Aggressive Endometrial Cancer Cells Research Articles

MicroRNA-365 Targets Multiple Oncogenes to Inhibit Proliferation, Invasion, and Self-Renewal of Aggressive Endometrial Cancer Cells [Retraction

[This retracts the article DOI: 10.2147/CMAR.S174889.].

PD-L1 Is a Tumor Suppressor in Aggressive Endometrial Cancer Cells and Its Expression Is Regulated by miR-216a and lncRNA MEG3.

BackgroundPoorly differentiated endometrioid adenocarcinoma and serous adenocarcinoma represent an aggressive subtype of endometrial cancer (EC). Programmed death-ligand-1 (PD-L1) was known to exhibit a tumor cell-intrinsic function in mediating immune-independent tumor progression. However, the functional relevance of tumor cell-intrinsic PD-L1 expression in aggressive EC cells and the mechanisms regulating its expression remain unknown.MethodsPD-L1 expression in 65 EC tissues and 18 normal endometrium samples was analyzed using immunohistochemical staining. The effects of PD-L1 on aggressive EC cell growth, migration and invasion were investigated by cell functional assays. Luciferase reporter assays were used to reveal the microRNA-216a (miR-216a)-dependent mechanism modulating the expression of PD-L1.ResultsPositive PD-L1 expression was identified in 84% of benign cases but only in 12% of the EC samples, and the staining levels of PD-L1 in EC tissues were significantly lower than those in the normal tissues. Higher PD-L1 expression predicts favorable survival in EC. Ectopic expression of PD-L1 in aggressive EC cells results in decreased cell proliferation and the loss of mesenchymal phenotypes. Mechanistically, PD-L1 exerts the anti-tumor effects by downregulating MCL-1 expression. We found that PD-L1 levels in aggressive EC cells are regulated by miR-216a, which directly targets PD-L1. We further identified a mechanism whereby the long non-coding RNA MEG3 represses the expression of miR-216a, thereby leading to increased PD-L1 expression and significant inhibition of cell migration and invasion.ConclusionThese results reveal an unappreciated tumor cell-intrinsic role for PD-L1 as a tumor suppressor in aggressive EC cells, and identify MEG3 and miR-216a as upstream regulators of PD-L1.

142 MicroRNA-101 targets EZH2, MCL-1 and FOS to suppress proliferation, invasion and stem cell-like phenotype of aggressive endometrial cancer cells

142 MicroRNA-101 targets EZH2, MCL-1 and FOS to suppress proliferation, invasion and stem cell-like phenotype of aggressive endometrial cancer cells

MicroRNA-101 targets EZH2, MCL-1 and FOS to suppress proliferation, invasion and stem cell-like phenotype of aggressive endometrial cancer cells.

MicroRNA-101 has been implicated as a tumor suppressor miRNA in human tumors. However, its potential functional impact and the underlying mechanisms in endometrial cancer progression have not been determined. Here, we report that in aggressive endometrial cancer cells, re-expression of microRNA-101 leads to inhibition of cell proliferation and induction of apoptosis and senescence. Ectopic overexpression of microRNA-101 attenuates the epithelial-mesenchymal transition-associated cancer cell migration and invasion, abrogates the sphere-forming capacity and enhances chemosensitivity to paclitaxel. Algorithm and microarray-based strategies identifies potential microRNA-101 targets. Among these, we validated EZH2, MCL-1 and FOS as direct targets of miR-101 and silencing of these genes mimics the tumor suppressive effects observed on promoting microRNA-101 function. Importantly, further results suggest an inverse correlation between low miR-101 and high EZH2, MCL-1 and FOS expression in EC specimens. We conclude that, as a crucial tumor suppressor, microRNA-101 suppresses cell proliferation, invasiveness and self-renewal in aggressive endometrial cancer cells via modulating multiple critical oncogenes. The microRNA-101-EZH2/MCL-1/FOS axis is a potential therapeutic target for endometrial cancer.

Abstract 137: MicroRNA-200c restores anoikis sensitivity in breast and gynecological cancers

Abstract Background: MicroRNA-200c directly targets ZEB1, an epithelial to mesenchymal (EMT)-inducing transcriptional repressor of E-cadherin and other key determinates of epithelial identity and polarity. Therefore, restoration of miR-200c results in repression of ZEB1, dramatic reduction in migration and invasion, and increased sensitivity to microtubule targeting chemotherapeutics. We hypothesized that in addition to ZEB1, miR-200c targets additional genes that contribute to its myriad effects on maintaining the epithelial phenotype by repressing mesenchymal genes. Results: We performed microarray analysis following restoration of miR-200c to aggressive endometrial cancer cells and identified 18 genes that were both significantly repressed and predicted to be direct targets of miR-200c. These genes, including fibronectin 1 (FN1), class III beta-tubulin (TUBB3), neurotrophic tyrosine receptor kinase type 2 (NTRK2 or TrkB), leptin receptor (LEPR), moesin (MSN1) and Rho GTPase activating protein 19 (ARHGAP19), are all typically expressed only in non-epithelial cells, such as fibroblasts or neurons. Utilizing luciferase reporter assays and mutational analysis, we validate each of these genes as direct targets of miR-200c. We also demonstrate that restoration of miR-200c leads to a dramatic decrease in mRNA and protein levels of these targets. Further we find that restoration of miR-200c restores anoikis sensitivity to suspended cells, leading to over a 1.5 fold increase in cell death. TrkB is a potent suppressor of anoikis in breast and ovarian cancer models. Addition of TrkB lacking the miR-200c binding site reversed the ability of miR-200c to suppress anoikis. Interestingly, neurotrophin 3 (NTF3), a ligand for TrkB, contains 2 putative miR-200c binding sites and is down regulated upon restoration of miR-200c. Thus, loss of miR-200c in carcinoma cells allows inappropriate translation of both TrkB and NTF3, setting up an autocrine loop that results in anoikis resistance. Conclusions: Our data demonstrate that miR-200c serves as a “guardian of the epithelial phenotype” and suppressor of EMT by directly targeting and repressing a program of genes that should not be on in differentiated epithelial cells. We identify a novel function of miR-200c, the ability to suppress anoikis resistance, an important yet understudied step in the metastatic cascade. Funding source: DOD Breast Cancer Program Idea Award BC084162 to JKR Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 137. doi:10.1158/1538-7445.AM2011-137