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Evaluation of angiogenesis biomarkers in cancer development and response to treatment.

Abstract

Introduction: Angiogenesis is one of the main processes involved in cancer development. In view of this, it is important to identify angiogenic biomarkers that can help in early diagnosis of cancer, prognosis, therapy and prevention strategies. Objectives: This project aims to identify angiogenic markers in head and neck cancer (CCP), thyroid cancer (CT) and hepatocellular carcinoma (HCC) through: 1) Evaluation of expression in mRNA (mRNA) of genes involved in Phase I metabolism (CYP and Oxygenases) and Phase II (antioxidants) of VEGFA gene in CCP and in normal adjacent tissues; 2) Analysis of the inhibitory effect of Atorvastatin on oxidative stress in SCC-15 CCP cell line; quantify the mRNA and protein expression of VEGFA in treated and untreated cell lines; to evaluate the effect of inhibition of oxidative stress in gene and protein expression of VEGFA, angiogenesis and cell invasion in vitro; 3) detection of involvement of miRNAs (hsa-miR-612, hsa-miR-1255th, hsa-miR-206, hsa-miR -874, hsa-miR-1, miR-15b, hsa) in the regulation of VEGFA gene through of studies in HCC cell line (HepG2 and SNU-182); 4) Evaluation of miRNAs hsa-miR-140-5p, hsa-miR-187-5p and VEGFA and NFE2L2 gene expression in CT cell line (K1 strain) and in tissues of human thyroid carcinoma and hyperplasia compared to samples from adjacent tissue and, verify with cell transfection technique, the involvement of miRNAs in the silencing of VEGFA and NFE2L2 genes; 5) Identification of cancer stem cells (CTT) in tissues of CCP patients after surgery; and administer Cetuximab and Docetaxel chemotherapy, separetely in vitro in tissues with CTT to verify cell viability in relation to time of exposure to chemotherapy; to compare the degree of resistance of CTT without the application of chemotherapy with CTT exposed to chemotherapy and evaluating the expression CD44, CD133 and ALDH1genes related CTT and genes TrkB, EGF, EGFR and KRAS related angiogenesis in HNC tumors according to the exposure time. Materials and Methods: The methodology will involve primary culture of CCP, CHC and CT tumors and cell lines (SCC-15, HepG2, SNU-182, K1). Cells from primary cultures of CCP tumors will be treated with Cetuximab and docetaxel chemotherapy, and subjected to analysis of cell viability by MTS assay of apoptosis by flow cytometry, gene and protein expression of CD44, CD133, ALDH1, TrkB, EGF, EGFR, KRAS. The SCC-15 cell line will be treated with atorvastatin to evaluate the intracellular generation of reactive oxygen species (ROS) and the effects of oxidative stress in angiogenesis, evaluating the potential of vessel formation and cell invasion using Cell invasionas kit. Cells from primary cultures of HCC and HepG2 line (SNU-182) will be subjected to transfection to mimic miRNAs miR-206, miR-612 and miR-1255th and miR-874, miR-1 and miR-15b for silencing of genes VEGFA and NFE2L2. Cells from primary cultures of CT and K1 cell line will be transfected with miRNAs hsa-miR-140-5p, hsa-miR-187-5p to silence of VEGFA and NFE2L2 genes. The results will be evaluated by statistical analysis in specific programs. The data will be written in scientific articles and published in high impact journals in the literature, providing technological innovation, efficient biomarkers significantly collaborating on prognosis, diagnosis and treatment of cancer. (AU)

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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)
STUCHI, LEONARDO P.; CASTANHOLE-NUNES, MARCIA MARIA U.; MANIEZZO-STUCHI, NATHALIA; BISELLI-CHICOTE, PATRICIA M.; HENRIQUE, TIAGO; PADOVANI NETO, JOAO ARMANDO; DE-SANTI NETO, DALISIO; GIROL, ANA PAULA; PAVARINO, ERIKA C.; GOLONI-BERTOLLO, ENY MARIA. VEGFA and NFE2L2 Gene Expression and Regulation by MicroRNAs in Thyroid Papillary Cancer and Colloid Goiter. GENES, v. 11, n. 9, . (15/04403-8)
SILVA GALBIATTI-DIAS, ANA LIVIA; MENDONCA FERNANDES, GLAUCIA MARIA; URBANIN CASTANHOLE-NUNES, MARCIA MARIA; HIDALGO, LUIZA FERNANDES; VIESI NASCIMENTO FILHO, CARLOS HENRIQUE; KAWASAKI-OYAMA, ROSA SAYOKO; MUNIZ FERREIRA, LETICIA ANTUNES; BISELLI-CHICOTE, PATRICIA MATTOS; PAVARINO, ERIKA CRISTINA; GOLONI-BERTOLLO, ENY MARIA. Relationship between CD44(high)/CD133(high)/CD117(high) cancer stem cells phenotype and Cetuximab and Paclitaxel treatment response in head and neck cancer cell lines. AMERICAN JOURNAL OF CANCER RESEARCH, v. 8, n. 8, p. 1633-1641, . (14/15009-6, 15/04403-8)
DE MENDONCA FERNANDES, GLAUCIA MARIA; SILVA GALBIATTI-DIAS, ANA LIVIA; MUNIZ FERREIRA, LETICIA ANTUNES; SERAFIM JUNIOR, VILSON; RODRIGUES-FLEMING, GABRIELA HELENA; DE OLIVEIRA-CUCOLO, JULIANA GARCIA; BISELLI-CHICOTE, PATRICIA MATOS; KAWASAKI-OYAMA, ROSA SAYOKO; MANIGLIA, JOSE VICTOR; PAVARINO, ERIKA CRISTINA; et al. Anti-EGFR treatment effects on laryngeal cancer stem cells. AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH, v. 13, n. 1, p. 143-155, . (16/20087-1, 15/04403-8, 14/15009-6)

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