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

• Grant number: 21/12284-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: May 01, 2022
• End date: April 30, 2025
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Edna Teruko Kimura
• Grantee: Hugo Werner Huth
• Host 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)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

HUTH, HUGO; FUZIWARA, CESAR; KIMURA, EDNA. The role of miR-200 in anaplastic thyroid cancer aggressiveness. Cancer Research, v. 83, n. 7, p. 2-pg., 2023-04-01. (21/12284-0, 19/25116-8, 19/17282-5)