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Role of microRNA-23 and microRNA-133 in the development of tumor resistance to tyrosine kinase inhibitors in a clear cell renal cell carcinoma model

Grant number: 24/17982-5
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Start date: March 01, 2025
End date: February 28, 2026
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Mirian Aparecida Boim
Grantee:Maria Vitória Moreira Albuquerque Gusmão
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Clear cell renal cell carcinoma (ccRCC) is frequently associated with inactivation of the Von Hippel-Lindau (VHL) gene, which is essential for regulating hypoxia-inducible factor-1¿ (HIF-1¿). The classic treatment for ccRCC includes tyrosine kinase inhibitors (TKIs), such as sunitinib. However, tumor resistance to these drugs is common and multifactorial, such as activation of alternative pathways and regulation of microRNAs (miR). Studies indicate that miR-23 and miR-133 are associated with tumor development and resistance to some treatments in other types of cancer. The objective of this project is to evaluate the role of miR-133 and miR-23 in tumor resistance induced by sunitinib in tumor cells in vitro. The immortalized ccRCC cell line (Caki-2) will be used. First, a dose-response curve with sunitinib will be performed to determine the LD50, through the cell viability assay by MTT. Subsequently, Caki-2 cells will be treated with this dose for several weeks until the cell becomes resistant to the drug. The control group will consist of cells not exposed to sunitinib and will be considered sensitive cells. The gene expression of miR-133 and miR-23 will be evaluated in the resistant and sensitive cells by real-time PCR. If changes in the expression of these miRs are detected, a bioinformatics analysis will then be performed to evaluate the predicted targets of these miRs that may be involved in tumor resistance and also the effect of silencing or overexpression of these miRs on the response to treatment.

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