cells, results confirmed that reduced levels of β-Klotho promoted CSF-1 secretion, and the migration ability of macrophages was significantly enhanced when co-cultured with normal endometrial cells. In contrast, the expression of CSF-1 was significantly reduced after overexpression of β-Klotho in EC cells, and the macrophage migration ability is significantly weakened when co-cultured with EC cells. Therefore, we believe that β-Klotho influences macrophage migration by regulating the expression of CSF-1, thereby interfering with the progression of EC. We investigated in depth the mechanism of β-Klotho regulating CSF-1 secretion and found that β-Klotho inhibits the phosphorylation of p65, which blocked the nuclear translocation of p65, thereby inhibiting the secretion of CSF-1 by EC cells. The above results indicate that β-Klotho-mediated inhibition of CSF-1 secretion reduces the migration of macrophages to tumor tissue and delays the progression of EC.

MLLT11-TRIL complex promotes the progression of endometrial cancer through PI3K/AKT/mTOR signaling pathway

ABSTRACT Endometrial cancer (EC) is a gynecological malignant tumor characterized by high incidence. EC occurrence and development are regulated by numerous molecules and signal pathways. There is a need to explore key regulatory molecules to identify potential therapeutic targets to reduce the incidence of EC. Treatment by targeting a single molecule is characterized by poor efficacy owing to the development of resistance and significant side effects. The current study explored potential candidates in EC by integrating bioinformatics analysis and in vivo and in vitro experimental validation to circumvent the limitation of low efficacy of currently used molecules. Molecular dynamics simulations provide details at the molecular level of intermolecular regulation. In the current study, MLLT11 and TRIL were identified as important regulatory molecules in EC. The two molecules formed a heteromultimer by binding to AKT protein, which induced its phosphorylation of threonine at position 308. Ultimately, the complex stimulates PI3K/AKT/mTOR signaling pathway, a pivotal pathway in tumors. The findings of the current study show a novel complex, MLLT11-TRIL, which can act as AKT protein agonist, thus inducing activity of PI3K/AKT/mTOR signaling pathway. Targeting MLLT11 and TRIL simultaneously, or blocking the formation of the MLLT11-TRIL complex, can abrogate progression of EC.

Targeting Cancer Metabolism Plasticity with JX06 Nanoparticles via Inhibiting PDK1 Combined with Metformin for Endometrial Cancer Patients with Diabetes.

Diabetes is closely related to the occurrence of endometrial cancer (EC) and its poor prognosis. However, there is no effective clinical treatment for EC patients with diabetes (patientEC+/dia+). To explore new therapeutic targets, Ishikawa is cultured with high glucose (IshikawaHG) mimicking hyperglycemia in patientEC+/dia+. Subsequently, it is discovered that IshikawaHG exhibits glucose metabolic reprogramming characterized by increased glycolysis and decreased oxidative phosphorylation. Further, pyruvate dehydrogenase kinase 1 (PDK1) is identified to promote glycolysis of IshikawaHG by proteomics. Most importantly, JX06, a novel PDK1 inhibitor combined metformin (Met) significantly inhibits IshikawaHG proliferation though IshikawaHG is resistant to Met. Furthermore, a reduction‐sensitive biodegradable polymer is adopted to encapsulate JX06 to form nanoparticles (JX06‐NPs) for drug delivery. It is found that in vitro JX06‐NPs have better inhibitory effect on the growth of IshikawaHG as well as patient‐derived EC cells (PDC) than JX06. Additionally, it is found that JX06‐NPs can accumulate to the tumor of EC‐bearing mouse with diabetes (miceEC+/dia+) after intravenous injection, and JX06‐NPs combined Met can significantly inhibit tumor growth of miceEC+/dia+. Taken together, the study demonstrates that the combination of JX06‐NPs and Met can target the cancer metabolism plasticity, which significantly inhibits the growth of EC, thereby provides a new adjuvant therapy for patientsEC+/dia+.

CDKN2B-AS1 Promotes Malignancy as a Novel Prognosis-Related Molecular Marker in the Endometrial Cancer Immune Microenvironment.

The prognosis of patients with endometrial cancer (EC) is closely associated with immune cell infiltration. Although abnormal long non-coding RNA (lncRNA) expression is also linked to poor prognosis in patients with EC, the function and action mechanism of immune infiltration-related lncRNAs underlying the occurrence and development of EC remains unclear. In this study, we analyzed lncRNA expression using The Cancer Genome Atlas and clinical data and identified six lncRNAs as prognostic markers for EC, all of which are associated with the infiltration of immune cell subtypes, as illustrated by ImmLnc database and ssGSEA analysis. Real-time quantitative polymerase chain reaction showed that CDKN2B-AS1 was significantly overexpressed in EC, whereas its knockdown inhibited the proliferation and invasion of EC cells and the in vivo growth of transplanted tumors in nude mice. Finally, we constructed a competing endogenous RNA regulatory network and conducted Gene Ontology enrichment analysis to elucidate the potential molecular mechanism underlying CDKN2B-AS1 function. Overall, we identified molecular targets associated with immune infiltration and prognosis and provide new insights into the development of molecular therapies and treatment strategies against EC.

Interaction Between Functionally Activate Endometrial Microbiota and Host Gene Regulation in Endometrial Cancer.

Objective: In this study, we mainly explored two questions: Which microorganisms were functionally active in the endometrium of patients with endometrial cancer (EC)? What kind of response did the human host respond to functionally active microorganisms?Methods: Nine endometrial cancer patients and eight normal subjects were included in this study. HMP Unified Metabolic Analysis Network 3 (HUMAnN3) was used to obtain functional information of microorganisms. In addition, metaCyc-based GSEA functional enrichment analysis was used to obtain information on the metabolic pathways of the human host. At the same time, the O2PLS model and Spearman correlation analysis were used to analyze the microorganisms–host interaction.Results: With the novel metatranscriptome analysis pipeline, we described the composition of more than 5,000 functionally active microorganisms and analyzed the difference in microorganisms between the EC and the normal group. Our research found that these microorganisms were involved in part of the metabolic process of endometrial cancer, such as 6-sulfo-sialyl Lewis x epitope, N-acetyl-beta-glucosaminyl. In addition, the host–microbiota crosstalk of EC endometrium also included many biological processes, mainly functions related to tumor migration and the Apelin signaling pathway.Conclusion: The functionally active microorganisms in the EC endometrium played an essential role in the occurrence and migration of tumors. This meant that functionally active microorganisms could not be ignored in the treatment of endometrial cancer. This study helped to better understand the possible role of endometrial functional, active microorganisms in the occurrence and development of EC in patients with endometrial cancer and provided new information for new attempts to treat EC.

Risk factors of endometrial cancer in patients with endometrial hyperplasia: implication for clinical treatments

BackgroundEndometrial hyperplasia (EH) is commonly-seen in the patients with endometrial cancer (EC), we aimed to evaluated the risk factors of EC in patients with EH, to provide evidence to the clinical prevention and treatment of EC.MethodsThis study was a retrospective study design. EH patients confirmed by pathological examinations and treated with hysterectomy in our hospital from June 1, 2018 to February 28, 2021 were included. The clinical characteristics of EC and no-EC patients were compared and analyzed. Logistics regression analyses were conducted to evaluate the risk factors of EC in patients with EH.ResultsA total of 228 EH patients were included, the incidence of EC in the EH patients was 31.58%. There were significant differences in the age, BMI, diabetes, hypertension and pathology of EH between EC and no EC groups (all P < 0.05), no significant differences in the hyperlipidemia, preoperative CA125, number of deliveries, menopause and endometrial thickness between EC and no EC groups were found (all P > 0.05). Logistic regression analyses indicated that age > 50 y (OR 3.064, 95% CI 1.945–5.931), BMI ≥ 25 kg/m2 (OR 2.705, 95% CI 1.121–3.889), diabetes (OR 3.049, 95% CI 1.781–5.114), hypertension (OR 2.725, 95% CI 1.108–3.431) and severe hyperplasia (OR 3.181, 95% CI 1.496–4.228) were the risk factors of EC in patients with EH (all P < 0.05).ConclusionsThe risk of EC in EH patients is high, especially for those patients with age > 50 y, BMI ≥ 25 kg/m2, diabetes, hypertension and severe hyperplasia, special attentions should be paid for occurrence of EC and early diagnosis and early treatment are needed for those patients.

Dual inhibition of RNAi therapeutic miR-26a-5p targeting cMet and immunotherapy against EGFR in endometrial cancer treatment

BackgroundPrecise prediction of drug combination targeting tumor cells effectively is a crucial challenge for tumor therapy, especially for endometrial cancer (EC). Considering the resistance, crosstalk that occurs between the receptor tyrosine kinase mesenchymal-epithelial transition factor (cMet) and epidermal growth factor receptor (EGFR), and their indispensable influence on the occurrence of EC, this study aimed to explore a novel therapeutic approach for EC treatment through blocking cMet and EGFR simultaneously.MethodsIn the present study, the expression of miR-26a-5p in EC cell lines was detected using quantitative real-time polymerase chain reaction assay. The potential role of miR-26a-5p in the development of EC was examined using cell counting kit assay, 5-ethynyl-2’- deoxyuridine staining, wound healing assay, and cell apoptosis staining assay. Subsequently, the effect of upregulated miR-26a-5p in vivo was confirmed on a xenograft model. Luciferase reporter assay and Western blot analysis were performed to verify the relation between miR-26a-5p and cMet. Furthermore, the dual therapeutic effect of miR-26a-5p and EGFR monoclonal antibody cetuximab was confirmed in vivo and in vitro.ResultsThe results indicated that miR-26a-5p expression significantly reduced in EC cell lines compared with the normal endometrial cell line. Furthermore, the overexpression of miR-26a-5p inhibited the progression of EC, including cell migration, cell proliferation, and cell apoptosis in vivo and in vitro. Subsequently, mir-26a-5p regulated the expression of cMet and the downstream the hepatocyte growth factor (HGF)/cMet pathway, thus exerting an inhibitory effect on EC cells. In addition, the study also demonstrated that the upregulation of miR-26a-5p could significantly enhance the inhibitory effect of cetuximab compared with the use of cetuximab alone in vivo and in vitro.ConclusionsRNAi therapeutic miR-26a-5p suppressed the progression of EC through regulating the cMet/HGF pathway. The dual therapy using RNA interference and neutralizing antibody simultaneously blocked tumor targets, including cMet and EGFR, thus providing a novel approach for overcoming the resistance to the inhibitors against a single target in EC treatment.

A metabolomic signature of FIGO stage I and II endometrial cancer.

Endometrial cancer (EC) is a malignant tumor of the female reproductive tract. Due to its rapid growth and invasiveness, EC is currently the only gynecological neoplasm with rising incidence and mortality rates. It is of great significance to explore the metabolomics signature of stage I and II EC for the diagnosis and treatment. A mass spectrometry-based untargeted metabolomics approach was used to explore preoperative serum metabolites in the normal and stage I and II EC patients. The metabolites were mapped to the Ingenuity pathway analysis (IPA) database to determine the potential biomarkers and metabolic pathways that differ between EC patients and healthy controls. The top analysis-ready molecules of upregulated D-glucose thiamine and downregulated cholesterol, arachidonic acid, palmitic acid, oleic acid, stearic acid, linoleic acid may be the most related metabolites. These potential biomarkers have essential functions in regulating vital metabolic pathways associated with stage I and II EC. Additionally, our pathway analysis revealed five significantly related pathways according to the metabolite differentials. Finally, the disease and function prediction of the initial pathway analysis suggested that small molecule biochemistry, lipid metabolism, and organismal injury and abnormalities were associated with EC cases. Over 25 metabolites were differentially expressed in stage I and II EC. In addition, the six most significant metabolites were related to stage I and stage II EC cases. Ingenuity pathway analysis revealed potential biomarkers and metabolic pathways revolved to EC. In this paper, candidate endogenous biomarkers were defined as the basis for disease diagnosis and individualized treatment monitoring and revealed the mechanism of EC occurrence and development.

Betaglycan Gene (TGFBR3) Polymorphism Is Associated with Increased Risk of Endometrial Cancer.

We investigated single nucleotide polymorphism (SNP) of the betaglycan gene (TGFBR3) encoding the TGFβ co-receptor in endometrial cancer (EC) and its association with betaglycan expression. The study group included 153 women diagnosed with EC and 248 cancer-free controls. SNP genotyping and gene expression were analyzed using TaqMan probes. Three out of the eight SNPs tested, i.e., rs12566180 (CT; OR = 2.22; 95% CI = 1.15–4.30; p = 0.0177), rs6680463 (GC; OR = 2.34; 95% CI = 1.20–4.53; p = 0.0120) and rs2296621 (TT; OR = 6.40; 95% CI = 1.18–34.84; p = 0.0317) were found to be significantly associated with increased risk of EC (adjusted to age, body mass index, menarche and parity). Among the analyzed SNPs, only rs2296621 demonstrated the impact on the increased cancer aggressiveness evaluated by the WHO grading system (G3 vs. G1/2, GT—OR = 4.04; 95% CI = 1.56–10.51; p = 0.0026; T—OR = 2.38; 95% CI = 1.16–4.85; p = 0.0151). Linkage disequilibrium (LD) analysis revealed high LD (r2 ≥ 0.8) in two haploblocks, constructed by rs2770186/rs12141128 and rs12566180/rs6680463, respectively. In the case of C/C haplotype (OR = 4.82; 95% CI = 1.54–15.07; p = 0.0116—Bonferroni corrected) and T/G haplotype (OR = 3.25; 95% CI = 1.29–8.15; p = 0.0328—Bonferroni corrected) in haploblock rs12566180/rs6680463, significantly higher frequency was observed in patients with EC as compared to the control group. The genotype-phenotype studies showed that SNPs of the TGFBR3 gene associated with an increased risk of EC, i.e., rs12566180 and rs2296621 may affect betaglycan expression at the transcriptomic level (rs12566180—CC vs. TT, p < 0.01; rs2296621—GG vs. TT, p < 0.001, GT vs. TT, p < 0.05). Functional consequences of evaluated TGFBR3 gene SNPs were supported by RegulomeDB search. In conclusion, polymorphism of the TGFBR3 gene may be associated with an increased EC occurrence, as well as may be the molecular mechanism responsible for observed betaglycan down-regulation in EC patients.

Exposure to endocrine disruptor alkylphenols and the occurrence of endometrial cancer

Exposure to environmental chemicals with oestrogenic effects has been associated with the development of endometrial cancer (EMCa). EMCa has become the most commonly diagnosed cancer of the female genital tract. To further understand the potential association between exposure to environmental endocrine disruptors and the occurrence of EMCa, we performed a case-control study between 2011 and 2014. We aimed to detect and compare concentrations of a known hormone disruptor, alkylphenol, between women diagnosed with either EMCa or uterine leiomyoma, and those who did not have either of these. Subjects were women diagnosed with either EMCa or uterine leiomyoma (LM) and healthy controls. A structured questionnaire was administered to collect information on lifestyle and health status. Gas chromatography/mass spectrometry was used to measure urinary NP and OP concentrations in participants. Multiple regression analysis was used to examine the association between exposure and outcomes. Overall, 397 women were recruited, including 49 with EMCa, 247 with LM, and 101 controls. Among them, 73.6% showed detectable levels of NP and 61.0% showed detectable levels of OP. The EMCa group had a significantly higher NP concentration than the control group. Higher OP concentrations were also found in participants with EMCa than those with LM and controls. In addition, women in the upper tertile of the NP group had a significantly increased risk of EMCa occurrence (odds ratio [95% confidence interval] = 4.47 [1.69–11.84] for EMCa vs. control). The same was found in the group of women with more than the median level of OP (odds ratio [95% confidence interval] = 4.32 [2.01–9.30] for EMCa vs. LM). Stratification of pre- and post-menopausal groups resulted in a similar association. The results show that NP/OP exposure is associated with EMCa. Further investigations and exposure minimisation are suggested.

Development and Validation of a Five-immune Gene Pair Signature in Endometrial Carcinoma.

Endometrial cancer (EC) is a common gynecological malignancy worldwide. Immunity is closely related to the occurrence and prognosis of EC. At the same time, immune-related genes have great potential as prognostic markers in many types of cancer. Therefore, we attempt to develop immune-related gene markers to enhance prognosis prediction of EC. 542 samples of EC gene expression data and clinical follow-up information were downloaded from The Cancer Genome Atlas (TCGA). The samples were randomly divided into two groups, one group as a training set (N=271), and one set as a validation set. (N=271). In the training set, the gene pairs were established based on the relative expression levels of 271 immune genes, and the prognosis-related gene pairs were screened. The lasso was used to select the features, and finally, the robust biomarkers were screened. Finally, the prognostic model of the immune gene pair was established and verified by the validation data set. 10030 immune gene pair (IRGPs) were obtained, and univariate survival analysis was used to identify 1809 prognostic-related IRGPs (p<0.05). 5-IRGPs were obtained by lasso regression feature selection, and multivariate regression was used to establish 5-IRGPs signature, 5-IRGPs signature is an independent prognostic factor for EC patients, and could be risk stratified in patients with TCGA datasets, age, ethnicity, stage, and histological classification (p<0.05). The mean AUC of survival in both the training set and the validation set was greater than 0.7, indicating that 5-IRGPs signature has superior classification performance in patients with EC. In addition, 5-IRGPs have the highest average C index (0.795) compared to the prognostic characteristics of the three endometrial cancers reported in the past and Stage and Age. This study constructed a 5-IRGPs signature as a novel prognostic marker for predicting survival in patients with EC.

Associations between metabolic syndrome and gynecologic cancer.

Metabolic syndrome (MetS) is a group of risk factors that causes cardiovascular and diabetic morbidity and mortality, which is diagnosed by central obesity, dyslipidemia, hyperglycemia, and hypertension. Increasing epidemiological data and experimental results indicate that the presence of MetS increases the incidence of common malignancies and related mortality. Epidemiological studies have previously reported an association of endometrial cancer occurrence with MetS. Aromatization of androstenedione to estrogen, insulin resistance, and diabetes can cause increased levels of free estrogen, and the detrimental effect of elevated estrogen as a carcinogen is well studied in endometrial cancer. Medications used to manage MetS such as metformin and statins are suggested to reduce endometrial cancer risk and improve survival. Some large population-based epidemiological studies have suggested that the MetS is related to an increased risk of cervical carcinoma. MetS may contribute to viral-host interactions, which lead to persistent human papilloma virus (HPV) infection, although limited epidemiological data are available. Specific effects of obesity and diabetes on the occurrence of ovarian cancer have been suggested. However, the direct correlation between MetS and ovarian cancer is still lacking. Previous retrospective studies reported that the use of metformin, statins, and beta-blockers could be associated with cancer prevention or better prognosis. Proper diagnosis and management of the MetS should be a part of the strategies undertaken to prevent and treat gynecologic cancer. So far, only limited data is available on this subject, and further clinical and fundamental research is required to further clarify the effect of these therapies on gynecologic cancer treatment.