MicroRNA and signaling pathways interrelationship in thyroid oncogenesis: seeking new therapeutic targets

• Grant number: 21/12284-0
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): May 01, 2022
• Effective date (End): April 30, 2024
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal researcher: Edna Teruko Kimura
• Grantee: Hugo Werner Huth
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Chemoresistance is a major problem faced by oncologist in Cancer treatment. As our understanding of the molecular biology of Cancer has advanced, the concept of plasticity in Cancer has emerged as a key player in drug resistance. One of the major mechanisms responsible for tumor cell plasticity is the Epithelial-Mesenchimal Transition (EMT), which allows cell phenotype transition leading to chemoresistance, metastasis and tumor relapse. With the emergence of gene therapy in Cancer, miRNAs have been drawing attention, specially miR-200 due to its antitumor activity by inhibiting EMT in a wide range of Cancers. In Anaplastic Thyroid Cancer (ATC), more specifically in KCT2 cell line, the miR-200 expression is downregulated, which might explain its aggressiveness. Although, the mechanisms controlled by miR-200 in ATC remains unknown. In this study, using plasmid overexpression, we intend to upregulate miR-200 in KTC2 cells in order to analyze miR-200 role in cell differentiation, proliferation and migration, correlating with EMT regulator proteins (EMT-TFs) and the expression of Cancer Stem Cell (CSC) markers. Further, we aim to identify new signaling pathways controlled by miR-200, focusing on TBK-1/NF-kB axis, which have been identified as a possible target for miR-200 by TargetScan. Yet, we will induce xenographic ATC tumors in athymics nude mice and will administrate intratumoral liposomes injections containing miR-200 associated with the pharmacological inhibition of TBK-1 in order to verify the viability of using this combination in in vivo models. The main goal of this project is to better characterize the correlation of miR-200 and EMT, aiming to control cell plasticity, tumor heterogeneity and tumor relapse, in order to offer new therapeutics targets for aggressive Thyroid Cancer treatment. (AU)