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PEA15 impairs cell migration and correlates with clinical features predicting good prognosis in neuroblastoma.

ABSTRACT: ERK and RSK2 drive proliferation and invasion of many cancers. Phosphoprotein enriched in astrocytes 15 (PEA15) binds ERK and RSK2 and high PEA15 levels can impair ERK- and RSK2-dependent transcription. PEA15 expression also inversely correlates with cell motility and invasiveness. We therefore tested PEA15 effects on neuroblastoma cells in vitro. We further analyzed PEA15 expression in the context of clinical and genetic features of neuroblastoma in tumor samples to determine its correlation with disease progression. Affymetrix microarray analysis was performed using 24 different neuroblastoma cell lines. Cell lines expressing low to intermediate levels of PEA15 were chosen for in vitro functional studies. The cell line results were verified by Affymetrix analysis of three different neuroblastic tumor types (total of 110 samples) PEA15 overexpression inhibited neuroblastoma migration in vitro. We verified that inhibition of motility required PEA15 interaction with its binding partners ERK and RSK2. Additionally, synthetic inhibitors of RSK2 suppressed integrin-dependent migration. PEA15 expression correlates with clinical parameters and a 25% increase in patient survival rate. The highest PEA15 levels were found in low stage, more differentiated and less metastatic neuroblastic tumors, and correlated with lack of MYCN amplification. PEA15 blocks neuroblastoma migration through inhibition of ERK/RSK2 signaling. PEA15 expression levels correlate with favorable clinical features suggesting that PEA15 limits metastatic progression of neuroblastoma. Thus, PEA15 and its partners ERK and RSK2 are potential targets for the development of new therapeutics to impede progression of minimal residual disease in patients with high-risk neuroblastoma.

SUBMITTER: Gawecka JE

PROVIDER: S-EPMC3757132 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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PEA15 impairs cell migration and correlates with clinical features predicting good prognosis in neuroblastoma.

Gawecka Joanna E JE Geerts Dirk D Koster Jan J Caliva Maisel J MJ Sulzmaier Florian J FJ Opoku-Ansah John J Wada Randal K RK Bachmann André S AS Ramos Joe W JW

International journal of cancer 20120131 7

ERK and RSK2 drive proliferation and invasion of many cancers. Phosphoprotein enriched in astrocytes 15 (PEA15) binds ERK and RSK2 and high PEA15 levels can impair ERK- and RSK2-dependent transcription. PEA15 expression also inversely correlates with cell motility and invasiveness. We therefore tested PEA15 effects on neuroblastoma cells in vitro. We further analyzed PEA15 expression in the context of clinical and genetic features of neuroblastoma in tumor samples to determine its correlation wi ...[more]

PMID: 22213050

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Project description:BACKGROUND:Neuroblastoma is one of the most common types of pediatric cancer. In current neuroblastoma prognosis, patients can be stratified into high- and low-risk groups. Generally, more than 90% of the patients in the low-risk group will survive, while less than 50% for those with the high-risk disease will survive. Since the so-called "high-risk" patients still contain patients with mixed good and poor outcomes, more refined stratification needs to be established so that for the patients with poor outcome, they can receive prompt and individualized treatment to improve their long-term survival rate, while the patients with good outcome can avoid unnecessary over treatment. METHODS:We first mined co-expressed gene modules from microarray and RNA-seq data of neuroblastoma samples using the weighted network mining algorithm lmQCM, and summarize the resulted modules into eigengenes. Then patient similarity weight matrix was constructed with module eigengenes using two different approaches. At the last step, a consensus clustering method called Molecular Regularized Consensus Patient Stratification (MRCPS) was applied to aggregate both clinical information (clinical stage and clinical risk level) and multiple eigengene data for refined patient stratification. RESULTS:The integrative method MRCPS demonstrated superior performance to clinical staging or transcriptomic features alone for the NB cohort stratification. It successfully identified the worst prognosis group from the clinical high-risk group, with less than 40% survived in the first 50?months of diagnosis. It also identified highly differentially expressed genes between best prognosis group and worst prognosis group, which can be potential gene biomarkers for clinical testing. CONCLUSIONS:To address the need for better prognosis and facilitate personalized treatment on neuroblastoma, we modified the recently developed bioinformatics workflow MRCPS for refined patient prognosis. It integrates clinical information and molecular features such as gene co-expression for prognosis. This clustering workflow is flexible, allowing the integration of both categorical and numerical data. The results demonstrate the power of survival prognosis with this integrative analysis workflow, with superior prognostic performance to only using transcriptomic data or clinical staging/risk information alone. REVIEWERS:This article was reviewed by Lan Hu, Haibo Liu, Julie Zhu and Aleksandra Gruca.

Project description:Ferroptosis genes have recently been reported to be involved in regulating the development of cancer, but their potential role in breast cancer (BRCA) is not fully understood. The purpose of this study is to systematically study the mechanism of ferroptosis in BRCA and its relationship with this cancer's prognosis, cell infiltration, gene mutation, and other clinical features. In this study, The Cancer Genome Atlas breast cancer (TCGA-BRCA) database (UCSC Xena) was used to mine the ferroptosis genes related to BRCA patients, and the genes with prognostic value were screened by Cox regression analysis, which were then used to construct a prognostic model for scoring prognostic molecular risk. The relationships between ferroptosis score and prognosis, molecular typing, and clinical characteristics of BRCA were also analyzed. A total of 176 ferroptosis genes related to BRCA were retrieved from the database, 22 of which were found to be significantly related to BRCA prognosis after screening by single-factor Cox regression analysis (p < 0.01). Unsupervised clustering of samples was performed using factoextra, and two subgroups (ferroptosis cluster A and ferroptosis cluster B) with significant differences in prognosis were identified. Subsequently, single-factor Cox regression analysis and random forest dimensionality reduction were used to screen characteristic genes to construct a ferroptosis score model, which included a high ferroptosis score group and a low ferroptosis score group. The results showed that there were significant differences in ferroptosis scores between the ferroptosis cluster A and B groups. The prognosis of patients with low ferroptosis scores was poor, and the overall survival (OS) rate of patients with high ferroptosis scores was significantly higher, indicating that the prognosis of the sample can be well characterized based on calculated ferroptosis scores. Ferroptosis scores differed significantly according to patient age, TP53 and PIK3CA gene mutations, different PAM50 molecular types, and clinical stages. Ferroptosis activation plays a non-negligible role in tumor occurrence and development. Evaluating the ferroptosis score within BRCA will help advance our understanding of the infiltrating properties of cells in the tumor microenvironment and may guide more effective immunotherapy strategies.

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PEA15 impairs cell migration and correlates with clinical features predicting good prognosis in neuroblastoma.

Publications

PEA15 impairs cell migration and correlates with clinical features predicting good prognosis in neuroblastoma.

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