Rationale: Recent studies have highlighted the cancer stem cell are related to tumor proliferation, drug resistance, recurrence and metastasis. CCAAT/Enhancer binding protein delta (CEBPD) has been shown to be a pivotal transcription factor for inhibiting tumorigenesis and is activated in response to many external stimuli. However, CEBPD is highly expressed in glioma patients. Here, we hypothesized that the protein acts as a key communicator that receives signals from the surrounding environment and then induces stemness features in glioma. Preliminary results: CEBPD was found to be overexpressed in glioma tissue compared to non-glioma brain tissue from both internet-based bioinformatics microarray profiles and a tumor tissue array we studied. The glioblastoma multiforme (GBM) cell line U87MG, with high expression of the glioma stem cell surface marker CD133, also exhibited a higher protein level of CEBPD. Exposure to IL-1 suggested that the increased CEBPD was due to a cellular response to extracellular stimulants promotes glioma stemness feature. Overexpression of CEBPD led to altered expression of stemness genes. Hypothesis: Activation of CEBPD by the inflammatory microenvironment is essential for the maintenance of stemness features in glioma. Specific Aims: According to our preliminary results, several experiments are proposed to study the functional role of CEBPD in inflammatory microenvironment and to investigate the sequential regulation of the stemness features in brain tumors. First, we will study the molecular mechanism of how proinflammatory cytokines stimulate CEBPD. Second, we will study the role of CEBPD in regulating stemness features, e.g., OCT4, SOX2 and NANOG, in glioma, and the analyses will be performed in clinical samples for validation in human disease. Third, we will replicate the study in an animal model to examine the pathway in an in vivo model. Novelty and application: CEBPD has been suggested to serve as a tumor suppressor in many cancers. Interestingly, several recent studies and our unpublished results showed that CEBPD may serve a protumor role in bladder cancer, prostate cancer and gallbladder cancer. The results implied that CEBPD’s role in tumorigenesis could be different in various cancer types. In this proposal, we focus on dissecting the role of CEBPD in glioma and its role in stemness features, which may be crucial for tumor initiation, self-renewal, and drug resistance. Notably, the investigation is designed to explore the effect of the tumor microenvironment, with a focus on inflammation, in glioma. The result will suggest the mechanism of how inflammatory microenvironment activates the transcription factor, which then induces the stemness feature of the disease. Understanding the biology may provide an opportunity to prevent the cancer stem cells induced malignant cells relapse after primary therapy through application of specific inhibitors treatment.
|Effective start/end date||10/1/17 → 7/31/18|
- inflammatory microenvironment
- proinflammatory cytokines
- glioma stem cell