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| Author(s): |
Keteryne Rodrigues da Silva
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Ribeirão Preto. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) |
| Defense date: | 2021-04-16 |
| Examining board members: |
Luiz Gonzaga Tone;
Oswaldo Keith Okamoto;
Jaqueline Carvalho de Oliveira;
Rodrigo Alexandre Panepucci
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| Advisor: | Luiz Gonzaga Tone |
| Abstract | |
Ependymoma (EPN) is the third most common brain tumor in pediatric patients, which 90% of cases are located in the intracranial area. The ependymoma originates from the ependymal cells that line the ventricular system and the spinal cord canal and is currently divided into nine molecular subgroups which the supratentorial ependymoma RELA (ST-EPN-RELA) and posterior fossa ependymoma A (PF-EPN-A) presenting the worst prognosis. The prognostic factors for EPN comprise age less or greater than 3 years-old (being less than 3 years-old worse prognosis) and degree of tumor resection. Because it is a highly invasive tumor, with frequent partial resection rate, the vast majority of EPN patients die due to tumor recurrence. The current treatment for EPN consists of surgical resection followed by radiation therapy. The use of chemotherapy has not shown satisfactory results on survival rate of EPN patients. Thus, it is necessary to search for new therapeutic approaches that enable improvement in the survival and quality of life of EPN patients. Some studies have shown that EPN presents alterations in important signaling pathways for several cellular processes, including the TGF-β pathway. The TGF-β signaling pathway acts mainly in the processes of cell migration and invasion in several tumors. Therefore, this study aimed to analyze the role of the TGF-β pathway in EPN aiming at the identification of possible new therapeutic targets based on genes from this signaling pathway. Through the RNAseq, it was possible to identify the enrichment of the TGF-β pathway in the subgroups with tee worst prognosis, ST-EPN-RELA and FP-EPN-A as well as, hub genes that participate or interact with components of the TGF-β pathway. The pharmacological inhibition of the TGF-β pathway with the drug SB431542 in the ependymoma cell line BXD-1425, despite causing a decrease in the gene and protein levels of the SMAD pathway, has not been shown to have an effect on cell viability, apoptosis, migration and cell invasion. However, after 24h of treatment with SB431542, there was a significant increase in cells in the G1 phase and decrease in cells in the S phase of the cell cycle. Hsa-miR-630 regulates several cellular processes, among which migration, cell invasion and epithelial-mesenchymal transition stand out, associated with the regulation of the TGF-β pathway in several tumors. As a possibility to modulate the TGF-β pathway and regulate the processes of migration and cellular invasion of EPN, the BXD-1425 cell line was transduced with the miR-630 hyperexpression lentivirus and its control. The overexpression of miR-630 led to a decrease in cell viability, an increase in the number of cells undergoing apoptosis, a decrease in the rate of migration and cell invasion. In addition, when overexpressing miR-630 there was a decrease in the gene and protein expression of components of the TGF-β/SMAD pathway. These results indicate that miR-630 may be modulating the TGF-β pathway and regulating ependymoma invasion and cell migration processes. (AU) | |
| FAPESP's process: | 16/19799-7 - Research therapeutic targets from gene expression networks of members of the TGF-b pathway associated with tumor progression of ependymomas of worse prognosis |
| Grantee: | Keteryne Rodrigues da Silva |
| Support Opportunities: | Scholarships in Brazil - Doctorate |