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Hierarchical regulation in a KRAS pathway-dependent transcriptional network revealed by a reverse-engineering approach (7TF and control)

ABSTRACT: RAS mutations are highly relevant for progression and therapy response of human tumours, but the genetic network that ultimately executes the oncogenic effects is poorly understood. Here we used a reverse-engineering approach in an ovarian cancer model to reconstruct KRAS oncogene-dependent cytoplasmic and transcriptional networks from perturbation experiments based on gene silencing and pathway inhibitor treatments. We measured mRNA and protein levels in manipulated cells by microarray, RT-PCR and Western Blot analysis, respectively. The reconstructed model revealed complex interactions among the transcriptional and cytoplasmic components, some of which were confirmed by double pertubation experiments. Interestingly, the transcription factors decomposed into two hierarchically arranged groups. To validate the model predictions we analysed growth parameters and transcriptional deregulation in the KRAS-transformed epithelial cells. As predicted by the model, we found two functional groups among the selected transcription factors. The experiments thus confirmed the predicted hierarchical transcription factor regulation and showed that the hierarchy manifests itself in downstream gene expression patterns and phenotype.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE38584 | GEO | 2012/08/01

SECONDARY ACCESSION(S): PRJNA168232

REPOSITORIES: GEO

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Hierarchical regulation in a KRAS pathway-dependent transcriptional network revealed by a reverse-engineering approach (RAS-ROSE and ROSE with siRNA)

Project description:RAS mutations are highly relevant for progression and therapy response of human tumours, but the genetic network that ultimately executes the oncogenic effects is poorly understood. Here we used a reverse-engineering approach in an ovarian cancer model to reconstruct KRAS oncogene-dependent cytoplasmic and transcriptional networks from perturbation experiments based on gene silencing and pathway inhibitor treatments. We measured mRNA and protein levels in manipulated cells by microarray, RT-PCR and Western Blot analysis, respectively. The reconstructed model revealed complex interactions among the transcriptional and cytoplasmic components, some of which were confirmed by double pertubation experiments. Interestingly, the transcription factors decomposed into two hierarchically arranged groups. To validate the model predictions we analysed growth parameters and transcriptional deregulation in the KRAS-transformed epithelial cells. As predicted by the model, we found two functional groups among the selected transcription factors. The experiments thus confirmed the predicted hierarchical transcription factor regulation and showed that the hierarchy manifests itself in downstream gene expression patterns and phenotype. RAS-ROSE cells and ROSE cells treated with Scrambled siRNA

2012-07-31 | E-GEOD-38585 | biostudies-arrayexpress

Hierarchical regulation in a KRAS pathway-dependent transcriptional network revealed by a reverse-engineering approach (7TF and control)

2012-07-31 | E-GEOD-38584 | biostudies-arrayexpress

Hierarchical regulation in a KRAS pathway-dependent transcriptional network revealed by a reverse-engineering approach (RAS-ROSE and ROSE with siRNA)

2012-08-01 | GSE38585 | GEO

Hierarchical regulation in a KRAS-dependent transcriptional network revealed by a reverse-engineering approach

Project description:Mutations in RAS proteins occur in 30% of human tumours and have a high relevance in tumor progression. Despite the importance of the underlying genetic network that governs the effects of oncogenic RAS, it is still poorly understood. We developed and applied a reverse-engineering approach in order to reconstruct the network structure of the signaling and gene-regulatory network downstream of RAS from perturbation experiments. We performed microarray, RT-PCR and Western Blot analysis to detect mRNA and protein levels of cytoplasmatic and nuclear targets downstream of RAS after systematic perturbation of the signaling pathways and knock-down of selected transcription factors in KRAS-transformed ovarian surface epithelium cell lines. The reconstructed model shows that the investigated components are connected through a complex network. The transcription factors decomposed into two hierarchically arranged groups. While knock-down of all investigated transcription factors showed a partial reversion of the malignant phenotype, different growth assays show that these two groups of transcription factors control different functions in the malignant anchorage-independent growth and cell cycle regulation of the ROSE cells. Furthermore, the model showed strong regulatory interplay of inhibitory and activating interactions between the RAS-dependent trancriptional network and cytoplasmatic signaling components.

2011-03-01 | GSE24668 | GEO

Hierarchical regulation in a KRAS-dependent transcriptional network revealed by a reverse-engineering approach

2011-03-01 | E-GEOD-24668 | biostudies-arrayexpress

SOD1 Regulates Ribosome Biogenesis in KRAS Mutant Non-Small Cell Lung Cancer

Project description:SOD1 is known as the major cytoplasmic superoxide dismutase and an anticancer target. However, the role of SOD1 in cancer is not fully understood. Herein we describe the generation of an inducible Sod1 knockout in KRAS-driven NSCLC mouse model. Sod1 knockout markedly reduces tumor burden in vivo and blocks growth of KRAS mutant NSCLC cells in vitro. Intriguingly, SOD1 is enriched in the nucleus and notably in the nucleolus of NSCLC cells. The nuclear and nucleolar, not cytoplasmic, form of SOD1 is essential for lung cancer cell proliferation. Moreover, SOD1 interacts with PeBoW complex and controls its assembly necessary for pre-60S ribosomal subunit maturation. Mechanistically, SOD1 regulates co-localization of PeBoW with and processing of pre-rRNA, and maturation of cytoplasmic 60S ribosomal subunits in KRAS mutant lung cancer cells. Collectively, our study unravels a nuclear SOD1 function essential for ribosome biogenesis and proliferation in KRAS-driven lung cancer.

2021-03-12 | MSV000087044 | MassIVE

Prognostic Model for Stage II/III Colon Cancer Based on Gene Expression Subtypes and KRAS Mutation Status

Project description:The purpose of this study was to establish a new prognostic model for stage II/III colon cancer. Using public DNA microarray data of colon cancer patients, we created an integrated prognostic model for classifying the patients into high- and low-risk groups based on the expression levels of 55 genes and the KRAS mutation status. For validation, we examined specimens from patients with stage II/III colon cancer who had undergone radical resection at our department, and successfully confirmed prognostic value of our model. We believe that our prognostic model may be clinically helpful to select patients for adjuvant chemotherapy.

2018-03-30 | GSE92921 | GEO

MicroRNA profile of tumorigenic cells during formation of pulmonary adenocarcinoma

2014-08-02 | GSE60001 | GEO

A Novel RNA Sequencing Data Analysis Method for Cell Line Authentication

Project description:We have developed a novel analysis method that can interrogate the authenticity of biological samples used for generation of transcriptome profiles in public data repositories. The method uses RNA sequencing information to reveal mutations in expressed transcripts and subsequently confirms the identity of analysed cells by comparison with publicly available cell-specific mutational profiles. Cell lines constitute key model systems widely used within cancer research, but their identity needs to be confirmed in order to minimise the influence of cell contaminations and genetic drift on the analysis. Using both public and novel data, we demonstrate the use of RNA-sequencing data analysis for cell line authentication by examining the validity of COLO205, DLD1, HCT15, HCT116, HKE3, HT29 and RKO colorectal cancer cell lines. We successfully authenticate the studied cell lines and validate previous reports indicating that DLD1 and HCT15 are synonymous. We also show that the analysed HKE3 cells harbour an unexpected KRAS-G13D mutation and confirm that this cell line is a genuine KRAS dosage mutant, rather than a true isogenic derivative of HCT116 expressing only the wild type KRAS. This authentication method could be used to revisit the numerous cell line based RNA sequencing experiments available in public data repositories, analyse new experiments where whole genome sequencing is not available, as well as facilitate comparisons of data from different experiments, platforms and laboratories.

2017-02-14 | GSE81194 | GEO

MicroRNA profile of tumorigenic cells during formation of pulmonary adenocarcinoma

Project description:Study designed to obtain microRNA profile of tumorigenic Sca-1+CD34+ cells during the formation of pulmonary adenocarcinoma. After intranasal infection with adenovirus CRE (Ad-Cre), lung adenocarcinoma was identified pathologically in Lox-stop-lox Kras (LSL-Kras) G12D mice. Sca-1+CD34+ cells were sorted by flow cytometry and tested for the tumor-initiating ability to undergo self-renewal and differentiation. MiRNA profile was obtained from the microarray and further confirmed by qRT-PCR.The function of miRNAs was predicted bioinformatically, and miR-294 was verified to explore its relationship with tumor migration and invasion. We taken lung tissues from the LSL-Kras G12D mouse on the 0, 15th, 30th days, and defined as Group A, B, C respectively. These 3 samples were analyzed. Each kind of probe has 4 repeat spots on the microarray. Total RNA are harvested using TRIzol (Invitrogen) and RNeasy mini kit (QIAGEN). All processing conducted at the Kang Cheng Biological chip Company Limited. Microarray was synthesized using μParafloTM microfluidic chip technology, and the information of miRNA probe sequence of each region was obtained from the database of Sanger miRBase version 11.0.

2014-08-02 | E-GEOD-60001 | biostudies-arrayexpress

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