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Study of cell cycle of adrenocortical tumor cells: analysis of oncogenes and tumor suppressor genes expression, and proliferation through the chemotherapeutic drugs action

Grant number: 12/21839-6
Support type:Regular Research Grants
Duration: March 01, 2013 - February 28, 2015
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Claudimara Ferini Pacicco Lotfi
Grantee:Claudimara Ferini Pacicco Lotfi
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil


Adrenocortical tumors event is bimodal, before 5 years and after 40-50 years. Adrenocortical carcinomas are rare and aggressive, with incidence of 0.05 to 0.2% of all cancers, but in Brazil, these rates are higher in the South and Southeast of the country due to the occurrence of a mutation in the gene suppressor tumor, the p53 gene. Even with the use of standardized criteria, there is difficulty in differentiating adenomas, carcinomas, especially in pediatric populations. Despite the existence of some molecular markers, these are not sufficient molecular markers for accurate diagnosis and prognosis of disease, and there are few biological models for the study of the mechanisms of cell signaling. Therefore, because they are rare and have different clinical aspects, the use of cell cultures is a valuable tool that can contribute to the understanding of pathophysiological processes responsible for the genesis and progression of adrenocortical tumors. The hypothesis is that new markers may help in the classification of these tumors so we will analyze oncogenes and tumor suppressor genes expression of cells obtained from adenomas, carcinomas and metastases of adult and pediatric patients with different clinical characteristics by using PCR array. Moreover, such plates allow analysis of the expression of Jun family genes (Jun, JunB and JunD), comprising the transcription factor AP-1 that is necessary in regulating the cell cycle. The validation of differentially expressed genes occurs by analysis of protein synthesis by immunoblotting and immunocytochemistry. Moreover, the cultures will be tested for synthesis and secretion of steroids in the culture medium by using specific commercial kits. In addition, we will test whether new chemotherapy alternatives, in combination or not with mitotane, can inhibit cell proliferation of adrenocortical tumors. To test drugs response we will evaluate, in vitro, the cytotoxic responses of adrenocortical tumor cell cultures in monolayer (2D) and spheroids (3D), which will be exposed to different chemotherapeutic drugs in different concentrations and combinations. Complementary assays will be used to analyze the viability and cell death, as MTS assay, labeling trypan blue exclusion, flow cytometry and TUNNEL labeling. We expect standardize an easy and reproducible protocol for chemotherapy treatment and routine analysis of adrenocortical tumor cells from patients in monolayer cultures and spheroids, which represent the best tumor environment. In summary, in this project we expected to increase the number of tools available for the study of different aspects of adrenocortical proliferative diseases, such as tumorigenesis mechanisms, control of steroidogenesis, mechanisms of resistance to chemotherapy, and even mechanisms of metastasis. (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)
FRANCA, MONICA MALHEIROS; LERARIO, ANTONIO M.; FRAGOSO, MARIA CANDIDA B. V.; PACICCO LOTFI, CLAUDIMARA FERINI. New evidences on the regulation of SF-1 expression by POD1/TCF21 in adrenocortical tumor cells. Clinics, v. 72, n. 6, p. 391-394, JUN 2017. Web of Science Citations: 1.
FRANCA, M. M.; ABREU, N. P.; VRECHI, T. A. M.; LOTFI, C. F. POD-1/Tcf21 overexpression reduces endogenous SF-1 and StAR expression in rat adrenal cells. Brazilian Journal of Medical and Biological Research, v. 48, n. 12, p. 1087-1094, DEC 2015. Web of Science Citations: 6.
FRANCA, MONICA MALHEIROS; FERRAZ-DE-SOUZA, BRUNO; LERARIO, ANTONIO MARCONDES; BARISSON VILLARES FRAGOSO, MARIA CANDIDA; PACICCO LOTFI, CLAUDIMARA FERINI. POD-1/TCF21 Reduces SHP Expression, Affecting LRH-1 Regulation and Cell Cycle Balance in Adrenocortical and Hepatocarcinoma Tumor Cells. BIOMED RESEARCH INTERNATIONAL, 2015. Web of Science Citations: 5.

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