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Effects of Increase of Cx43 gene expression in neoplasic lung cells transformed by tobacco carcinogen: In vitro and in vivo studies.

Grant number: 13/17108-9
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): January 01, 2014
Effective date (End): April 30, 2016
Field of knowledge:Agronomical Sciences - Veterinary Medicine - Animal Pathology
Principal Investigator:Maria Lucia Zaidan Dagli
Grantee:Lucas Martins Chaible
Home Institution: Faculdade de Medicina Veterinária e Zootecnia (FMVZ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated scholarship(s):14/19222-6 - Role of connexins during breast tumor development: study in tritransgenic mice and 3D primary cell culture, BE.EP.PD

Abstract

The lung cancer is a major cause of death in modern society, responsible for over than10 million deaths per year worldwide, and its incidence is directly related with habits of the day-to-day, among them smoking. The tobacco in cigarettes has more than ninety known carcinogens, including NNK (4 - (methylnitrosamino) -1 - (3-pyridyl)-1-butanone), the most important. This carcinogen is responsible for the formation of DNA adducts and subsequent genetic mutations that cause neoplasic clones. E10 lung cells exposed to NNK showed higher proliferative index, higher rate of migration, greater ability to perform metastases and decrease of intercellular communication mediated by Cx43 protein. This reduction in intercellular communication has been correlated with higher malignancy in tumors, because tumor clones are not suppressed by the microenvironment surrounding them. In this work, we aim to observe whether the increased expression of Cx43 gene causes restoration of intercellular communication and hence the change in the characteristics of malignancy of tumor cells. For this, we use lung cells transformed by the carcinogen NNK cells called E10-NNK20 where we will reestablish the cell communication by transfection of an inducible gene expression system drived by doxycycline (TetON-Cx43). In the presence of this antibiotic the system is activated and the Cx43 gene is expressed, its expression is turned off with the withdrawal of the drug. This project is divided into three different stages organized in a logical sequence of knowledge and complexity. The first step is performed in order to verify if in vitro phenotypic changes caused by restoration of cellular communication, these results will be compared with the known results as normal behaviors that lineage obtained previously by our group, the second stage will be the standardization of the in vivo system TetON-Cx43 expression to check the effect dose vs. response of drug and to observe the behavior of the Cx43 gene activation in vivo and in the third step,we will transplant in mice NNK20-E10 cells transfected by the system TetON-Cx43, and evaluate the impact of restoration of cellular communication in the rates of malignancy, infiltration and survival in mice. In this proposal the post-doctoral student will continue his work of PhD, and will continue getting new data also very important for the progress of the Laboratory of Experimental Oncology FMVZ - USP