Biological significance of EZH2 in uterine cancer
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ABSTRACT:
PROVIDER: PRJNA473513 | ENA |
REPOSITORIES: ENA
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Project description:Change of gene expression profile by EZH2 silencing EZH2 is overexpressed in a number of malignancies, and is an attractive target for cancer treatment. The overexpression of EZH2 was significantly associated with disease free survival and overall survival of patients with ovarian cancer. EZH2 silencing resulted in decreased cell viability and invasion ability, and increased apoptosis. EZH2 silencing significantly enhanced cytotoxicity of paclitaxel, docetaxel and cisplatin in Hec-1A and Ishikawa cells. EZH2 silencing using siRNA incorporated into chitosan nanoparticles (siRNA/CH) resulted in significant inhibition of tumor growth compared to control siRNA/CH. Moreover, EZH2 siRNA/CH in combination with taxanes showed robust anti-tumor effects compared to monotherapy groups. These effects were associated with decreased tumor cell proliferation and angiogenesis, and increased tumor cell apoptosis. Genomic analyses revealed that EZH2 gene silencing resulted in decreased expression of many genes associated with tumor growth.
2019-05-01 | GSE115010 | GEO
Project description:Platelet-derived growth factor receptor alpha (PDGFRα) expression is frequently observed in many kinds of cancer and is a candidate for therapeutic targeting. Here, we evaluated the biological significance of PDGFRα and PDGFRα blockade (using a fully humanized monoclonal antibody, 3G3) in uterine cancer. PDGFRα was expressed in uterine cancer cells, and its blockade with 3G3 resulted in inhibition of PDGFRα phosphorylation and of downstream signaling molecules, AKT and MAPK. Cell viability and invasive potential of uterine cancer cells were also inhibited by treatment of 3G3. Moreover, greater therapeutic effects were observed for 3G3 in combination with chemotherapy than for either drug alone in orthotopic mouse models of uterine cancer. These findings identify PDGFRα as an attractive therapeutic target for uterine cancer.
2014-06-04 | GSE55483 | GEO
Project description:Platelet-derived growth factor receptor alpha (PDGFRα) expression is frequently observed in many kinds of cancer and is a candidate for therapeutic targeting. Here, we evaluated the biological significance of PDGFRα and PDGFRα blockade (using a fully humanized monoclonal antibody, 3G3) in uterine cancer. PDGFRα was expressed in uterine cancer cells, and its blockade with 3G3 resulted in inhibition of PDGFRα phosphorylation and of downstream signaling molecules, AKT and MAPK. Cell viability and invasive potential of uterine cancer cells were also inhibited by treatment of 3G3. Moreover, greater therapeutic effects were observed for 3G3 in combination with chemotherapy than for either drug alone in orthotopic mouse models of uterine cancer. These findings identify PDGFRα as an attractive therapeutic target for uterine cancer. Two groups of samples are included: 1.Hec-1A 2.Rl-95-2. Gene expression profiles of Hec-1A cells were compared to that of RL95-2 cells.
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Project description:Histone proteins undergo various modifications that alter chromatin structure, including addition of methyl groups. Enhancer of homolog 2 (EZH2), is a histone methyltransferase that methylates lysine residue 27, and thereby, suppresses gene expression. EZH2 plays integral role in the uterus and other reproductive organs. We have previously shown that conditional deletion of uterine EZH2 results in increased proliferation of luminal and glandular epithelial cells, and RNAseq analyses reveal several uterine transcriptomic changes in Ezh2 conditional (c) knockout (KO) mice that can affect estrogen signaling pathways. To pinpoint the origin of such gene expression changes, we used the recently developed spatial transcriptomics (ST) method with the hypotheses that Ezh2cKO mice would predominantly demonstrate changes in epithelial cells and/or ablation of this gene would disrupt normal epithelial/stromal gene expression patterns. Uteri were collected from ovariectomized adult WT and Ezh2cKO mice and analyzed by ST. Asb4, Cxcl14, Dio2, and Igfbp5 were increased, Sult1d1, Mt3, and Lcn2 were reduced in Ezh2cKO uterine epithelium vs. WT epithelium. For Ezh2cKO uterine stroma, differentially expressed key hub genes included Cald1, Fbln1, Myh11, Acta2, and Tagln. Conditional loss of uterine Ezh2 also appears to shift the balance of gene expression profiles in epithelial vs. stromal tissue toward uterine epithelial cell and gland development and proliferation, consistent with uterine gland hyperplasia in these mice. Current findings provide further insight into how EZH2 may selectively affect uterine epithelial and stromal compartments. Additionally, these transcriptome data might provide the mechanistic understanding and valuable biomarkers for human endometrial disorders with epigenetic underpinnings.
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Project description:Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. We have shown that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. Here, we explore the interactome of EZH2 and of a phosphodeficient mutant EZH2_T367A. We identified novel interactors of EZH2, and identified interactions that are dependent on the phosphorylation and cellular localization of EZH2 that may play a role in EZH2 dependent metastatic progression.
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Project description:To determine the mesenchymal function of EZH2 in the mouse uterus, we generated Ezh2 cKO mice using anti-Mullerian hormone type 2 (Amhr2)-Cre that is expressed in the mesenchymal and not epithelial compartment of the uterus
2022-12-28 | GSE201973 | GEO