The role of tumor-associated macrophages in the progression, prognosis and treatment of endometrial cancer.

Tumor-associated macrophages (TAMs) are the main immune cells in the tumor microenvironment (TME) of endometrial cancer (EC). TAMs recruitment and polarization in EC is regulated by the TME of EC, culminating in a predominantly M2-like macrophage infiltration. TAMs promote lymphatic angiogenesis through cytokine secretion, aid immune escape of EC cells by synergizing with other immune cells, and contribute to the development of EC through secretion of exosomes so as to promoting EC development. EC is a hormone- and metabolism-dependent cancer, and TAMs promote EC through interactions on estrogen receptor (ER) and metabolic factors such as the metabolism of glucose, lipids, and amino acids. In addition, we have explored the predictive significance of some TAM-related indicators for EC prognosis, and TAMs show remarkable promise as a target for EC immunotherapy.

Reanalysis of single-cell data reveals macrophage subsets associated with the immunotherapy response and prognosis of patients with endometrial cancer.

Endometrial cancer (EC) is an aggressive gynecological malignancy with an increased incidence rate. The immune landscape crucially affects immunotherapy efficacy and prognosis in EC patients. Here, we characterized the distinct tumor microenvironment signatures of EC tumors by analyzing single-cell RNA sequencing data from Gene Expression Omnibus and bulk RNA sequencing data from The Cancer Genome Atlas, which were compared with normal endometrium. Three macrophage subsets were identified, and two of them showed tissue-specific distribution. One of the macrophage subsets was dominant in macrophages derived from EC and exhibited characteristic behaviors such as promoting tumor growth and metastasis. One of the other macrophage subsets was mainly found in normal endometrium and served functions related to antigen presentation. We also identified a macrophage subset that was found in both EC and normal endometrial tissue. However, the pathway and cellular cross-talk of this subset were completely different based on the respective origin, suggesting a tumor-related differentiation mechanism of macrophages. Additionally, the tumor-enriched macrophage subset was found to predict immunotherapy responses in EC. Notably, we selected six genes from macrophage subset markers that could predict the survival of EC patients, SCL8A1, TXN, ANXA5, CST3, CD74 and NANS, and constructed a prognostic signature. To verify the signature, we identified immunohistochemistry for the tumor samples of 83 EC patients based on the selected genes and further followed up with the survival of the patients. Our results provide strong evidence that the signature can effectively predict the prognosis of EC patients.

Evaluation of immunotherapy efficacy in gynecologic cancer.

Various immunotherapies have demonstrated remarkable success over the past few decades, and have been approved for the treatment of different cancer types. However, patient responses to immunotherapy are variable, and approximately 50% of cases are refractory to these agents. Tumor biomarker-based stratification of cases may therefore help identify subpopulations that are sensitive/resistant to immunotherapy; it may also improve prediction of response in various cancers including gynecologic cancer. These biomarkers include the tumor mutational burden, microsatellite instability, mismatch repair deficiency, T cell-inflamed gene expression profile, programmed cell death protein 1 ligand 1, tumor-infiltrating lymphocytes, and numerous other genomic alterations. Future directions in the treatment of gynecologic cancer include the utilization of these biomarkers to select ideal candidates. This review focused on recent advances in the predictive ability of molecular biomarkers in patients with gynecologic cancer who undergo immunotherapy. The most recent developments in combined immunotherapy and targeted therapy strategies and novel immune interventions against gynecologic cancers have also been discussed.

[The one-stage technology of epiglottis function and voice reconstruction after total laryngectomy with the sternohyoid myocutaneous flap].

Objective:To investigate the clinical effect of one-stage sternohyoid musculocutaneous flap after total laryngectomy for reconstruction of epiglottis function and vocalization. Methods:A retrospective analysis of 8 patients who underwent total laryngectomy from November 2019 to September 2020. The sternohyoid myocutaneous flap was designed after total laryngectomy. The lower edge of the flap was sewed with the posterior upper edge of the tracheostomy opening, and the lateral and medial edges of the flap were anastomosed to create a vocal tube. The lateral edge of the upper end of tube was sutured with the anterolateral wall of the hypopharynx, then made full use of residual epiglottis and tongue root tissue to reconstruct epiglottis function. Results:None of the 8 patients had serious complications after total laryngectomies. Fifteen months after operation,the vocal tube flaps survived and had intact structure under fiberoptic laryngoscope. All patients could speak clearly and forcefully, and the swallowing function was intact. Conclusion:The use of adjacent myocutaneous flap to construct the vocal canal and reconstruct the epiglottis function is a simple and effective technique that can be completed in one stage and improve the voicing of patients undergoing total laryngectomy.

Discovery of immune-related diagnostic biomarkers and construction of diagnostic model in varies polycystic ovary syndrome.

AIMS: The various diagnostic criteria for polycystic ovary syndrome (PCOS) raised problem for PCOS research worldwide. PCOS has been demonstrated to be significantly associated with immune response. We aimed to identify several immune-related biomarkers and construct a nomogram model for diagnosis in PCOS. METHODS: The mRNA expression data were downloaded from Gene Expression Omnibus (GEO) database. Significant immune-related genes were identified to be the biomarkers for the diagnosis of PCOS using random forest model (RF), support vector machine model (SVM) and generalized linear model (GLM). The key biomarkers were selected from the optimal model and were utilized to construct a diagnostic nomogram. Receiver operating characteristic (ROC) curves was used to evaluate diagnostic ability of nomogram. Moreover, the relative proportion of 22 immune cell types was calculated by CIBERSORT algorithm. RESULTS: Four immune-related biomarkers (cAMP, S100A9, TLR8 and IL6R) were demonstrated to be highly expressed in PCOS. The nomogram constructed on the ground of the four key biomarkers showed perfect performance in diagnosis of PCOS, whose AUC were greater than 0.7. Higher infiltrating abundance of neutrophils, resting NK cells and activated dendritic cells were observed in PCOS and were tightly associated with the four key biomarkers. CONCLUSIONS: This study identified several immune-related diagnostic biomarkers for PCOS patients. The diagnostic nomogram constructed based the biomarkers provide a theory foundation for clinical application. Multiple immune cells were associated with the expression of these four biomarkers and might played a vital role in the procession of PCOS.

Development of a Genomic Instability-Derived lncRNAs-Based Risk Signature as a Predictor of Prognosis for Endometrial Cancer.

Endometrial cancer (EC) ranks fourth in the incidence rate among the most frequent gynaecological malignancies reported in the developed countries. Approximately 280,000 endometrial cancer cases are reported worldwide every year. Genomic instability and mutation are some of the favourable characteristics of human malignancies such as endometrial cancer. Studies have established that the majority of genomic mutations in human malignancies are found in the chromosomal regions that do not code for proteins. In addition, the majority of transcriptional products of these mutations are long non-coding RNAs (lncRNAs). In this study, 78 lncRNA genes were found on the basis of their mutation counts. Then, these lncRNAs were investigated to determine their relationship with genomic instability through hierarchical cluster analysis, mutation analysis, and differential analysis of driving genes responsible for genomic instability. The prognostic value of these lncRNAs was also assessed in patients with EC, and a risk factor score formula composed of 15 lncRNAs was constructed. We then identified this formula as genome instability-derived lncRNA-based gene signature (GILncSig), which stratified patients into high- and low-risk groups with significantly different outcome. And GILncSig was further validated in multiple independent patient cohorts as a prognostic factor of other clinicopathological features, such as stage, grade, overall survival rate. We observed that a high-risk score is often associated with an unfavourable prognosis in patients with EC.

Predictive value of hemoglobin, platelets, and D-dimer for the survival of patients with stage IA1 to IIA2 cervical cancer: a retrospective study.

OBJECTIVE: Coagulation indexes may be useful survival biomarkers for cervical cancer. This study evaluated the ability of hemoglobin, red blood cells (RBCs), platelets, and D-dimer levels to predict post-hysterectomy survival outcomes in patients with stage IA1 to IIA2 cervical cancer. METHODS: In this retrospective study, coagulation-related indexes were compared between the anemia and non-anemia groups. Independent variables were analyzed by the Cox proportional hazards model. Survival was assessed by the Kaplan-Meier method with the log-rank test. Mortality predictions were evaluated by receiver operating characteristic curves. RESULTS: Among this study's 1088 enrolled patients, 152 had anemia. The 10-year overall survival and recurrence-free survival rates were 90.8% and 86.5%, respectively. Hemoglobin, RBC, and the rate of abnormal platelet counts were significantly lower in the anemia group. Abnormal preoperative D-dimer was an independent factor for recurrence-free survival. Receiver operating characteristic curves showed that D-dimer had area under the curve of 0.734 (cut-off value: 0.685, sensitivity: 85.7%, and specificity: 64.0%). Hemoglobin and platelets had areas under the curves of 0.487 and 0.462, respectively. CONCLUSION: Preoperative D-dimer was the most effective prognostic predictor for patients with cervical cancer. The prognosis of patients with cervical cancer was poorer if their D-dimer levels were >0.685 mg/L.

Expression profile of epithelial-mesenchymal transition-related genes as a prognostic biomarker for endometrial cancer.

Epithelial-mesenchymal transition (EMT) is regulated by inducible factors, transcription factors, and a series of genes involved in diverse signaling pathways, which are correlated with tumor invasion and progression. In the present study, we analyzed the expression profile data of 1169 EMT-related genes in endometrial cancer (EC) from the Cancer Genome Atlas (TCGA) dataset, and performed consistency clustering to divide EC samples into two subgroups based on overall survival. The genes differentially expressed between the two subtypes included EMT-related genes. Univariate Cox analysis and least absolute shrinkage and selection operator (LASSO) were applied to construct a prognostic model based on the 44 genes signature. Five genes (L1CAM, PRKCI, ESR1, CDKN2A, and VIM) were finally included to establish a formula for prognostic risk score. The low-risk group showed significantly better prognosis compared with the high-risk group in the TCGA dataset. In addition, the risk-scoring model successfully predicted prognosis in an external GEO dataset (GSE102073). The relationship between ERα and vimentin levels was confirmed through immunohistochemistry. In conclusion, these data indicate that the expression profile of EMT-related genes could predict prognosis in EC.

Altered Lipid Profile Is a Risk Factor for the Poor Progression of COVID-19: From Two Retrospective Cohorts.

Background: The coronavirus disease 2019 (COVID-19) pandemic has spread worldwide. However, the impact of baseline lipid profile on clinical endpoints in COVID-19 and the potential effect of COVID-19 on lipid profile remain unclear. Methods: In this retrospective cohort study, we consecutively enrolled 430 adult COVID-19 patients from two Chinese hospitals (one each in Chengdu and Wuhan). The lipid profile before admission and during the disease course and the clinical endpoint including in-hospital death or oropharyngeal swab test positive again (OSTPA) after discharge were collected. We used Kaplan-Meier and Cox regression to explore the lipid risk factors before admission associated with endpoints. Then, we assessed the lipid level change along with the disease course to determine the relationship between pathology alteration and the lipid change. Results: In the Chengdu cohort, multivariable Cox regression showed that low-density lipoprotein cholesterol (LDL-C) dyslipidemia before admission was associated with OSTPA after discharge for COVID-19 patients (RR: 2.51, 95% CI: 1.19, 5.29, p = 0.006). In the Wuhan cohort, the patients with triglyceride (TG) dyslipidemia had an increased risk of in-hospital death (RR: 1.92, 95% CI: 1.08, 3.60, p = 0.016). In addition, in both cohorts, the lipid levels gradually decreased in the in-hospital death or OSTPA subgroups since admission. On admission, we also noticed the relationship between the biomarkers of inflammation and the organ function measures and this lipid level in both cohorts. For example, after adjusting for age, sex, comorbidities, smoking, and drinking status, the C-reactive protein level was negatively associated with the TC lipid level [ß (SE) = -0.646 (0.219), p = 0.005]. However, an increased level of alanine aminotransferase, which indicates impaired hepatic function, was positively associated with total cholesterol (TC) lipid levels in the Chengdu cohort [ß (SE) = 0.633 (0.229), p = 0.007]. Conclusions: The baseline dyslipidemia should be considered as a risk factor for poor prognosis of COVID-19. However, lipid levels may be altered during the COVID-19 course, since lipidology may be distinctly affected by both inflammation and organic damage for SARS-CoV-2.

The Preoperative Diagnostic Value of MRI and Otoneural Tests in Acoustic Neuroma.

OBJECTIVES: To determine the preoperative diagnostic accuracy of MRI and otoneural tests (ONT) for acoustic neuroma (AN) in a cohort of unselected patients with pontocerebellar angle tumors. To find a convenient way to screening out the potential asymptomatic AN patient earlier. DESIGN: This diagnostic accuracy study was performed in a central hospital and included a consecutive sample of unilateral incipient pontocerebellar angle tumor patients referred for MRI and ONT before surgery. Different AN features of MRI and ONT were collected and concluded into preoperative diagnostic variables or variable combinations. Those of MRI and ONT are analyzed and compared with biopsy results by multivariable receiver operating characteristic (ROC) analysis. The early-stage group, the course of which is 1 year or less, was separately computed and compared. RESULTS: Eighty-three subjects were collected from June 2013 to June 2019; 62 were confirmed AN postoperatively by biopsy, whereas others are not AN. The area under the curve (AUC) of MRI was 0.611, whereas the AUC of ONT was 0.708. In the early-stage group, the AUC of MRI was 0.539, and the AUC of ONT was 0.744. CONCLUSIONS: ONT was able to identify more subjects affected by unilateral incipient AN than MRI preoperatively. Given that ONT is a functional test for internal auditory canal nerves, it is an optimal screening test for AN patients because it provides more information than MRI for the further clinical plan. It is particularly noteworthy for identifying asymptomatic AN patients and for early stage. Therefore, it may help more patients from unnessesary surgery. Furthermore, an MRI follow-up is suggested if the patient was found alert in ONT.

LncRNA APTR Promotes Uterine Leiomyoma Cell Proliferation by Targeting ERα to Activate the Wnt/ß-Catenin Pathway.

The molecular mechanisms by which uterine leiomyoma (UL) cells proliferate are unclear. Long noncoding RNA (lncRNA) is reported to participate in the occurrence and development of gynecological cancers. We investigated the molecular mechanisms that lncRNA uses in UL. We found that lncRNA Alu-mediated p21 transcriptional regulator (APTR) showed higher expression in UL tumor tissues compared with that in normal uterine tissues. APTR induced cell proliferation and colony formation both in vitro and in vivo. The JASPAR database showed that APTR was likely interacted with ERα, and these molecules were identified via laser scanning confocal microscopy and RNA immunoprecipitation analysis. To verify the correlation between APTR and ERα, we overexpressed and underexpressed APTR and simultaneously expressed ERα. The results showed that APTR function was suppressed. APTR increased the expressions of the proteins in the Wnt pathway, and inhibiting ERα eliminated these responses. In conclusion, our data suggest that APTR promoted leiomyoma cell proliferation through the Wnt pathway by targeting ERα, suggesting a new role of APTR in the Wnt signaling pathway in UL.

Prognostic significance of immune landscape in tumour microenvironment of endometrial cancer.

Tumour microenvironment (TME) is crucial to tumorigenesis. This study aimed to uncover the differences in immune phenotypes of TME in endometrial cancer (EC) using Uterine Corpus Endometrial Carcinoma (UCEC) cohort and explore the prognostic significance. We employed GVSA enrichment analysis to cluster The Cancer Genome Atlas (TCGA) EC samples into immune signature cluster modelling, evaluated immune cell profiling in UCEC cohort (n = 538) and defined four immune subtypes of EC. Next, we analysed the correlation between immune subtypes and clinical data including patient prognosis. Furthermore, we analysed the expression of immunomodulators and DNA methylation modification. The profiles of immune infiltration in TCGA UCEC cohort showed significant difference among four immune subtypes of EC. Among each immune subtype, natural killer T cells (NKT), dendritic cells (DCs) and CD8+ T cells were significantly associated with EC patients survival. Each immune subtype exhibited specific molecular classification, immune cell characterization and immunomodulators expression. Moreover, the expression immunomodulators were significantly related to DNA methylation level. In conclusion, the identification of immune subtypes in EC tissues could reveal unique immune microenvironments in EC and predict the prognosis of EC patients.

The significance of plasma D-dimer level in predicting high risk factors of endometrial cancer.

BACKGROUND: Activated clotting-fibrinolytic system is associated with poor outcome of cancer patients. This retrospective study aimed to evaluate the significance of plasma D-dimer level in predicting high risk factors of endometrial cancer (EC) patients. METHODS: Total 176 EC patients who underwent radiotherapy between January 2018 and June 2019 at Shanghai First Maternity and Infant Hospital were retrospectively analyzed. Their preoperative and postoperative plasma D-dimer levels were measured as routine assessment in our hospital, and analyzed for their association with clinicopathological data retrieved from medical records of the patients. RESULTS: High risk group had significantly higher 1st day postoperative D-dimer levels. The 1st day postoperative D-dimer predicted higher grade EC with the specificity of 63.7% and the sensitivity of 63.4%; predicted late stage EC with the specificity of 83.7% and the sensitivity of 58.6%; predicted deeper myoinvasion of EC with the specificity of 84.9% and the sensitivity of 43.3%; predicted lymphovascular space invasion positive EC with the specificity of 84.0% and the sensitivity of 50.0%; predicted lymph node metastasis of EC with the specificity of 50.9% and the sensitivity of 100%; and predicted cervical invasion of EC with the specificity of 82.1% and the sensitivity of 65.0%. CONCLUSIONS: Increased postoperative plasma D-dimer levels accurately predicted high risk factors in patients with EC.

A Prospective Study of Sentinel Lymph Node Mapping for Endometrial Cancer: Is It Effective in High-Risk Subtypes?

BACKGROUND: The efficacy of sentinel lymph node (SLN) mapping for high-risk endometrial cancer remains unclear. This prompted us to evaluate the sensitivity, negative predictive value (NPV), and false-negative (FN) rate of cervical injection of indocyanine green (ICG) SLN mapping in patients with endometrial cancer. MATERIALS AND METHODS: This prospective interventional study was performed at a single university teaching hospital. Consecutive patients with early-stage endometrial cancer who underwent laparoscopic surgical staging were included. Cervical injection of ICG and near-infrared SLN identification and biopsy were performed for all study patients followed by systematic pelvic lymphadenectomy, whereas para-aortic lymphadenectomy was performed in all patients with high-risk histologies. SLN detection rates, sensitivity, NPV, and FN rates were calculated. RESULTS: Between July 2016 and July 2018, 131 patients were enrolled. The overall SLN detection rate was 93.1%, with a bilateral detection rate of 61.8%. Four positive SLNs were identified in four patients. Lymph node metastasis was observed in four additional patients without positive SLNs. These four patients belonged to a group of patients with a high-risk subtype. Three of the four patients had isolated para-aortic node metastases. In low-risk endometrial cancers, the sensitivity of the SLN technique to identify nodal metastatic disease was 100% (95% confidence interval [CI] 31.0-100), with an NPV and FN rate of 100% (95% CI 95.1-100) and 0%, respectively. In high-risk endometrial cancers, the sensitivity, NPV, and FN rate were 20% (95% CI 1.0-70.1), 83.3% (95% CI 61.8-94.5), and 80%, respectively. CONCLUSION: Cervical injection of ICG and SLN mapping yielded a low sensitivity and a high FN rate for the identification of node metastasis in endometrial cancer with high-risk histologies. IMPLICATIONS FOR PRACTICE: The efficacy of sentinel lymph node (SLN) mapping for high-risk endometrial cancer remains unclear. This study enrolled 131 patients with early-stage endometrial cancer who underwent cervical injection of indocyanine green SLN mapping followed by systematic pelvic lymphadenectomy and para-aortic lymphadenectomy. The key result was that SLN mapping yielded a low sensitivity and a high false-negative rate for the identification of node metastasis in endometrial cancer with high-risk histologies. The SLN strategy in these patients may increase the risk of missed diagnosis of isolated para-aortic node metastases and seems to be unacceptable in clinical practice.

TRIB3 suppresses proliferation and invasion and promotes apoptosis of endometrial cancer cells by regulating the AKT signaling pathway.

OBJECTIVE: The aim of this study was to examine the effect of TRIB3 on proliferation, apoptosis, and migration of endometrial cancer (EC) cells and explore the relationship between TRIB3 and AKT signaling pathway in EC progression. METHODS: Immunohistochemical analysis was performed to measure the expression level of TRIB3 in normal endometrium tissues and EC tissues. Overexpression and shRNA knockdown techniques were applied by transfecting EC cells (ISK and AN3CA), and the effect of TRIB3 on EC cell biological behaviors was evaluated. Cell Counting Kit-8 and colony formation assays were utilized to investigate EC cell proliferation ability, and flow cytometry was performed to assess the apoptosis of EC cells. Moreover, the migration and invasion of EC cells were detected by transwell assay, and the levels of MMP-2 and MMP-9 were measured by ELISA. Additionally, Western blot analysis was carried out to determine the levels of AKT and p-AKT. RESULTS: The expression level of TRIB3 was higher in EC than normal endometrium tissues, and its overexpression promoted apoptosis and suppressed proliferation of EC cells. Furthermore, TRIB3 retarded the migration and invasion of EC cells and decreased the levels of MMP-2 and MMP-9. Conversely, TRIB3 inhibition enhanced the expression levels of MMP-2 and MMP-9, and proliferation and migration of EC cells but suppressed their apoptosis. Similarly, TRIB3 overexpression reduced while its knockdown increased the level of p-AKT. CONCLUSION: TRIB3 inhibited proliferation and migration and promoted apoptosis of EC cells probably through regulating AKT signaling pathway.

Loss of exosomal miR-148b from cancer-associated fibroblasts promotes endometrial cancer cell invasion and cancer metastasis.

Cancer-associated fibroblasts (CAFs) play crucial roles in tumor progression, given the dependence of cancer cells on stromal support. Therefore, understanding how CAFs communicate with endometrial cancer cell in tumor environment is important for endometrial cancer therapy. Exosomes, which contain proteins and noncoding RNA, are identified as an important mediator of cell-cell communication. However, the function of exosomes in endometrial cancer metastasis remains poorly understood. In the current study we found that CAF-derived exosomes significantly promoted endometrial cancer cell invasion comparing to those from normal fibroblasts (NFs). We identified a significant decrease of miR-148b in CAFs and CAFs-derived exosomes. By exogenously transfect microRNAs, we demonstrated that miR-148b could be transferred from CAFs to endometrial cancer cell through exosomes. In vitro and in vivo studies further revealed that miR-148b functioned as a tumor suppressor by directly binding to its downstream target gene, DNMT1 to suppress endometrial cancer metastasis. In endometrial cancer DNMT1 presented a potential role in enhancing cancer cell metastasis by inducing epithelial-mesenchymal transition (EMT). Therefore, downregulated miR-148b induced EMT of endometrial cancer cell as a result of relieving the suppression of DNMT1. Taken together, these results suggest that CAFs-mediated endometrial cancer progression is partially related to the loss of miR-148b in the exosomes of CAFs and promoting the transfer of stromal cell-derived miR-148b might be a potential treatment to prevent endometrial cancer progression.

The role of lncRNAs in the development of endometrial carcinoma.

Endometrial carcinoma (EC) is one of the most common types of gynecological cancer. Long noncoding RNAs (lncRNAs) are associated with the carcinogenesis and progression of EC. In the following review, the emerging role of lncRNAs in EC initiation and progression is considered. The profile of lncRNAs is becoming higher as the contribution of lncRNAs to carcinogenesis through diverse mechanisms is being increasingly recognized, including in EC. A number of lncRNA-profiling studies have identified aberrantly expressed lncRNAs in EC tissue, and the regulatory network associated with these lncRNAs may be critical in EC progression. Additionally, certain lncRNAs may have diagnostic and/or prognostic significance. The potential function of lncRNAs as prospective therapeutic and prognostic targets in EC will be evaluated.

Cross-talk between p21-activated kinase 4 and ERα signaling triggers endometrial cancer cell proliferation.

Cross-talk between estrogen receptor alpha (ERα) and signal transduction pathways plays an important role in the progression of endometrial cancer (EC). Here, we show that 17ß-estradiol (E2) stimulation increases p21-activated kinase 4 (Pak4) expression and activation in ER-positive EC cells. The estrogen-induced Pak4 activation is mediated via the PI3K/AKT pathway. Estrogen increases Pak4 and phosphorylated-Pak4 (p-Pak4) nuclear accumulation, and Pak4 in turn enhances ERα trans-activation. Depletion or functional inhibition of Pak4 abrogates EC cell proliferation induced by E2, whereas overexpression of Pak4 rescues cell proliferation decreased by inhibiting the estrogen pathway. Pak4 knockdown decreases cyclin D1 expression and induces G1-S arrest. Importantly, Pak4 suppression inhibits E2 induced EC tumor growth in vivo, in a mouse xenograft model. These data demonstrate that estrogen stimulation increases Pak4 expression and activation, which in turn enhances ERα transcriptional activity and ERα-dependent gene expression, resulting in increased proliferation of EC cells. Thus inhibition of Pak4-ERα signaling may represent a novel therapeutic strategy against endometrial carcinoma.

DICER1 regulates endometrial carcinoma invasion via histone acetylation and methylation.

Endometrial carcinoma (EC) is one of the most common gynecologic malignancy, but molecular mechanisms of the development and progression of EC remain unclear. Here we showed that the expression of DICER1 was negatively associated with the level of histone methylation, histone acetylation and PRC2 components SUZ12 and EZH2 in EC cells. In addition, knockdown of DICER1 significantly downregulated miR-200b and let-7i, which may then regulate their targets SUZ12 and EZH2. Furthermore, knockdown of DICER1 remarkably suppressed the expression of epithelial cell marker E-cadherin, induced the expression of mesenchymal cell marker Vimentin, and promoted the invasion of EC cells. In conclusion, our data suggest that DICER1 suppresses SUZ12 and EZH2 via affecting their upstream miRNA synthesis, and inhibits epithelial-mesenchymal transition(EMT) and invasion of EC cells via histone modification.

DNMT1 regulates human endometrial carcinoma cell proliferation.

Endometrial carcinoma (EC) is the most common gynecologic malignancy, but the molecular events involved in the development and progression of EC remain unclear. This study aimed to investigate the role of DNA methyltransferase 1 (DNMT1), a member of DNA methyltransferases, in EC. AN3CA cells were transfected with DNMT1 siRNA. The proliferation, cell cycle, and apoptosis of AN3CA cells were evaluated by Cell Counting Kit-8 (CCK-8) assay and flow cytometry. The expression of related genes was detected by polymerase chain reaction and Western blot analysis. Knockdown of DNMT1 inhibited the proliferation, induced apoptosis, and G0/G1 phase arrest of AN3CA cells. Furthermore, knockdown of DNMT1 upregulated the expression of nuclear factor kappa-B-inhibitor alpha (NF-κBIA) and Bax and downregulated the expression of Bcl-2 and CCND1/2 in AN3CA cells. In conclusion, this study provides the first evidence that knockdown of DNMT1 affects the expression of cell cycle- and apoptosis-associated proteins in EC cells, suggesting the potential of DNMT1 in EC therapy.