Reactivation of Tumor Suppressor in Breast Cancer by Enhancer Switching through NamiRNA Network
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE174002 | GEO | 2021/09/14
REPOSITORIES: GEO
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Project description:Reactivation of Tumor Suppressor in Breast Cancer by Enhancer Switching through NamiRNA Network
| PRJNA727844 | ENA
Project description:Chromatin plasticity can be exploited therapeutically for the selective manipulation of the epigenetic state, to ultimately restore transcriptional aberrations driving tumorigenesis. Abnormal epigenetic silencing of tumor suppressors genes (TSGs) is one of the carcinogenesis features in hepatocellular carcinoma (HCC). We computationally identified a panel of 12 putative TSGs exhibiting an anti-correlation between transcript abundance and promoter DNA methylation, while harbouring no genetic alterations. Silencing of at least one of these TSGs was bioinformatically predicted for any given HCC sample case, and encompassing all the subtypes of HCC, making it possible the targeting of any patient in a personalized manner. To specifically reactivate one or more TSGs of this panel we produced CRISPR activators (CRISPRa) multiplexing systems tailored to representative HCC lines. Unlike epigenetic drugs, which lack locus-selectivity, CRISPRa systems enabled a potent and precise (“at will”) reactivation of up to 4 TSG simultaneously. We show that reactivation of HHIP, MT1M, PZP, and TTC36 TSGs in Hep3B cells led to a functional decrease in cell viability, cell proliferation, and cell migration. By combining different effector domains, we identified a toolbox of epigenetic effectors and gRNAs for the functional interrogation and targeting of putative TSGs silenced in liver cancer patients. We outlined a highly personalized precision oncology approach for the treatment of aggressive forms of HCC.
2023-04-10 | GSE211837 | GEO
Project description:The transcribed ultraconserved regions (T-UCRs) are a family of long non-coding RNAs implicated in human carcinogenesis. The mechanism of action of T-UCRs and the factors regulating their expression in human cancers are poorly understood. In this study we show that high expression of uc.339 correlates with lower survival in 204 non-small cell lung cancer (NSCLC) patients. We also show that uc.339 found up-regulated in archival NSCLC samples, functions as a decoy for miR-339-3p, -663-3p and -95-5p. As a result, Cyclin E2, a direct target of these microRNAs is up-regulated, promoting cancer growth and migration. We provide evidence from cell lines and primary samples suggesting that TP53 directly regulates uc.339. Our results support a key role for uc.339 in lung cancer.
2015-07-07 | GSE70540 | GEO
Project description:KRAS activation drives DNA methylation and silencing of specific tumor suppressor genes (TSGs). We previously showed that the ERK pathway induces transcriptional repression of TET1, which results in conversion of TSG promoters from a hydroxymethylated, active state to a hypermethylated and silenced state. Here we identified miR-29b as a KRAS-induced molecule that represses TET1 expression. In KRAS-transformed cells, ectopic miR-29b inhibition restores expression of TET1, thereby reactivating TSGs by reducing methylation and restoring hydroxymethylation. Mining gene expression data of lung cancer cell lines identified additional TSGs suppressed by KRAS signaling whose expression was restored by inhibition of miR-29b and re-expression of TET1. Because KRAS changes TSG promoters from hydroxymethylated to hypermethylated with miR-29b-dependent silencing of TET1, we demonstrate a model in which DNMT1 is present on target promoters prior to KRAS transformation. We also propose miR-29b as a potential circulating biomarker and target for rational treatment of specific malignancies.
2017-07-31 | GSE100857 | GEO
Project description:Development of gene expression signatures for partial downreualtion of ARID1A protein. ARID1A was down-regulated by si-RNA in a breast cancer cell, MDA-MB-157. Subsequently, RNAs was extracted from control siRNA treated cells or partially ARID1A-down regulated cells. cDNAs were synthesized and cRNAs were labeled using low input quick Amp labeling kit (Agilent). Aftere washing and dry, scanned by Agilent Technologies Micorarrray Scanner and calculated using Agilent Feature 10.7.3.1. control siRNA treated MDA-MB-157 breast cancer cells (MOK) and siRNA-midiated ARID1A-downregulated MDA-MB157 breast cancer cells.
2015-09-03 | E-GEOD-72669 | biostudies-arrayexpress
Project description:The transcribed ultraconserved regions (T-UCRs) are a family of long non-coding RNAs implicated in human carcinogenesis. The mechanism of action of T-UCRs and the factors regulating their expression in human cancers are poorly understood. In this study we show that high expression of uc.339 correlates with lower survival in 204 non-small cell lung cancer (NSCLC) patients. We also show that uc.339 found up-regulated in archival NSCLC samples, functions as a decoy for miR-339-3p, -663-3p and -95-5p. As a result, Cyclin E2, a direct target of these microRNAs is up-regulated, promoting cancer growth and migration. We provide evidence from cell lines and primary samples suggesting that TP53 directly regulates uc.339. Our results support a key role for uc.339 in lung cancer. 4 experimental groups in triplicate (total: 12 samples). A339= A549 infected with a lentivirus over-expressing uc.339; AE= A549 infected with an empty lentivirus (control of A339); L339= LoVo infected with a lentivirus over-expressing uc.330; LE= LoVo infected with an empty lentivirus (control of L339). 1-2-3 refer to each experiment.
2015-07-07 | E-GEOD-70540 | biostudies-arrayexpress
Project description:Liver cancer is a common cause of cancer death, with a male-predominant incidence due, in part, to increased estrogen levels in cirrhotic patients. It is unknown, however, how estrogen is sensed to influence this process. Here, we show that estrogen activates the G protein-coupled estrogen receptor 1 (GPER1), expressed in hepatocytes, to enhancing hepatocyte size, cell cycle progression and cell proliferation, thereby increasing liver growth in zebrafish larvae and adults. GPER1 stimulation activates PI3K/mTOR signaling, and mTOR is essential for both normal and regenerative organ growth. Genetic loss of GPER1 diminishes and estrogen exposure accelerates chemical carcinogenesis, specifically in males. Chemical inhibition of GPER1 significantly reduces cancer incidence and progression in a gender-specific fashion. Our studies identify GPER1 as a hepatic estrogen sensor that mediates gender dimorphic growth, mTOR activation, and can serve as a therapeutic target for liver cancer treatment.
2019-05-29 | GSE92544 | GEO
Project description:Breast cancer is one of the cancer-related leading causes of death worldwide. Treatment of breast cancer is complex and challenging especially when metastasis is developed. In this study, we established a new concept of using infrared radiation as an alternative approach to breast cancer treatment. We used middle infrared (MIR) in the wavelength range of 3 to 5 μm to irradiate breast cancer cells. MIR significantly inhibited cell proliferation in several breast cancer cells, but did not affect the growth of normal breast epithelium cells. We performed iTRAQ-coupled LC-MS/MS system to investigate the MIR-triggered molecular mechanisms in breast cancer cells. A total of 1,749 proteins were quantified and 167 proteins were considered to be regulated by MIR. Applying the functional enrichment analysis on the proteomics results, we confirmed that MIR caused G2/M cell cycle arrest, remodeled microtubule network to an astral pole arrangement, altered actin filament formation and focal adhesion molecule localization, and reduced cell migration activity and invasion ability. Together, our results uncover the collaborative effects of MIR regulated physiological responses in concentrated networks, demonstrating the potential implementation of infrared radiation in breast cancer therapy.
2015-06-23 | PXD001078 | Pride
Project description:Breast Cancer is the cancer with most incidence and mortality in women. microRNAs are emerging as novel prognosis/diagnostic tools. Our aim was to identify a serum microRNA signature useful to predict cancer development. We focused on studying the expression levels of 30 microRNAs in the serum of 96 breast cancer patients versus 92 control individuals. Bioinformatic studies provide a microRNA signature, designated as a predictor, based upon the expression levels of 5 microRNAs. Then, we tested the predictor in a group of 60 randomly chosen women. Lastly, a proteomic study unveiled the over-expression and down-regulation of proteins differently expressed in the serum of breast cancer patients versus that of control individuals. Twenty-six microRNAs differentiate cancer tissue from healthy tissue and 16 microRNAs differentiate the serum of cancer patients from that of the control group. The tissue expression of miR-99a-5p, mir-497-5p, miR-362, and miR-1274, and the serum levels of miR-141 correlated with patient survival. Moreover, the predictor consisting of mir-125b-5p, miR-29c-3p, mir-16-5p, miR-1260, and miR-451a was able to differentiate breast cancer patients from controls. The predictor was validated in 20 new cases of breast cancer patients and tested in 60 volunteer women, assigning 11 out of 60 women to the cancer group. An association of low levels of mir-16-5p with a high content of CD44 protein in serum was found. Circulating microRNAs in serum can represent biomarkers for cancer prediction. Their clinical relevance and use of the predictor here described might be of potential importance for breast cancer prediction.
2020-09-18 | PXD020795 | Pride
Project description:Activation of G protein-coupled estrogen receptor 1 (GPER1) is an attractive therapeutic strategy to treat a variety of human diseases, including cancer. Here, we show that GPER1 is remarkably upregulated in tumor cells derived from different cohorts of Waldenström Macroglobulinemia (WM) patients respect to normal B cells. Using the clinically relevant GPER1-selective small-molecule agonist G-1 (also named Tespria), we demonstrate that pharmacological activation of GPER1 leads to G2/M cell cycle arrest and apoptosis both in vitro and in vivo in animal model, even in the context of the protective bone marrow milieu. We report that activation of GPER1 triggers the TP53 pathway, which remains actionable during WM progression. This study identifies a novel druggable target in WM and paves the way for the clinical development of the GPER1 agonist G-1.
2024-07-01 | GSE207488 | GEO