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Regulation of cell migration by microRNAs: implications for Diabetes mellitus, tissue repair and cancer

Grant number: 12/03990-9
Support type:Regular Research Grants
Duration: June 01, 2012 - November 30, 2014
Field of knowledge:Biological Sciences - Morphology
Principal Investigator:Marinilce Fagundes dos Santos
Grantee:Marinilce Fagundes dos Santos
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Cell migration is an essential process during development, for tissue homeostasis, for the defense system, during wound healing and also for the development and progression of several diseases, such as cancer. Tumor invasiveness is directly related to the ability of tumor cells to migrate and invade surrounding normal tissues, spreading via blood and lymphatic circulation. In wound healing, proliferation and migration of fibroblasts is an essential process. The arrangement of the actin and microtubules cytoskeleton, as well as the cell migratory behavior, are dependent on a group of low molecular weight signaling proteins with GTPase activity belonging to the Rho family. In addition to cell migration, proteins of this family also regulate other cellular processes such as apoptosis, cell proliferation and gene expression. Rho GTPases can be activated by a variety of stimuli and exert their diverse functions through different effector proteins, whose expression may be tissue-specific. The regulation of these proteins is quite complex and this complexity increased significantly during the past few years, after the discovery of microRNAs (miRNAs) and their potential regulatory role on cell migration. In several types of cancer, for example, the altered expression of miRNAs has been related to the invasive behavior of tumor cells. There is still little information about the regulation of Rho GTPases by miRNAs. Similarly, in Diabetes Mellitus wound healing is very poor, partly due to a deficiency in the migration and proliferation of fibroblasts. The mechanisms involved in the impairment of cell migration under those circumstances are not yet fully understood, nor is the role of miRNAs in fibroblast migration or the potential regulatory role of hyperglycemia on the expression of miRNAs. This project consists of two sub-projects that aim to assess the role of different miRNAs on the activity of Rho GTPases and cell migratory behavior in two experimental models: 1) invasiveness of tumor cells of papillary thyroid carcinoma and 2) fibroblasts from the human periodontal ligament, important not only for healing but also for the regeneration of this tissue. Additionally, the effects of hyperglycemia on miRNAs expression in fibroblasts will be evaluated. The specific objectives of each subproject will be detailed within the project. Our laboratory has extensive experience in studies of cell migration, and over the past few years has been studying the regulation of migration in different systems, eg. during epithelial restitution (the earliest stage of superficial wound healing in skin and mucosal membranes)and during cutaneous wound healing in normal and diabetic animals. We have also been studying the role of Rho GTPases in different systems, such as epithelial restitution, cell differentiation, development, morphology and proliferation of glial cells, apoptosis, macrophage migration and phagocytosis and cell migration during acinar differentiation. We expect that the results obtained in the current project may contribute to the development of new therapies for the inhibition of metastasis formation, as well as therapies that improve the rate of periodontal regeneration in humans, especially diabetics. (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)
MARCAL PESSOA, ANA FLAVIA; FLORIM, JULIANA COSTA; RODRIGUES, HOSANA GOMES; ANDRADE-OLIVEIRA, VINICIUS; TEIXEIRA, SIMONE A.; VITZEL, KAIO FERNANDO; CURI, RUI; SARAIVA CAMARA, NIELS OLSEN; MUSCARA, MARCELO N.; LAMERS, MARCELO LAZZARON; SANTOS, MARINILCE FAGUNDES. Oral administration of antioxidants improves skin wound healing in diabetic mice. WOUND REPAIR AND REGENERATION, v. 24, n. 6, p. 981-993, NOV-DEC 2016. Web of Science Citations: 3.
ALMEIDA, MAIRA ESTANISLAU S.; MONTEIRO, KELLY S.; KATO, ELLEN E.; SAMPAIO, SANDRA C.; BRAGA, TARCIO T.; CAMARA, NIELS O. S.; LAMERS, MARCELO L.; SANTOS, MARINILCE F. Hyperglycemia reduces integrin subunits alpha v and alpha 5 on the surface of dermal fibroblasts contributing to deficient migration. Molecular and Cellular Biochemistry, v. 421, n. 1-2, p. 19-28, OCT 2016. Web of Science Citations: 9.
LIMA, CILENE REBOUCAS; GERALDO, MURILO VIEIRA; FUZIWARA, CESAR SEIGI; KIMURA, EDNA TERUKO; SANTOS, MARINILCE FAGUNDES. MiRNA-146b-5p upregulates migration and invasion of different Papillary Thyroid Carcinoma cells. BMC CANCER, v. 16, FEB 16 2016. Web of Science Citations: 32.

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