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Transcriptional profiling of liver tissue from mice with wild-type, N750F mutant or exon 19 deleted RB1, after treatment with diethylnitrosamine.

ABSTRACT: The LXCXE peptide motif facilitates interaction between the RB tumor suppressor and a large number of cellular proteins that are expected to impinge on diverse biological processes. In vitro and in vivo analyses demonstrated that LXCXE-binding function is dispensable for RB promoter association and control of basal gene expression. Dependence on this function of RB is unmasked after DNA damage, wherein LXCXE-binding is essential for exerting control over E2F3 and suppressing cell cycle progression in the presence of genotoxic stress. Gene expression profiling revealed that the transcriptional program coordinated by this specific aspect of RB is associated with progression of human hepatocellular carcinoma and poor disease outcome. Consistent with these findings, biological challenge revealed a requirement for LXCXE-binding in suppression of genotoxin-initiated hepatocellular carcinoma in vivo. Together, these studies establish an essential role of the LXCXE-binding motif for RB-mediated transcriptional control, response to genotoxic insult, and tumor suppression.

ORGANISM(S): Mus musculus

PROVIDER: GSE31169 | GEO | 2011/12/01

SECONDARY ACCESSION(S): PRJNA144791

REPOSITORIES: GEO

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Transcriptional profiling of liver tissue from mice with wild-type, N750F mutant or exon 19 deleted RB1, after treatment with diethylnitrosamine.

Project description:The LXCXE peptide motif facilitates interaction between the RB tumor suppressor and a large number of cellular proteins that are expected to impinge on diverse biological processes. In vitro and in vivo analyses demonstrated that LXCXE-binding function is dispensable for RB promoter association and control of basal gene expression. Dependence on this function of RB is unmasked after DNA damage, wherein LXCXE-binding is essential for exerting control over E2F3 and suppressing cell cycle progression in the presence of genotoxic stress. Gene expression profiling revealed that the transcriptional program coordinated by this specific aspect of RB is associated with progression of human hepatocellular carcinoma and poor disease outcome. Consistent with these findings, biological challenge revealed a requirement for LXCXE-binding in suppression of genotoxin-initiated hepatocellular carcinoma in vivo. Together, these studies establish an essential role of the LXCXE-binding motif for RB-mediated transcriptional control, response to genotoxic insult, and tumor suppression. Mice transgenic for Cre-recombinase under the albumin promoter contain indicated combinations of loxP sites flanking exon 19 of Rb1 (f), N750F mutation (NF) or wild-type (plus) genotypes. For gene expression microarray analysis, mice were aged to 14 days and treated for 24 hours with diethylnitrosamine (DEN) or saline as an M-bM-^@M-^\untreatedM-bM-^@M-^] control. Liver tissue was obtained from DEN treated livers and compared to normal liver tissue of saline treated littermates.

2011-12-01 | E-GEOD-31169 | biostudies-arrayexpress

Differential gene expression in Gaddβ KO mice treated with diethylnitrosamine and phenobarbital

Project description:To find Gadd45β dependent gene regulation in mouse hepatocellular carcinoma induced by diethylnitorsamine + phenobarbital

2023-09-25 | GSE231793 | GEO

Argonaute CLIP defines a deregulated miR-122 bound transcriptome that correlates with patient survival in human liver cancer (Mouse RNA-Seq)

Project description:MicroRNA-122, an abundant and conserved liver-specific miRNA, regulates hepatic metabolism and functions as a tumor suppressor, yet systematic and direct biochemical elucidation of the miR-122 target network remains incomplete. To this end, we performed Argonaute crosslinking immunoprecipitation (Ago-CLIP) sequencing in miR-122 knockout and control mouse livers, as well as in matched human hepatocellular carcinoma (HCC) and benign liver tissue to identify miRNA target sites transcriptome-wide in two species. We observed a majority of miR-122 binding on 3’-UTRs and coding exons followed by extensive binding to other genic and non-genic sites. Motif analysis of miR-122 dependent binding revealed a novel G-bulged motif in addition to canonical motifs. A large number of miR-122 targets were found to be species-specific. Upregulation of several common mouse and human targets, most notably BCL9, predicted survival in HCC patients. These results broadly define the molecular consequences of miR-122 downregulation in hepatocellular carcinoma.

2017-03-28 | GSE97060 | GEO

Argonaute CLIP defines a deregulated miR-122 bound transcriptome that correlates with patient survival in human liver cancer (Mouse CLIP-Seq)

2017-03-28 | GSE97058 | GEO

Argonaute CLIP defines a deregulated miR-122 bound transcriptome that correlates with patient survival in human liver cancer (Human CLIP-Seq)

2017-03-28 | GSE97056 | GEO

Colibactin-driven colon cancer requires adhesin-mediated epithelial binding

Project description:Various bacteria are suggested to contribute to colorectal cancer (CRC) development, including pks+ E. coli, which produces the genotoxin colibactin that induces characteristic mutational signatures in host epithelial cells. However, it remains unclear how the highly unstable colibactin molecule is able to access host epithelial cells to cause harm. Using the microbiota-dependent ZEB2-transgenic mouse model of invasive CRC, we demonstrate that the oncogenic potential of pks+ E. coli critically depends on bacterial adhesion to host epithelial cells, mediated by the type-1 pilus adhesin FimH and the F9-pilus adhesin FmlH. Blocking bacterial adhesion using a pharmacological FimH inhibitor attenuates colibactin-mediated genotoxicity and CRC exacerbation. We also show that allelic switching of FimH strongly influences genotoxic potential of pks+ E. coli and can induce a genotoxic gain-of-function in the probiotic strain Nissle 1917. Adhesin-mediated epithelial binding subsequently allows the production of the genotoxin colibactin in close proximity to host epithelial cells, which promotes DNA damage and drives CRC development. These findings present promising therapeutic avenues for the development of anti-adhesive therapies aimed at mitigating colibactin-induced DNA damage and inhibiting the initiation and progression of CRC, particularly in individuals at risk for developing CRC.

2024-08-19 | GSE241851 | GEO

Gene expression profile of hepatocellular carcinoma in low-dose, repeated diethylnitrosamine (DEN)-treated rat treated with erlotinib

Project description:Gene-expression profiles of rat hepatocellular carcinoma induced by diethylnitrosamine (DEN) and the effect of erlotinib Hepatocellular carcinoma (HCC) is the sixth most common solid tumor worldwide and the third leading cause of cancer-related death. Given the lack of successful treatment options, chemoprevention in high-risk patients has been proposed as an alternative strategy. Mounting evidence supports a role for epidermal growth factor (EGF) during chronic liver disease and hepatocellular transformation. We address the hypothesis that blocking the EGF-EGF receptor (EGFR) pathway may be an effective strategy for inhibiting fibrogenesis and hepatocarcinogenesis. A rat model of diethylnitrosamine (DEN)-induced cirrhosis was used to examine the effects of erlotinib on underlying chronic liver disease and HCC formation. The DEN-induced rat model closely resembles disease progression in humans both pathologically and molecularly. Erlotinib significantly prevented the development of HCC tumor nodules in a dose-dependent fashion. Further, erlotinib inhibited the activation of hepatic stellate cells and prevented fibrogenesis. Erlotinib also reduced hepatotoxicity and improved liver function. Finally, a gene expression signature predictive of poor survival in human cirrhosis patients was reversed in response to erlotinib. Our data demonstrate for the first time that EGFR inhibition prevents liver fibrogenesis. Further, our results suggest that erlotinib is a potentially effective HCC chemoprevention strategy through inhibition of cirrhosis progression which can be monitored at the molecular level.

2014-02-28 | GSE27638 | GEO

The retinoblastoma tumor suppressor modulates DNA repair and radio responsiveness

Project description:In this study, we show that RB loss promotes sensitization to genotoxic stress through mechanisms distinct from cell cycle checkpoint control, and identify RB as a potent effector of the response to radiotherapy.

2014-12-03 | GSE58711 | GEO

DNA methyltransferase inhibitor zebularine inhibits human hepatic carcinoma cells proliferation and induces apoptosis.

Project description:Hepatocellular carcinoma is one of the most common cancers in world wide. During tumorigenesis, tumor suppressor and cancer-related genes are commonly silenced by aberrant DNA methylation in their promoter regions. Zebularine [1-(β-ᴅ-ribofuranosyl)-1,2-dihydropyrimidin-2-one] acts as an inhibitor of DNA methylation and exhibits chemical stability and minimal cytotoxicity both in vitro and in vivo. In this study, we explore the effect and possible mechanism of action of zebularine on hepatocellular carcinoma cell line HepG2. Here, we demonstrated that zebularine exhibited antitumor activity on HepG2 cells by inhibiting cell proliferation and inducing apoptosis. Zebularine treatment down-regulated CDK2 and phosphorylation of retinoblastoma protein (RB), and up-regulated p21WAF/CIP1 and p53. We also found that zebularine treatment up-regulated phosphorylation of p44/42 MAPK. These results suggest that p44/42 MAPK pathway play a role in zebularine induced cell cycle arrest by regulating activity of p21WAF/CIP1 and Rb. Furthermore, we found that zebularine induced apoptosis. Although proapoptotic protein Bax levels were not affected, antiapoptotic protein Bcl-2 level was down-regulated with zebularine treatment. The data in the present study suggest that the action of the double-stranded RNA-dependent protein kinase (PKR) is involved in inducing apoptosis with zebularine. These results provide a novel mechanism of zebularine-induced cell growth arrest and apoptosis in hepatocellular carcinoma. Three each independent batches of zebuluarine-treated and control HepG2 cells were subjected to illumina Human methylation 450K Beadchip analysis.

2013-12-01 | E-GEOD-42490 | biostudies-arrayexpress

Role of radio-labelled GCC-compounds in diagnosis and treatment planning of colorectal cancer

Project description:Primary outcome(s): 68Ga-DOTA-GCC-RB PET/CT imaging (Assessment of 68Ga-DOTA-GCC-RB PET/CT imaging to detect lesions in patients with colorectal carcinoma)Timepoint: 45 minutes to 1 hour from time of injection

| 29930 | ecrin-mdr-crc

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