Invasion In Endometrial Carcinoma Research Articles

Characterization of the Endometrial MSC Marker Ectonucleoside Triphosphate Diphosphohydrolase-2 (NTPDase2/CD39L1) in Low- and High-Grade Endometrial Carcinomas: Loss of Stromal Expression in the Invasive Phenotypes.

Ectonucleoside triphosphate diphosphohydrolase-2 (NTPDase2/CD39L1) has been described in human non-pathological endometrium in both epithelial and stromal components without changes along the cycle. It was identified as a stromal marker of basalis. In the present study, we aimed to evaluate NTPDase2 distribution, using immunolabeling and in situ enzyme activity approaches, in endometrial carcinoma (EC) at different tumor grades. NTPDase2 was present in tumor epithelial EC cells, as in the non-pathological endometria, but the expression underwent changes in subcellular distribution and also tended to decrease with the tumor grade. In stroma, NTPDase2 was identified exclusively at the tumor-myometrial junction but this expression was lost in tumors of invasive phenotype. We have also identified in EC samples the presence of the perivascular population of endometrial mesenchymal stem cells (eMSCs) positive for sushi domain containing 2 (SUSD2) and for NTPDase2, already described in non-tumoral endometrium. Our results point to NTPDase2 as a histopathological marker of tumor invasion in EC, with diagnostic relevance especially in cases of EC coexisting with other endometrial disorders, such as adenomyosis, which occasionally hampers the assessment of tumor invasion parameters.

MRI-based traditional radiomics and computer-vision nomogram for predicting lymphovascular space invasion in endometrial carcinoma

PurposeTo determine the capabilities of MRI-based traditional radiomics and computer-vision (CV) nomogram for predicting lymphovascular space invasion (LVSI) in patients with endometrial carcinoma (EC). Materials and methodsA total of 184 women (mean age, 52.9±9.0 [SD] years; range, 28–82 years) with EC were retrospectively included. Traditional radiomics features and CV features were extracted from preoperative T2-weighted and dynamic contrast-enhanced MR images. Two models (Model 1, the radiomics model; Model 2, adding CV radiomics signature into the Model 1) were built. The performance of the models was evaluated by the area under the curve (AUC) of the receiver operator characteristic (ROC) in the training and test cohorts. A nomogram based on clinicopathological metrics and radiomics signatures was developed. The predictive performance of the nomogram was assessed by AUC of the ROC in the training and test cohorts. ResultsFor predicting LVSI, the AUC values of Model 1 in the training and test cohorts were 0.79 (95% confidence interval [CI]: 0.702–0.889; accuracy: 65.9%; sensitivity: 88.8%; specificity: 57.8%) and 0.75 (95% CI: 0.585–0.914; accuracy: 69.5%; sensitivity: 85.7%; specificity: 62.5%), respectively. The AUC values of Model 2 in the training and test cohorts were 0.93 (95% CI: 0.875–0.991; accuracy: 94.9%; sensitivity: 91.6%; specificity: 96.0%) and 0.81 (95% CI: 0.666–0.962; accuracy: 71.7%; sensitivity: 92.8%; specificity: 62.5%), respectively. The discriminative ability of Model 2 was significantly improved compared to Model 1 (Net Reclassification Improvement [NRI]=0.21; P=0.04). Based on histologic grade, FIGO stage, Rad-score and CV-score, AUC values of the nomogram to predict LVSI in the training and test cohorts were 0.98 (95% CI: 0.955–1; accuracy: 91.6%; sensitivity: 91.6%; specificity: 96.0%) and 0.92 (95% CI: 0.823–1; accuracy: 91.3%; sensitivity: 78.5%; specificity: 96.8%), respectively. ConclusionsMRI-based traditional radiomics and computer-vision nomogram are useful for preoperative risk stratification in patients with EC and may facilitate better clinical decision-making.

Lymphovascular space invasion in endometrial carcinoma: Tumor size and location matter

ObjectiveTo analyze histological factors possibly associated with lymphovascular space invasion (LVSI) and to determine which of those can act as independent surrogate markers. MethodsRetrospective cohort study performed between January 2001 and December 2014. LVSI was defined as the presence of tumor cells inside a space completely surrounded by endothelial cells. Risk factors evaluated included myometrial invasion, tumor grade, size, location, and cervical invasion. Univariate logistical regression models were applied to study any possible association of LVSI with these factors. Values were adjusted by multivariate logistic regression analysis. ResultsA total of 327 patients with endometrial carcinoma treated in our Centre were included. LVSI was observed in 120 patients (36.7%). Lower uterine segment involvement (OR 5.21, 95% CI:2.6–10.4, p < 0.001) and size ≥2 cm (OR 2.62, 95% CI: 1.14–6.1, p < 0.001) were independent factors for LSVI in multivariate analysis. In univariate analysis, LVSI was a surrogate marker in type 1 tumors with deep myometrial invasion (IB, 51.9% vs. IA, 16.0%; p < 0.001), grade 3 (G3 55.8% vs. G1 16.2%; p < 0.001), size ≥2 cm (37.9% vs. 16.1%, p = 0.005), those with involving the lower segment of the uterus (58.9% vs. 22.5%, p < 0.001) and/or with cervical stromal invasion (65.4% vs. 26.1%, p < 0.001), and in type 2 tumors (61.5% vs. 30.5%, p < 0.001). The use of uterine manipulator did not increase the rate of LVSI (35.5% vs. 40.5%, p = 0.612) as compared to no manipulator use. ConclusionsSize ≥2 cm and involvement of the lower uterine segment are independent factors for LSVI, in type 1 tumors, which can be used for surgical planning. LVSI is also more common in type 1 tumors with deep myometrial invasion, grade 3 and/or cervical stromal invasion, and also in type 2 tumors. The use of a uterine manipulator does not increase LVSI.

Assessment of myometrial invasion of endometrial carcinoma with preoperative transvaginal sonography

Objective: Routine pelvic and para-aortic lymphadenectomy up to the level of the renal veins is controversial in endometrial cancer as the complication rate and prolonging the operation time is considerable. Intraoperative frozen section analysis of the uterus is the mainstay for the decision of performing a staging lymphadenectomy. Preoperative estimation of myometrial invasion may be useful for surgical planning. Our objective is to assess the accuracy of preoperative transvaginal ultrasound for identifying myometrial invasion. Methods: 80 consecutive patients operated between August 2017 and December 2019 with a histologically confirmed diagnosis of endometrial carcinoma evaluated within two weeks before surgery by transvaginal ultrasound are the subject of this study. Myometrial invasion estimation is documented and intraoperative frozen section analysis and final pathologic diagnosis as the reference standard was recorded. Results: Preoperative TVUS had 76.5% sensitivity, 91.3% specificity, whereas frozen section analysis had 85.3% sensitivity and 93.5% specificity, and they correlate well with each other (P &lt; 0.01). Agreement between these two methods was substantial according to Cohen’s kappa index (κ) = 0.74 (P &lt; 0.01) and percentage of agreement was 88%. Increasing tumor diameter decreased the prediction accuracy of preoperative ultrasound (P &lt; 0.01). Conclusion: There is good correlation of preoperative transvaginal ultrasound with intraoperative frozen section analysis and final pathology results. The subjective assessment of transvaginal ultrasound can guide surgeons as a useful preoperative tool for preparing surgery

Long Non-Coding RNA SNHG14 Impedes Viability, Migration and Invasion of Endometrial Carcinoma Cells Through Modulating miR-93-5p/ZBTB7A Axis.

BackgroundThe function of long non-coding RNA small nucleolar RNA host gene 14 (SNHG14) in endometrial carcinoma (EC) has not been thoroughly reported. This research is designed to research the action mechanism of SNHG14 in EC development.MethodsThe expression of SNHG14 was estimated in The Cancer Genome Atlas and was verified by qRT-PCR in EC tissues. The correlation between SNHG14 expression and clinicopathological features of EC patients was analyzed. Cell viability, wound healing rate, and relative invasion rate were examined by MTT, wound healing, and transwell assay. StarBase, TargetScan, RNA pull-down, and dual luciferase reporter gene (DLR) assay were conducted to analyze the relationship among SNHG14, miR-93-5p and ZBTB7A.ResultsSNHG14 was underexpressed in EC. SNHG14 expression was significantly relevant to menstruation, FIGO stage, histological grade and lymphatic metastasis of EC patients. SNHG14 overexpression hampered viability, migration and invasion of EC cells. SNHG14 functioned as a sponge for miR-93-5p, and miR-93-5p inhibition restrained cell viability, migration and invasion in EC. In addition, miR-93-5p directly targeted to ZBTB7A, which was underexpressed in EC. The suppressive action of SNHG14 overexpression on the viability, migration and invasion of EC cells was partly rescued by miR-93-5p overexpression or ZBTB7A silencing.ConclusionLncRNA SNHG14 hampered the viability, migration and invasion of EC cells via modulating miR-93-5p/ZBTB7A axis.

High resolution diffusion-weighted imaging with readout segmentation of long variable echo-trains for determining myometrial invasion in endometrial carcinoma

BackgroundWe assessed the image quality of endometrial cancer lesions by readout segmentation of long variable echo-trains (RESOLVE) diffusion-weighted imaging (DWI) compared with that by single-shot echo-planar imaging (SS-EPI) DWI, aimed to explore the value of RESOLVE DWI for determining myometrial invasion and clinical stage in endometrial cancer.Materials and methodsFrom April 2017 to March 2018, a total of 30 endometrial cancer patients (mean age 52.8 ± 9.0 years), who had undergone RESOLVE DWI and SS-EPI DWI, were included in the study. The image quality of endometrial carcinoma by two kinds of DWI scanning methods was compared qualitatively and quantitatively. The Spearman rank correlation test was used to assess the correlation of qualitative image quality scores between two readers. The accuracy of two DWI methods in detecting myometrial invasion and staging of endometrial carcinoma was calculated according to postoperative pathological results. The indexes were analyzed including sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV).ResultsThe qualitative score of RESOLVE DWI group was superior to SS-EPI DWI group in every aspect of five aspects (all P < 0.001). Interobserver agreement of depiction was good or excellent in two DWI sequences. Signal to noise ratio and contrast to noise ratio values in RESOLVE DWI group were both higher than those in SS-EPI DWI group (P<0.001). No statistical difference of apparent diffusion coefficient value was observed between two DWI groups (P = 0.261). The specificity, accuracy, PPV, and NPV of estimating myometrial invasion by RESOLVE DWI in three cases (intramucosal lesion, <50% superficial invasion and ≥ 50% deep invasion) were all higher than those by SS-EPI DWI for endometrial carcinoma. Especially RESOLVE DWI was valuable in judging <50% superficial invasion (95%CI:0.586, 0.970). No significant difference in accuracy staging was between the two DWI groups (P = 0.125).ConclusionRESOLVE DWI can provide higher quality images of endometrial carcinoma than SS-EPI DWI. The high-quality images are helpful for precise assessment of myometrial invasion in endometrial cancer.

Estrogen-Induced Stromal FGF18 Promotes Proliferation and Invasion of Endometrial Carcinoma Cells Through ERK and Akt Signaling.

ObjectiveThe aim of this study was to evaluate whether estrogen promoted the proliferation and invasion of endometrial carcinoma (EC) cells through paracrine FGFs in endometrial stromal cells (ESCs).Patients and MethodsWe screened gene alterations in a primary ESC culture after 10 nM estrogen treatment using an Agilent mRNA microarray. We knocked down stromal FGF18 expression in a co-culture system and aimed to explore the contribution of E2-induced stromal FGF18 to the proliferation and invasion of EC cells. To determine the effective receptors and detailed downstream signaling of FGF18, we co-cultured estrogen-treated hESCs with FGFR1-, FGFR2-, FGFR3- or FGFR4-knockdown Ishikawa cells. Finally, we detected FGF18 expression in clinical samples, including several primary cultures of different ESCs and a series of tissue microarrays (TMAs) of 90 patients with EC.ResultsA few genes altered significantly in estrogen-treated primary ESCs, but only FGF18 was noticeably enhanced among the FGF family genes. Knockdown of FGF18 expression in hESCs inhibited the promoting effect of FGF18 on the proliferation and invasion of EC cells. FGF18 bound FGFR2 and FGFR3 in Ishikawa cells to activate downstream ERK and Akt pathways and to promote the viability of EC cells. The FGF18-FGFR2 and FGF18-FGFR3 pathways had close correlations with Survivin and CD44V6 expression but not with P53. Primary ESCs of endometrioid EC (EEC, type I EC) had higher FGF18 expression than ESCs of normal endometrium (NE), endometrial atypical hyperplasia (EAH) and type II EC.ConclusionEstrogen induced FGF18 in ESCs to promote the proliferation and invasion of EC cells, and FGFR inhibitors should be considered as promising candidate targets for EC treatment.

Ginkgetin Inhibits Growth and Invasion of Endometrial Carcinoma by Disruption of Janus Kinase 1/Signal Transducers and Activators of Transcription 3 and Phosphoinositide-3-Kinase/ Protein Kinase B Pathways

Ginkgetin, a bioflavonoid derived from Ginkgo biloba leaves has been shown to promote tumor cell apoptosis and suppress cell growth in a variety of tumors. This study has examined the role and mechanism of ginkgetin on the tumorigenesis of endometrial carcinoma. Results of the studies show that ginkgetin treatment led to a dose-dependent decrease in cell viability, enhanced expression of cleaved caspase-3 protein, and reduced expression of Bcl-2 protein. In addition, cell migration and invasion of HEC1B and Ishikawa cells were repressed by ginkgetin treatment. Levels of phosphoprotein kinase B, Janus kinase 1, and signal transducers and activators of transcription 3 were decreased in HEC1B and Ishikawa cells by ginkgetin treatment. In conclusion, ginkgetin presents with potential for further investigations into its possible role in management of endometrial carcinoma.

Activating transcription factor 3 inhibits endometrial carcinoma aggressiveness via JunB suppression.

The function of activating transcription factor 3 (ATF3) in cancer is context-dependent and its role in endometrial carcinoma (EC) is yet to be elucidated. In the present study, ATF3 was indicated to be downregulated, while one of the ATF3-interacting proteins, JunB, was upregulated in ECs according to western blot analysis. After overexpression in ECs, ATF3 inhibited the proliferation and invasion of EC cells and enhanced apoptosis, as well as suppressed the expression of JunB. The properties of EC cells, including the expression of matrix metalloproteinases, tissue inhibitors of metallo-proteinases, the cell cycle and apoptosis were all altered by overexpression of ATF3. Furthermore, luciferase activity assay, chromatin precipitation and DNA affinity assay results indicated that ATF3 exerted the aforementioned functions via JunB binding and activator protein-1 signaling. However, the interaction between ATF3 and JunB did not occur in EC cells under basal conditions, but in ATF3-overexpressing ECs, which was capable of mitigating EC proliferation, invasion and metastasis. Collectively, the present results suggested that the ATF3/JunB interaction may serve as a potential therapeutic target for ECs.

LncRNA AFAP1-AS1 contributes to the progression of endometrial carcinoma by regulating miR-545-3p/VEGFA pathway

Endometrial carcinoma (EC) accounts for 20%–30% of female reproductive tumors. Targeted therapy for EC has shown great advantages with small side effects. To improve the survival of EC patients, more new therapeutic targets need to be found. Long non-coding RNAs (lncRNAs) are series of RNAs with over 200 nucleotides that regulate various cellular functions. LncRNA actin filamentin-1 antisense RNA 1 (AFAP1-AS1) is involved in the development of a variety of cancers, such as pancreas ductal adenocarcinoma and esophageal adenocarcinoma. However, it is not clear whether AFAP1-AS1 has any effects on EC or the exact regulatory mechanism. Herein, we found the high expression of AFAP1-AS1 in human EC tissues, and AFAP1-AS1 was correlated with EC patients’ prognosis and clinical features. AFAP-AS1 could affect EC cell proliferation, migration, and invasion, and contributed to endothelial cell angiogenesis. We further showed that AFAP-AS1 could promote the expression of VEGFA through the adsorption of miR-545-3p, thus promoting the angiogenesis and invasion of EC, and contribute to tumor growth and metastasis in vivo. Thus, we thought AFAP1-AS1 had the potential to serve as an EC therapeutic target.

RETRACTED: LncRNA PCAT1 promotes metastasis of endometrial carcinoma through epigenetical downregulation of E-cadherin associated with methyltransferase EZH2

More than 140 thousands of women suffer from endometrial carcinoma in the worldwide, and over 40 thousand of the patients die before and after in surgery and chemoradiotherapy because of its metastasis. However, its molecular mechanism is much less known compared to other cancers. In this study, we demonstrated that long non-coding RNA PCAT1 is dramatically increased in the tissues and plasma from endometrial carcinoma (EC) (n = 100, all p < 0.001) controlled by its paracancerous tissue, and cell lines including RL-952, HEC-1-B, KLE, Ishikawa, and AN3CA compared to the cells from normal endometrium (all p < 0.001). When lncRNA PCAT1 was knocked-down, the KLE and AN3CA cells exhibited slow capability on proliferation and colony formation in vitro. With the silence of lncRNA PCAT1, the cells were markedly inhibited on migration and invasion in vitro (all p < 0.001), which were confirmed on the EC patient subjects. When expressions of lncRNA PCAT1 were interfered in the cells, expressions of E-cadherin but not N-cadherin and Vimentin were significantly promoted with a strong up-regulation accompanied by nearly completed recoveries on migration and invasion (all p < 0.001). In order to analyze the association of lncRNA PCAT1 and E-cadherin, we silenced the expressions of both genes and unveiled that EC migration and invasion were significantly congested (all p < 0.001). Importantly, we found that the E-cadherin down-regulation caused by lncRNA PCAT1 associates with histone methyltransferase EZH2. When over-expression of EZH2 was applied in the PCAT1 silenced cells, the expression of E-cadherin experienced significant decrease in the cell lines. Reversely, when expression of EZH2 was annulled in the PCAT1 silenced cells, the expression of E-cadherin was significantly boosted in the cells (all p < 0.001). Furthermore, the interaction of lncRNA PCAT1 and EZH2 were approved with immunoprecipitation. Our data demonstrated that the methyltransferase EZH2 related up-regulation of lncRNA PCAT1 along with down-regulation of E-cadherin could be essential in oncogenesis of endometrial carcinoma in both EC cells and patient subjects. These compact data suggest that combination of lncRNA PCAT1, EZH2 and E-cadherin could provide valued information for efficient EC diagnostics, which would propose a potential target for EC treatment with EZH2i on methyltransferation.

Risk of postmenopausal hormone therapy and patient history factors for the survival rate in women with endometrial carcinoma.

Postmenopausal hormone therapy (HT) is known to affect the development of hormone-dependent endometrial carcinoma (type I EC). Several studies on breast and ovarian carcinoma have shown that HT influences the molecular profile and prognostic behavior of these tumors. This study aimed to investigate the influence of prior HT and other risk factors on the prognosis in a cohort of patients with invasive endometrial carcinoma (EC). Among 525 patients diagnosed with EC between 1987 and 2010, 426 postmenopausal patients were identified. Information regarding HT was available in 287 of these patients, 78 of whom had a history of HT and 209 of whom did not. Both overall survival (OS) and progression-free survival (PFS) were analyzed. In addition to OS and PFS, risk factors such as age at diagnosis, postmenopausal HT, body mass index (BMI), diabetes mellitus, tumor stage, EC type (I or II), and recurrences were analyzed. Relative to HT alone, women with EC and a history of HT had a longer survival than those with no HT. However, the Cox proportional hazards model showed that it was not HT itself, but rather other characteristics in the HT group that were causally associated with longer survival. Age (the older, the worse) and tumor stage (the higher, the worse) were significant influences on overall survival. Patients with HT also had lower BMIs, less diabetes, more type I EC, and fewer recurrences in comparison with the non-HT group. With regard to the PFS, it made no difference whether the patient was receiving HT.

γ-Glutamyl cyclotransferase contributes to endometrial carcinoma malignant progression and upregulation of PD-L1 expression during activation of epithelial-mesenchymal transition

Recent increases in the incidence of endometrial carcinoma represent a significant risk to women’s health. We found that γ-glutamyl cyclotransferase (GGCT) was significantly up-regulated in endometrial carcinoma tissues and cells, which suggested that it may be a potential target for treatment of endometrial carcinoma. Furthermore, the impact of GGCT on proliferation, migration, and invasion of endometrial carcinoma has been demonstrated in vitro and in vivo using GGCT silencing and overexpression techniques. In addition, the epithelial-mesenchymal transition (EMT) was significantly inhibited in response to GGCT knockdown, which indicated that GGCT may contribute endometrial carcinoma malignancy during activation of the EMT. We also found that GGCT regulated PD-L1 expression during EMT activation. Furthermore, co-culture of endometrial carcinoma cells with CD8+ T lymphocytes showed that downregulation of PD-L1 expression following GGCT knockdown contributed to the killing activity of CD8+ T lymphocytes on endometrial carcinoma cells. In conclusion, our study showed that GGCT contributed to malignant progression and upregulation of PD-L1 expression of endometrial carcinoma, and may be a potential target for treatment of endometrial carcinoma.

MicroRNA-202 inhibits cell migration and invasion through targeting FGF2 and inactivating Wnt/β-catenin signaling in endometrial carcinoma.

Recently, many mircroRNAs (miRNAs) involved in the development and progression of cancer have been reported to regulate cell growth and metastasis, including microRNA-202 (miR-202). The purpose of the present study was to elucidate the effect of miR-202 on endometrial carcinoma (EC) cell migration and invasion. First, qRT-PCR showed that miR-202 was down-regulated in EC tissues, which was associated with poor prognosis in EC patients. Functionally, transwell assay indicated that miR-202 inhibited cell migration and invasion in EC cells. In addition, miR-202 also blocked epithelial–mesenchymal transition (EMT) through suppressing N-cadherin and Vimentin expressions and promoting E-cadherin expression. Moreover, the dual-luciferase reporter assay showed that fibroblast growth factor 2 (FGF2) is a direct target gene for miR-202 in EC cells. Furthermore, up-regulation of FGF2 attenuated the inhibitory effect of miR-202 on cell migration and invasion in EC. Besides that, miR-202 inactivated the Wnt/β-catenin signaling by suppressing β-catenin expression in EC. In conclusion, miR-202 inhibited cell migration and invasion by targeting FGF2 and inactivating the Wnt/β-catenin signaling in EC.

Targeting Thyroid Receptor Interacting Protein 6 by MicroRNA-589-5p Inhibits Cell Proliferation, Migration, and Invasion in Endometrial Carcinoma.

Background: MicroRNA-589-5p (miR-589-5p) has been recently reported to be aberrantly regulated in hepatocellular carcinoma, but its functional role and molecular mechanisms still remains unknown in the endometrial carcinoma (EC) as one of the most common female malignancies. Methods: EC tissues and adjacent tissues were collected to determine the expression of miR-589-5p and thyroid receptor interacting protein 6 (TRIP6) using quantitative real time-PCR. Subsequently, two EC cell lines HEC-1B and AN3CA were transfected with miR-589-5p to achieve miR-589-5p overexpression. Using Cell Counting Kit-8 (CCK-8), a wound healing assay and the Transwell assay, we analyzed cell proliferation, migration and invasion. Dual-luciferase reporter assay confirmed that thyroid receptor interacting protein 6 (TRIP6) was a direct target of miR-589-5p. Results: We first observed that miR-589-5p was down-regulated in EC tissues compared with normal endometrial tissues. MiR-589-5p overexpression significantly suppressed EC cell proliferation, migration and invasion. Thyroid receptor interacting protein 6 (TRIP6) was a direct target of miR-589-5p. Besides, TRIP6 knockdown presented similar effects on cell proliferation, migration and invasion to miR-589-5p overexpression. Furthermore, TRIP6 knockdown efficiently enhanced the effects of miR-589-5p on the above cellular function. Moreover, miR-589-5p up-regulated E-cadherin expression, but down-regulated N-cadherin and Vimentin by targeting TRIP6. Conclusions: In summary, miR-589-5p might function as a tumor suppressor by targeting TRIP6, which will provide new insights into the molecular mechanism underlying the development of EC.

Expression of TRA2B in endometrial carcinoma and its regulatory roles in endometrial carcinoma cells.

Expression levels of Transformer 2 protein homolog beta (TRA2B) in patients with endometrial carcinoma were assessed to investigate the impact of TRA2B on endometrial carcinoma cells. Furthermore, we analyzed the expression of several genes in the tissue samples from patients with endometrial cancer (EC) to identify whether cancer related genes we chose are differently expressed between the endometrial carcinoma tissues and adjacent normal tissues. The results of RT-qPCR analysis, western blot technology and immunofluorescence method consistently manifested that the expression of several genes in endometrial carcinoma tissue was significantly dysregulated between the two groups. Among the dysregulated genes, the strongly upregulated TRA2B in the tissues and serum from patients with EC was selected for further analysis. Endometrial carcinoma cells were transfected with chemically synthesized TRA2B plasmid, siRNA-TRA2B and their corresponding negative control respectively to assess the effects of TRA2B on the EC cells. Overexpression of TRA2B increased both the cell viability and proliferation potency of EC cells. Whereas, the viability and the proliferation ability of EC cells were strongly decreased by siRNA-TRA2B treatment. Furthermore, the invasion of EC cells was promoted by transfection of TRA2B and overexpression of TRA2B decreased the apoptosis of EC cells. Moreover, siRNA-TRA2B transfection inhibited the invasion but accelerated apoptosis of EC cells. Our results demonstrated that TRA2B is closely related to the development of endometrial carcinoma, and inhibition of TRA2B can decrease viability, proliferation and invasion of endometrial carcinoma, suggesting TRA2B is associated with the pathogenesis of human EC. Knockdown of TRA2B may be used for treatment of endometrial carcinoma, furthermore, these findings suggest an experimental foundation to clinical prognostic role of TRA2B in patients with endometrial carcinoma.

Abstract 4205: Pan-cancer molecular study of disparities among African Americans

Abstract Objective: Several factors have been proposed to contribute to racial disparities in gynecologic cancers, however there are no comprehensive studies that have investigated inherent molecular features that may be racially unique. Our objective was to perform a pan-cancer clinical and molecular analysis of African-Americans (AA) and European American (EA) patients. Methods: We performed cross-platform analyses utilizing cancer registry and molecular databases [Surveillance, Epidemiology and End Results (SEER) and The Cancer Genome Atlas (TCGA)] to evaluate differences in AA vs EA patients. To characterize genetic ancestry we utilized the recently established The Cancer Genetic Ancestry Atlas (TCGAA). We further evaluated epigenetic modifications through non-coding RNA expression in these tumors. Results: A total of 2,045,500 patients (87.5% EA, 12.5% AA) with 64 primary tumor types were evaluated using SEER to evaluate clinical outcome differences. Compared to white race, AA race had higher rate of death in 45 cancer types (HR&amp;gt;1.0, CI 1.00-5.23). 19 cancer types were then identified to have the largest differences in overall survival (HR&amp;gt;1.2). Utilizing TCGA, we analyzed molecular data of 7028 tumors (88.9% EA, 10.9% AA) having miRSeq data and genetic ancestry data. We identified differentially expressed miRNA’s in five cancer types: breast invasive (300 miRs, p&amp;lt;0.068, FDR&amp;lt;0.1), renal cell (408 miRs, p&amp;lt;0.205, FDR&amp;lt;0.1), prostate (102 miRs, p&amp;lt;2.68e-01, FDR&amp;lt;0.1), thyroid (63 miRs, p&amp;lt;1.28e-.02, FDR&amp;lt;0.1), and uterine corpus endometrial (177 miRs, p&amp;lt;8.18e-02, FDR&amp;lt;0.1) carcinomas. Differentially expressed miRs among all cancer types were associated with canonical pathways of cancer drug resistance by drug efflux, altered T- cell function, and regulation of epithelial-mesenchymal transition using Ingenuity Pathway Analysis (IPA) software. We identified miR-130, miR-180, miR-146, and miR-8 as commonly dysregulated miRs in these cancer types which may represent a molecular signature unique to African Americans. Conclusions: Our results identify molecular and genetic features unique to African Americans that may contribute to worse survival outcomes. While the cause of cancer disparities is multifactorial, a focus on molecular signatures unique to AA may identify actionable molecular abnormalities. Note: This abstract was not presented at the meeting. Citation Format: Olivia D. Lara, Ying Wang, Wei Hu, Lin Zhang, Alejandro Rauh-Hain, Anil Sood. Pan-cancer molecular study of disparities among African Americans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4205.

CTHRC1 promotes M2-like macrophage recruitment and myometrial invasion in endometrial carcinoma by integrin-Akt signaling pathway.

The infiltration of tumor-associated macrophages (TAMs) is associated with tumor progression and poor prognosis in endometrial cancer (EC). Collagen triple helix repeat containing 1 (CTHRC1), a secreted ECM protein, has been reported to have important roles in promoting cancer invasion and metastasis, but the functional role of CTHRC1 and its association with TAMs in EC remain unclear. Here we report that, in EC patients, CTHRC1 expression was up-regulated in endometrial cancer tissues compared with normal endometrium (P < 0.0001), and is positively correlated with tumor grade and depth of myometrial invasion (P = 0.024 and P = 0.0002, respectively). Meanwhile, CTHRC1 expression was positively correlated with an increased number of infiltrating TAMs, especially M2-like TAMs (P = 0.003, P = 0.001). In the tumor microenvironment of EC, CTHRC1 not only promoted myometrial invasion by interacting with Integrin β3-Akt signaling pathway, but also promoted infiltration of M2-like TAMs by upregulating Fractalkine chemokine receptor (CX3CR1) expression in macrophages. Changing levels of recombinant CTHRC1 protein (rCTHRC1) promoted tumor migration and invasion via enhancing macrophage recruitment in vitro. In summary, our findings eventually provided a novel role for CTHRC1 in remodeling the tumor immune microenvironment to promote tumor metastasis in EC patients.

Microcystic, elongated and fragmented invasion pattern in endometrial carcinoma: the clinicopathology analysis

Objective: To assess the clinical value for the clinicopathological features of microcystic elongated and fragmented (MELF) invasion in endometrial carcinoma (EEC) . Methods: The clinicopathological data of 108 cases of endometrial carcinoma with total hysterectomy, bilateral adnexectomy, and pelvic dissection were retrospectively analysis in Peking University People's Hospital from April 2015 to October 2016. Twenty-five patients with endometrial carcinoma showing MELF invasion pattern were collected. We analyzed retrospectively the association of MELF pattern invasion with clinical pathology data and prognosis of the patients, partial immunohistochemical staining was implemented. MELF invasion was a special invasion pattern and characterized by microcystic, elongated, fragmented (composed of cluster cells) gland in muscular layer. Results: The incidence rate was 23.1% (25/108). These patients mean age was (59.3±10.9) years old. Four cases were premenopausal, and 21 were postmenopausal. Abnormal vaginal bleeding was the main clinical presentation. The lesions tend to appear adjacent to the tumor body. Sometimes, it may be appears away from the tumor body in the deep muscle layer.Lymph node metastasis were present in 5 cases (20%, 5/25). Thirteen cases (52%, 13/25) of them demonstrated lymph vascular space involvement (LVSI). The immunohischemical expression of ER,PR, Ki-67 and galectin-3 showing MELF invasion pattern were weaker than no showing MELF invasion pattern endometrial carcinoma, cktokeratin (CK) was showed diffuse strong positive expression, E-cadherin was moderately positive expression. All 25 cases were followed up for (23.2±5.9) months (14-33 months) after the therapy with no recurrence on metastasis. Conclusions: MELF invasion pattern is a special invasion pattern in low-grade EEC. The incidence of LVSI and lymph node metastasis rate in endometrial carcinoma with MELF invasion are significantly increased. The prognosis of MELF invasion pattern may be poor.

MiR‑107‑5p promotes tumor proliferation and invasion by targeting estrogen receptor‑α in endometrial carcinoma.

The aberrant expression of miR107-5p is closely related to the development of several types of human cancers. However, the role of miR-107-5p in endometrial carcinoma (EC) has not been fully confirmed. In the present study, we aimed to explore the function of miR-107-5p in EC carcinogenesis. EC samples and normal endometrial tissues were obtained by laser capture microdissection. It was determined that the expression of miR-107-5p in EC was significantly higher than that in normal endometrium, and higher miR-107-5p expression was related to advanced FIGO stages, lymph node metastasis and myometrial invasion in EC patients. Blocking miR-107-5p significantly inhibited cell proliferation, migration and invasion of EC cells in vitro and in vivo. The results of bioinformatic algorithms and luciferase reporter assays revealed that estrogen receptor α (ERα) was a direct target of miR-107-5p. miR-107-5p downregulated the expression of ERα mRNA and protein. In conclusion, our results highlighted that miR-107-5p is a novel prognostic factor that targets ERα to promote tumor proliferation and invasion of EC.