Evaluation of cooperation between variants in the RAS and HIPK2 genes in the genesis and progression of differentiated thyroid Cancer

• Grant number: 22/16827-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: November 01, 2023
• End date: October 31, 2027
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Janete Maria Cerutti
• Grantee: Welbert Gomes Rocha
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Cancer is the second cause of death in the world. Specifically, thyroid cancer is the most common type to affect the head and neck region. This cancer has been experiencing an increase in its incidence in recent years. The increase in this number seems to be related to the improvement in the sensitivity of diagnostic tests that can detect thyroid nodules. Mutations in the RAS gene family of oncogenes are among the most common in thyroid cancer. In vitro and in vivo models have demonstrated that the presence of a pathogenic variant in RAS alone is not sufficient for malignant transformation of thyroid follicular cells. With cooperation with pathogenic variants in other "driver" genes, such as PTEN, there is an increase in the potential for malignant transformation of thyroid cells. In this sense, our group analyzed 120 cases of thyroid carcinoma and identified those with RAS mutations. Through RNA sequencing (RNA-Seq) of these samples, we identified variants in 4 Hippo pathway genes (PAK1, RASSF4, HIPK2 and DVL1) that co-occur with mutations in RAS genes. In this project we will evaluate whether the variant in the HIPK2 gene (p.R117Q) can increase the potential for malignant transformation of the p.Q61R variant in the NRAS gene in the mouse normal thyroid cell line (PCCL3). For this, the variants will be cloned into an expression vector and will be transfected alone (NRAS or HIPK2) or in combination (NRAS and HIPK2) in PCCL3 cells. In vitro studies will be carried out to evaluate the biological effect of the cooperation of HIPK2 and RAS in the rates of proliferation, migration, invasion, apoptosis and in the activation of the MAPK and Hippo pathways. (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)

DA SILVA, DANILO DIAS; ARALDI, RODRIGO PINHEIRO; BELIZARIO, MARIANA ROCHA; ROCHA, WELBERT GOMES; MACIEL, RUI MONTEIRO DE BARROS; CERUTTI, JANETE MARIA. DLK1 Is Associated with Stemness Phenotype in Medullary Thyroid Carcinoma Cell Lines. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 25, n. 22, p. 19-pg., 2024-11-01. (23/16471-4, 21/02752-6, 22/16827-0, 22/09713-9)