• breast cancer
• drug-target Mendelian randomization
• endometrial cancer
• lipid-lowering drugs

• National Natural Science Foundation of China

• centromere coiled-coil protein 110
• colony formation
• endometrial carcinoma
• long non-coding RNA X-inactive-specific transcript
• microRNA-129-2-3p
• migration and invasion
• proliferation

• Circular RNA SMAD Family Member 2
• Endometrial Cancer
• MicroRNA-1277-5p
• Milk Fat Globule Epidermal Growth Factor 8

• Female
• Humans
• RNA, Circular/genetics
• Endometrial Neoplasms/genetics
• Endometrial Hyperplasia
• Cell Proliferation/genetics
• MicroRNAs/genetics
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• Antigens, Surface
• Milk Proteins

• Endometrial carcinoma
• HSPB7
• Invasion
• Migration
• PI3K/AKT/mTOR
• Proliferation

• cancer
• endometrial carcinoma
• estrogen receptor
• hormone receptors
• progesterone receptor

• endometrial cancer
• lymphadenectomy
• nodal status
• sentinel lymph node biopsy
• staging

This study strived to explore the role and mechanism of glucagon‐like peptide‐1 receptor (GLP1R) in endometrial carcinoma (EC).

In detail, after transfection of GLP1R overexpression vector and small interfering RNA targeting PKA, the mRNA expressions of GLP1R and PKA in EC cells (Ishikawa and RL95‐2) were quantified by quantitative reverse transcription polymerase chain reaction (qRT‐PCR). The cell biological behaviors, including proliferation, migration, invasion, and apoptosis, were detected using 5‐ethynyl‐2′‐deoxyuridine (EdU), wound healing, transwell, and flow cytometry assays, respectively. The cyclic adenosine monophosphate (cAMP) content and related protein expressions (GLP1R, p‐PKA, and PKA) were determined by enzyme‐linked immunosorbent assay (ELISA) and western blot. The effects of GLP1R and PKA on tumorigenesis were evaluated by measuring the tumor volume and weight of mice bearing EC.

According to the results, GLP1R expression was downregulated in EC tissues and cells, and there was a positive correlation between GLP1R and PKA expressions. Upregulation of GLP1R promoted apoptosis and activated the cAMP/PKA signaling pathway in EC cells, while hindering the EC cell proliferation, invasion, migration, and the growth of tumor in mice. However, these effects were blunted by downregulation of PKA, which also accelerated the progression of EC in vitro and in vivo via inhibiting the activation of cAMP/PKA signaling pathway.

Collectively, upregulation of GLP1R impeded EC progression via inducing the activation of cAMP/PKA signaling pathway, which may be a potential treatment for EC.

• cyclic adenosine monophosphate
• endometrial carcinoma
• glucagon-like peptide-1 receptor
• protein kinase  A 

Endometrial carcinoma (EC) is one of the most common gynecological cancers with a poor prognosis. Therefore, clarifying the details of the molecular mechanisms is of great importance for EC diagnosis and clinical management. Interferon-stimulated gene 15 (ISG15) plays an important role in the development of various cancers. However, its role in EC remains unclear. High ISG15 expression was observed in EC, which was associated with poor clinical outcomes and pathological stage of patients with EC, thus representing a promising marker for EC progression. Further exploratory analysis revealed that the elevated ISG15 levels in EC were driven by aberrant DNA methylation, independent of copy number variation and specific transcription factor aberrations. Accordingly, knockdown of ISG15 by small interfering RNA attenuated the malignant cellular phenotype of EC cell lines, including proliferation and colony formation in vitro. Finally, investigation of the molecular mechanisms indicated that ISG15 promoted the cell cycle G1/S transition in EC. Furthermore, ISG15 promoted EC progression by activating the MYC proto-oncogene protein signaling pathway. Moreover, ECs with high levels of ISG15 harbored a more vital immune escape ability, evidenced not only by significantly less invasive CD8⁺ T cells, but also higher expression of T cell inhibitory factors, such as programmed death-ligand 1. These results suggest a tumor-promoting role of ISG15 in EC, which may be a promising marker for diagnosis, prognosis and therapeutic immunity.

• DNA methylation
• cell cycle
• endometrial carcinoma
• immunological escape
• interferon‑stimulated gene 15

• EC
• SLC7A5
• circZNF124
• miR-199b-5p

• USP46
• endometrial cancer
• miR-27a
• oncogenic miRNA

Cell lines are widely used for various research purposes including cancer and drug research. Recently, there have been studies that pointed to discrepancies in the literature and usage of cell lines. That is why we have prepared a comprehensive overview of the most common gynaecological cancer cell lines, their literature, a list of currently available cell lines, and new findings compared with the original studies. A literature review was conducted via MEDLINE, PubMed and ScienceDirect for reviews in the last 5 years to identify research and other studies related to gynaecological cancer cell lines. We present an overview of the current literature with reference to the original studies and pointed to certain inconsistencies in the literature. The adherence to culturing rulesets and the international guidelines helps in minimizing replication failure between institutions. Evidence from the latest research suggests that despite certain drawbacks, variations of cancer cell lines can also be useful in regard to a more diverse genomic landscape.

• breast neoplasm
• cell line
• cervix cancer
• endometrial neoplasms
• gynaecology
• in vitro techniques
• pathology
• tumour cell line

• Bioinformatics
• Endometrial cancer
• Prognostic biomarker
• RNA sequencing

• Brain metastasis
• CNS
• Central nervous system
• Endometrial carcinoma
• Gynecologic
• Gynecology
• Uterine cancer

Endometrial cancer (EC) is one of the most common malignant gynaecological tumours worldwide. This study was aimed at identifying EC prognostic genes and investigating the molecular mechanisms of these genes in EC.

Two mRNA datasets of EC were downloaded from the Gene Expression Omnibus (GEO). The GEO2R tool and Draw Venn Diagram were used to identify differentially expressed genes (DEGs) between normal endometrial tissues and EC tissues. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Next, the protein-protein interactions (PPIs) of these DEGs were determined by the Search Tool for the Retrieval of Interacting Genes (STRING) tool and Cytoscape with Molecular Complex Detection (MCODE). Furthermore, Kaplan-Meier survival analysis was performed by UALCAN to verify genes associated with significantly poor prognosis. Next, Gene Expression Profiling Interactive Analysis (GEPIA) was used to verify the expression levels of these selected genes. Additionally, a reanalysis of the KEGG pathways was performed to understand the potential biological functions of selected genes. Finally, the associations between these genes and clinical features were analysed based on TCGA cancer genomic datasets for EC.

In EC tissues, compared with normal endometrial tissues, 147 of 249 DEGs were upregulated and 102 were downregulated. A total of 64 upregulated genes were assembled into a PPI network. Next, 14 genes were found to be both associated with significantly poor prognosis and highly expressed in EC tissues. Reanalysis of the KEGG pathways found that three of these genes were enriched in the cell cycle pathway. TTK, CDC25A, and ESPL1 showed higher expression in cancers with late stage and higher tumour grade.

In summary, through integrated bioinformatics approaches, we found three significant prognostic genes of EC, which might be potential therapeutic targets for EC patients.

• endometrial cancer
• cullin 4A
• proliferation
• invasion
• migration

• Cell line
• Clear cell carcinoma
• Endometrium
• Mutation
• Proliferation

• Adenocarcinoma, Clear Cell/genetics
• Adenocarcinoma, Clear Cell/pathology
• Animals
• Cell Line, Tumor
• DNA-Binding Proteins/genetics
• Endometrial Neoplasms/genetics
• Endometrial Neoplasms/pathology
• Female
• Humans
• Karyotyping
• Mice
• Middle Aged
• Mutation
• Neoplasm Transplantation
• Receptor, Fibroblast Growth Factor, Type 3/genetics
• Serial Passage
• Transcription Factors/genetics

• MOST 104-2314-B-303-MY3 Ministry of Science and Technology, Taiwan
• TCRD 104-08, 108-43 Hualien Tzu Chi Hospital
• TCMF-EP-108-02 Buddhist Tzu Chi Medical Foundation

Endometrial cancer (EC) is a common gynecologic malignancy worldwide. This study investigated the regulatory effects of circular RNA (circRNA) hsa_circ_0002577 on the tumorigenesis of EC.

Tumor samples and adjacent normal tissues were obtained from 84 EC patients. Recombinant lentiviral vectors expressing hsa_circ_0002577 (Lv-circRNA), short hairpin RNAs against hsa_circ_0002577 (sh-circRNA), miR-625-5p mimics, miR-625-5p inhibitor, lentiviral vectors expressing insulin-like growth factor 1 receptor (IGF1R) and their corresponding controls were transfected into EC cells as designated. A mouse xenograft model was established in BALB/c mice by inoculating Ishikawa cells transfected with sh-circRNA or control sequence.

Hsa_circ_0002577 was upregulated in EC tissue samples and cells as compared to normal controls. EC patients with higher expression of hsa_circ_0002577 showed poorer overall survival and more advanced tumor stage. EC cells transfected with Lv-circRNA showed promoted proliferation, migration, and invasion, whereas the delivery of sh-circRNA exerted an opposite effect. Further analyses showed that hsa_circ_0002577 acted as a miR-625-5p sponge in EC cells. IGF1R was a potential downstream target of miR-625-5p. The expression of IGF1R in EC tissues was significantly higher than that in matched controls. Hsa_circ_0002577 accelerated EC development by inducing IGF1R expression and activating PI3K/Akt signaling pathway. Also, the knockdown of hsa_circ_0002577 delayed tumor growth and metastasis in the inoculated mice.

Our study showed that circRNA hsa_circ_002577 accelerated EC progression by acting as a miR-625-5p sponge, upregulating IGF1R and activating the PI3K/Akt pathway, suggesting the potential therapeutic use of hsa_circ_002577 in EC treatment.

Not Applicable.

• Circular RNA
• Endometrial cancer
• IGF1R
• PI3K/Akt pathway
• miRNA sponge

• Paclitaxel
• SPR064
• apoptosis
• cell proliferation
• endometrial cancer

• R37 CA226969 NCI NIH HHS

Background and objectives: B-lymphoma Mo-MLV insertion region 1 (Bmi-1) is a stem cell factor that is overexpressed in various human cancer tissues. It has been implicated in cancer cell proliferation, cell invasion, distant metastasis, and chemosensitivity, and is associated with patient survival. Several reports have also identified Bmi-1 protein overexpression in endometrial carcinoma; however, the relationship between Bmi-1 expression and its significance as a clinicopathological parameter is still insufficiently understood. Accordingly, the present study aimed to clarify whether immunohistochemical staining for Bmi-1 in human endometrial carcinoma and normal endometrial tissues can be used as a prognostic and cell proliferation marker. Materials and Methods: Bmi-1 expression was assessed in endometrioid carcinoma (grade 1–3) and normal endometrial tissues (in the proliferative and secretory phases) by immunohistochemistry; protein expression was evaluated using the nuclear labeling index (%) in the hot spot. Furthermore, we examined other independent prognostic and proliferation markers, including the protein levels of Ki-67, p53, and cyclin A utilizing semi-serial sections of endometrial carcinoma tissues. Results: The expression of the Bmi-1 protein was significantly higher in all grades of endometrial carcinoma than in the secretory phase of normal tissues. Moreover, Bmi-1 levels tended to be higher in G2 and G3 tissues than in G1 tissue, without reaching significance. Bmi-1 expression showed no notable differences among International Federation of Gynecology and Obstetrics (FIGO) stages in endometrial carcinoma. Furthermore, we observed a significant positive relationship between Bmi-1 and Ki-67, cyclin A, or p53 by Spearman’s rank correlation test, implying that high Bmi-1 expression can be an independent prognostic marker in endometrial carcinoma. Conclusions: Our study suggests that Bmi-1 levels in endometrial carcinoma tissues may be useful as a reliable proliferation and prognostic biomarker. Recently, the promise of anti-Bmi-1 strategies for the treatment of endometrial carcinoma has been detected. Our results provide fundamental data regarding this anti-Bmi-1 strategy.

• Bmi-1
• biomarker
• endometrial carcinoma
• immunohistochemical staining

• Endometrial Cancer
• TCGA
• Multiomics
• Ovarian cancer

• Cancer cell line
• Cell isolation
• Cell line
• Endometrial cancer
• In vitro models
• Tissue culture

Endometrial cancer (EC) is the fourth most common malignancy in women worldwide and the most common gynecological cancer in developed countries. The endometrioid subtype has an excellent prognosis with conventional treatment; however, recurrence reduces overall survival.

Describe the most relevant evidence regarding selected potential molecular biomarkers that may predict overall survival (OS), relapse-free survival (RFS), and cancer-specific survival (CSS) in EC.

An exhaustive search was performed in PUBMED with the search terms endometrial cancer, molecular biomarker, and survival. We selected original articles written in English about endometrial cancer, molecular biomarkers, and that included survival analysis published between January 2000 and December 2016.

Several molecular prognostic biomarkers have been studied in terms of survival and therapeutic response in women with endometrial cancer; hormone receptors, microRNAs, and other molecules have emerged as potentially useful biomarkers, including HER2, p21, HE4, PTEN, p27, ANCCA, and ANXA2.

The use of biomarkers in the assessment of OS, RFS, and CSS requires large trials to expand our understanding of endometrial carcinogenesis. Several molecular markers are significantly associated with a high tumor grade and advanced clinical stage in EC and, therefore, could have additive effects when combined.

• endometrial cancer
• molecular biomarkers
• overall survival
• prognosis

• Gene Expression Omnibus database
• bioinformatics analysis
• differentially expressed genes
• endometrial cancer

Endometrial adenocarcinoma is the most prevalent type of endometrial cancer. Diagnostic codes to identify endometrial adenocarcinoma in administrative databases, however, have not been validated.

To develop and validate an algorithm for identifying the occurrence of endometrial adenocarcinoma in a health insurance claims database.

To identify potential cases among women in the HealthCore Integrated Research Database (HIRD), published literature and medical consultation were used to develop an algorithm. The algorithm criteria were at least one inpatient diagnosis or at least two outpatient diagnoses of uterine cancer (International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) 182.xx) between 1 January 2010 and 31 August 2014. Among women fulfilling these criteria, we obtained medical records and two clinical experts reviewed and adjudicated case status to determine a diagnosis. We then estimated the positive predictive value (PPV) of the algorithm.

The PPV estimate was 90.8% (95% CI 86.9–93.6), based on 330 potential cases of endometrial adenocarcinoma. Women who fulfilled the algorithm but who, after review of medical records, were found not to have endometrial adenocarcinoma, had diagnoses such as uterine sarcoma, rhabdomyosarcoma of the uterus, endometrial stromal sarcoma, ovarian cancer, fallopian tube cancer, endometrial hyperplasia, leiomyosarcoma, or colon cancer.

An algorithm comprising one inpatient or two outpatient ICD-9-CM diagnosis codes for endometrial adenocarcinoma had a high PPV. The results indicate that claims databases can be used to reliably identify cases of endometrial adenocarcinoma in studies seeking a high PPV.

• endometrial cancer
• microRNA-23a
• sine oculis homeobox homolog 1

• Endometrial cancer
• indocyanine green dye
• natural orifices transvaginal endoscopic surgery
• sentinel lymph node mapping

Obesity is a recognized risk factor for endometrial cancer (EmCa) and other cancer types. Leptin levels are significantly increased in obese individuals. Leptin-induced signaling crosstalk [Notch, Interleukin-1 (IL-1) and leptin outcome, NILCO] has been associated with breast cancer progression. This complex signaling crosstalk affects cancer cell proliferation, migration, invasion, angiogenesis, apoptosis and chemoresistance. NILCO expression was previously detected in human EmCa. However, it is unknown whether leptin regulates NILCO and alters EmCa’s response to chemotherapeutics. It is hypothesized that leptin induces NILCO and increases aggressiveness and chemoresistance in EmCa cells.

To determine whether leptin induces NILCO molecules in EmCa affecting cell proliferation, aggressiveness and chemoresistance.

Leptin’s effects on the expression of NILCO molecules [mRNAs and proteins for Notch receptors (Notch1-4), ligands (JAG1 and DLL4) and downstream effectors (survivin, Hey2), and leptin (OB-R) and IL-1 (IL-1R tI) receptors] was examined in EmCa cells (type I: Ishikawa, and HEC-1A, and type II: An3Ca and KLE) using Real-time PCR and Western blot analysis, respectively. In addition, the effects of leptin on cell cycle, proliferation and cell invasion were determined using cytometric analysis (Cellometer Vision CBA system), MTT cell proliferation and Matrigel-based invasion assays, respectively. Inhibitors of leptin (nanoparticle-bound leptin peptide receptor antagonist-2, IONP-LPrA2), IL-1 (anti-IL-1R tI antibody) and Notch (siRNA interference RNA) were used to investigate NILCO’s effects on cell proliferation and invasion. Leptin’s effects on Paclitaxel cytotoxicity in EmCa cells was determined by the CCK8 and Cellometer-based Annexin V assays.

For the first time it was shown that leptin is an inducer of Notch in EmCa. Experimental data suggest that leptin induced the expression of NILCO molecules, promoted proliferation and S- phase progression, and reduced Paclitaxel cytotoxicity on EmCa cells. Leptin’s effects were higher in type II EmCa cells. The progression of this more aggressive form of the disease is associated with obesity. Remarkably, the use of the leptin signaling antagonist, IONP-LPrA2, re-sensitized EmCa cells to Paclitaxel.

Present data suggest the notion that leptin-induced NILCO could be a link between obesity and EmCa progression and chemoresistance. Most aggressive type II EmCa cells were higher sensitive to leptin, which appears to increase proliferation, cell cycle progression, aggressiveness, and chemoresistance to Paclitaxel. Therefore, leptin and NILCO could be novel therapeutic targets for type II EmCa, which does not have targeted therapy. Overall, IONP-LPrA2 has a potential as a novel adjuvant drug to enhance the effectiveness of type II EmCa chemotherapy.

• Endometrial cancer
• Leptin
• Notch
• Interleukin-1
• Notch, IL-1 and Leptin crosstalk outcome
• Chemoresistance

• endometrial cancer
• uterine cancer

• Clinical Trials as Topic
• Endometrial Neoplasms/therapy
• Female
• Humans
• Lymph Node Excision
• Quality of Life
• Sentinel Lymph Node
• Sentinel Lymph Node Biopsy

• Checkpoints
• Endometrial cancers
• Immunotherapies
• Tumor-infiltrating leukocytes

• diagnosis
• endometrial cancer
• survivorship
• treatment

Cyclin A, a cell cycle regulatory protein, promotes cell proliferation and has been observed to be highly expressed in cancer and to promote tumor growth; however, its value as a marker for endometrial carcinoma has not yet been established. Accordingly, the aim of the present study was to clarify whether cyclin A can be used as a cell proliferation marker using the endometrial carcinoma cell lines Ishikawa and HEC-50B, derived from patients with low-grade and high-grade cancer, respectively. The expression of cyclin A was determined by flow cytometry using double staining with FITC and 7-AAD, and immunocytochemical staining. The results were compared to those of Ki-67, the widely used cell proliferation marker that is considered to be a prognostic marker in endometrial cancer. The flow cytometry results revealed that cyclin A expression was significantly higher in HEC-50B than in Ishikawa cells during the logarithmic growth phase. In addition, cyclin A expression was consistently higher than Ki-67 expression in the examined cell lines. Immunocytochemical staining confirmed cyclin A expression in HEC-50B and Ishikawa cells, demonstrating significantly higher expression during the logarithmic growth phase than during the stationary phase. By contrast, Ki-67 was expressed in almost 90% of the cells, irrespective of their growth state. These results indicate that cyclin A expression is significantly increased in cells with higher proliferative ability and is specifically expressed in cells that have passed the G1-S checkpoint. Therefore, cyclin A may be a reliable proliferation biomarker for endometrioid carcinoma.

• cell-proliferation marker
• cyclin A
• endometrial cancer
• flow cytometry
• immunocytochemical staining

• BCAT1
• LC-MS/MS analysis
• cellular metabolism
• endometrial cancer

• endometrial cancer
• meta-analysis
• statin
• survival outcomes

• Endometrial Neoplasms/complications
• Endometrial Neoplasms/mortality
• Female
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Hypercholesterolemia/complications
• Hypercholesterolemia/drug therapy
• Observational Studies as Topic
• Survival Analysis

• Ishikawa
• MHY2256
• apoptosis
• autophagy
• endometrial cancer
• histone deacetylase inhibitor
• p53

• Acetylation/drug effects
• Animals
• Apoptosis/drug effects
• Autophagy/drug effects
• Blotting, Western
• Cell Cycle Checkpoints/drug effects
• Cell Line, Tumor
• Endometrial Neoplasms/metabolism
• Female
• Flow Cytometry
• Histone Deacetylase Inhibitors/pharmacology
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Sirtuin 1/metabolism
• Tumor Suppressor Protein p53/metabolism

• Bcl-2 family
• Mcl-1 in cancers
• Mcl-1 isoforms
• cancer care
• cancer-stem-cells
• targeting Mcl-1

• checkpoint inhibition
• endometrial cancer
• immunotherapy
• pd-1 inhibitor

With the goal of identifying diagnostic and prognostic biomarkers in endometrial cancer, miRNA-profiling was carried out with formalin-fixed paraffin embedded (FFPE) tissue samples from 49 endometrial cancer patients. Results using an 84-cancer specific miRNA panel identified the upregulation of miR-141-3p and miR-96-5p along with a downregulation of miR-26, miR-126-3p, miR-23b, miR-195-5p, miR-374a and let-7 family of miRNAs in endometrial cancer. We validated the dysregulated expression of the identified miRNAs in a panel of endometrial cancer cell-lines. Immunohistochemical analysis of the tissue micro array derived from these patients established the functional correlation between the decreased expression of tumor suppressive miRNAs and their target oncogenes: ERBB2, EGFR, EPHA2, BAX, GNA12, GNA13, and JUN. Comparative analysis of the samples from the patients with extended progression-free survival (PFS) ( > 21 months) versus the patients with the PFS of < 21 months indicated increased expression of tumor suppressive miR-142-3p, miR-142-5p, and miR-15a-5p in samples from extended PFS patients. In addition to defining a specific set of miRNAs and their target genes as potential diagnostic biomarkers, our studies have identified tumor suppressive miR-142 cluster and miR-15a as predictors of favorable prognosis for therapy response in endometrial cancer.

• Endometrial cancer
• miR-142
• miR-15a
• miRNA
• therapy response

• gynecologic cancer
• meta-analysis
• statin
• survival outcomes

• Disease-Free Survival
• Female
• Genital Neoplasms, Female/drug therapy
• Genital Neoplasms, Female/mortality
• Genital Neoplasms, Female/pathology
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Survival Analysis
• Treatment Outcome