Identification of the metabolic profile of cells with ectopic expression of PVALB and investigation of the molecular mechanism associated with its expression in Hürthle cell adenomas

• Grant number: 17/06487-0
• Support type: Scholarships in Brazil - Doctorate
• Effective date (Start): January 01, 2018
• Effective date (End): October 31, 2020
• Field of knowledge: Health Sciences - Medicine
• Principal researcher: Janete Maria Cerutti
• Grantee: Thais Biude Mendes
• Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

From the analysis performed by SAGE (Serial Analysis of Gene Expression) on benign and malignant thyroid samples, with subsequent validation by real-time PCR and immunohistochemistry, we found that the combined expression of five markers (PVALB, ITM1 and C1orf24, ARG2 and DDIT3), can distinguish benign and malignant thyroid lesions with high sensitivity and specificity. Among these, PVALB is specifically expressed in Hürthle cell adenomas, thus, it is a marker of benignity. To understand the role of PVALB in the pathogenesis of thyroid tumors, our group performed in vitro studies. We demonstrated, by the ectopic expression of PVALB in follicular thyroid carcinoma cell lines, that PVALB reduces the rates of free Ca2 + in cytoplasm and mitochondria. In addition, we found that PVALB reduced cell proliferation rate and induced cell death, probably via decreased GSK-3² and AKT phosphorylation and expression of proteins associated with reticulum stress (PERK). In addition, through the analysis by transmission electron microscopy, we observed that cells expressing PVALB have modifications in cell morphology. PVALB promoted an increase in cell size and number of mitochondrias. Finally, we observed that the expression of PVALB is correlated with the presence of calcium in the ACH samples, confirming our results obtained in vitro. These data together suggest an important role of PVALB in the acquisition of the phenotypic characteristics commonly observed in Hürthle cells and that PVALB can act as a tumor suppressor gene. In this project, we propose to investigate the mechanism associated to alteration of PVALB expression in Hürthle cell tumors. We aim to investigate whether these changes are due to some epigenetic mechanism (methylation) or by copy number variation. We propose also to analyze the metabolic profile associated with ectopic expression of PVALB in the cell lines of follicular thyroid carcinomas and, in this way, to identify possible metabolic pathways that may contribute to the pathogenesis of thyroid tumors. (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)

ARAUJO, ALINE NEVES; CAMACHO, CLEBER PINTO; MENDES, THAIS BIUDE; LINDSEY, SUSAN CHOW; MORAES, LAIS; MIYAZAWA, MARTA; DELCELO, ROSANA; PELLEGRINO, RENATA; MAZZOTTI, DIEGO ROBLES; MACIEL, RUI MONTEIRO DE BARROS; CERUTTI, JANETE MARIA. Comprehensive Assessment of Copy Number Alterations Uncovers Recurrent AIFM3 and DLK1 Copy Gain in Medullary Thyroid Carcinoma. CANCERS, v. 13, n. 2 JAN 2021. Web of Science Citations: 0.

DE JESUS PANIZA, ANA CAROLINA; MENDES, THAIS BIUDE; BORGES VIANNA, MATHEUS DUARTE; DIAS THOMAZ, DEBORA MOTA; CHIAPPINI, PAULA B. O.; COLAZZA-GAMA, GABRIEL A.; LINDSEY, SUSAN CHOW; DE CARVALHO, MARCOS BRASILINO; FERREIRA ALVES, VENANCIO AVANCINI; CURIONI, OTAVIO; BASTOS, ANDRE UCHIMURA; CERUTTI, JANETE MARIA. Revised criteria for diagnosis of NIFTP reveals a better correlation with tumor biological behavior. ENDOCRINE CONNECTIONS, v. 8, n. 11, p. 1529-1538, NOV 2019. Web of Science Citations: 0.