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Myeloid derived suppressor cells enhance stemness of cancer cells by inducing miRNA101 and suppressing the corepressor CtBP2

ABSTRACT: The work identifies an immune associated cellular, molecular and clinical network involving MDSCs-microRNA101-CtBP2-stem cell core genes, which extrinsically controls cancer stemness and impacts patient outcome.

ORGANISM(S): Homo sapiens

PROVIDER: GSE50082 | GEO | 2013/08/23

SECONDARY ACCESSION(S): PRJNA216919

REPOSITORIES: GEO

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Myeloid derived suppressor cells enhance stemness of cancer cells by inducing miRNA101 and suppressing the corepressor CtBP2

Project description:The work identifies an immune associated cellular, molecular and clinical network involving MDSCs-microRNA101-CtBP2-stem cell core genes, which extrinsically controls cancer stemness and impacts patient outcome. Primary ovarian cancer cells (5 x105) were co-cultured with freshly sorted ovarian cancer associated-MDSCs, peripheral blood lin-CD45+CD33+ cells (5 x105) or medium in a transwell (Corning) for 24 hours. Then, RNA was extracted from the cancer cells by Trizol reagent. The RNAs were applied for microRNA profiling using OpenArray system (Applied Biosystems, Cat# 4470187) (Mestdagh et al., 2008) at University of Michigan Sequencing Core

2013-08-23 | E-GEOD-50082 | biostudies-arrayexpress

Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2.

Project description:Myeloid-derived suppressor cells (MDSCs) and cancer stem cells (CSCs) are important cellular components in the cancer microenvironment and may affect cancer phenotype and patient outcome. The nature of MDSCs and their interaction with CSCs in ovarian carcinoma are unclear. We examined the interaction between MDSCs and CSCs in patients with ovarian carcinoma and showed that MDSCs inhibited T cell activation and enhanced CSC gene expression, sphere formation, and cancer metastasis. MDSCs triggered miRNA101 expression in cancer cells. miRNA101 subsequently repressesed the corepressor gene C-terminal binding protein-2 (CtBP2), and CtBP2 directly targeted stem cell core genes resulting in increased cancer cell stemness and increasing metastatic and tumorigenic potential. Increased MDSC density and tumor microRNA101 expression predict poor survival, as does decreased tumor CtBP2 expression, independent of each other. Collectively, our work identifies an immune-associated cellular, molecular, and clinical network involving MDSCs-microRNA101-CtBP2-stem cell core genes, which extrinsically controls cancer stemness and impacts patient outcome.

| S-EPMC3831370 | biostudies-literature

Myeloid-derived suppressor cells promote epithelial ovarian cancer cell stemness by inducing the CSF2/p-STAT3 signalling pathway

Project description:Myeloid-derived suppressor cells (MDSCs) are known to contribute to tumour immune escape, studies have verified that MDSCs can induce cancer stem cells (CSCs) and promote tumour immune evasion in breast cancers, cervical cancers and glioblastoma. However, the potential function of MDSCs in regulating CSCs in epithelial ovarian cancer (EOC) progression is unknown. Our results indicated that compared to nonmalignant ovarian patients, EOC patients showed a significantly increased proportion of MDSCs in the peripheral blood. In addition, MDSCs dramatically promoted tumour sphere formation, cell colony formation and CSC accumulation, and MDSCs enhanced the expression of the stemness biomarkers NANOG and c-MYC in EOC cells during co-culture. Moreover, the mechanisms by which MDSCs enhance EOC stemness were further explored, and 586 differentially expressed genes were found in EOC cells co-cultured with or without MDSCs; during co-culture, the expression level of colony stimulating factor 2 (CSF2) was significantly increased in EOC cells co-cultured with MDSCs. Furthermore, the depletion of CSF2 in EOC cells was successfully performed, the promotive effects of MDSCs on EOC cell stemness could be markedly reversed by downregulating CSF2 expression, p-STAT3 signalling pathway molecules were also altered, and the p-STAT3 inhibitor could markedly reverse the promotive effects of MDSCs on EOC cell stemness. In addition, the CSF2 expression level was correlated with EOC clinical staging. Therefore, MDSCs enhance the stemness of epithelial ovarian cancer cells by inducing the CSF2/p-STAT3 signalling pathway. Targeting MDSCs or CSF2 may be a reasonable strategy for enhancing the efficacy of conventional treatments.

2020-12-31 | GSE145374 | GEO

C-terminal binding protein (CTBP2) is a novel tumor suppressor targeting the MYC-IRF4 axis in multiple myeloma

Project description:Multiple myeloma (MM) cells are addicted to MYC and its direct transactivation target IRF4 for proliferation and survival. MYC and IRF4 are still considered “undruggable” as the majority of small molecule inhibitors suffers from low potency, suboptimal pharmacokinetic properties and undesirable off-target effects. Indirect inhibition of MYC/IRF4 emerges as a therapeutic vulnerability in MM. Here, we uncover an unappreciated tumor suppressive role of C-terminal Binding Protein 2 (CTBP2) in MM via strong inhibition of the MYC-IRF4 axis. In contrast to epithelial cancers, CTBP2 is frequently downregulated in MM, in association with shortened survival, hyperproliferative features and adverse clinical outcomes. Restoration of CTBP2 exhibited potent anti-tumor effects against MM in vitro and in vivo, with marked repression of MYC-IRF4 network genes. Mechanistically, CTBP2 impeded transcription of MYC and IRF4 by histone H3 lysine 27 deacetylation (H3K27ac), and indirectly via activation of MYC repressor IFIT3. In addition, activation of interferon gene signature by CTBP2 suggested its concomitant immunomodulatory role in MM. Epigenetic studies revealed contribution of polycomb-mediated silencing and DNA methylation to CTBP2 inactivation in MM. Notably, inhibitors of Enhance of zeste homolog 2 (EZH2), histone deacetylase (HDACs) and DNA methyltransferase (DNMTs) currently under evaluation in clinical trials were effective in restoring CTBP2 expression in MM. Our findings indicated that loss of CTBP2 plays an essential role in myelomagenesis and decipher an additional mechanistic link on MYC-IRF4 dysregulation in MM. We envision that identification of novel critical regulators would facilitate the development of selective and effective approaches for treating this MYC/IRF4-addicted malignancy.

2024-03-10 | GSE255266 | GEO

Liver transcriptome regulated by CtBP2

Project description:adenovirus mediated overexpression of wild-type CtBP2 and Rossmann fold mutant CtBP2 along with control GUS in dietary induced obese mice

2021-09-27 | GSE128145 | GEO

CtBP2 ChIP-seq normal mouse liver

Project description:CtBP2 recruitment on genome in normal mouse liver

2021-09-27 | GSE127660 | GEO

Genome wide expression analysis of Ctbp2 knock down mouse F9 cells

Project description:Using an RNA interference-based genetic screen in mouse F9 cells we identify the transcriptional corepressor CTBP2 as a coactivator critically required for retinoic acid (RA)-induced transcription. Here we perfom a whole genome transcriptome analysis in F9 cells expressing shRNA for Ctbp2 and Rxr in the absence or presence of retinoic acid (RA). A total of 2,754 genes were found to be upregulated (>2 fold) and 1518 genes were downregulated (>2 fold) in response to RA treatment in the control cells. We find that around 52% and 55% of upregulated genes are dependent on Ctbp2 and Rxr for activation respectively suggesting that Ctbp2 is a coactivator of RA signaling. Whole genome RNA-sequencing in F9 cells expressing shGFP or shCtbp2 or shRxr

2013-06-21 | E-GEOD-47708 | biostudies-arrayexpress

Genome-wide analysis upon ZBTB18 expression and/or CTBP2 silencing in Glioblastoma

Project description:We have identified the CTBP2 protein as a new ZBTB18 interactor. Here we have evaluated transcriptomic changes upon CTBP2 knockdown in the GBM cell line SNB19. Moreover, we have analyzed whether CTBP2 is required for ZBTB18-mediated gene repression.

2019-12-01 | GSE138890 | GEO

MIN6 beta cell CtBP2 ChIP-seq

Project description:CtBP2 ChIP-seq analysis was performed in a murine pancreatic beta cell line MIN6.

2023-08-08 | GSE221257 | GEO

Genome wide expression analysis of Ctbp2 knock down mouse F9 cells

2013-06-21 | GSE47708 | GEO