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Roles of nitric oxide (NO) and inducible nitric oxide synthase for epithelial-mesenchymal promotion in colon Cancer human cells line

Grant number: 19/12591-0
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): July 01, 2020
Effective date (End): February 28, 2023
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Principal Investigator:Hugo Pequeno Monteiro
Grantee:Maytê dos Santos Toledo
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated research grant:18/15038-7 - Tumor development under the perspective of redox signaling: temporal modulation of the production of nitric oxide and reactive oxygen species, AP.TEM

Abstract

Cancer is a set of more than 200 diseases that are characterized by mutations in genes that regulate cellular proliferation and differentiation. A chronic inflammatory condition characterizes the development and establishment of various types of Cancer, including Colorectal Cancer (CCR). In addition, Nitric Oxide (NO) and other reactive species generated in these chronic inflammatory processes appear to play a key role in the regulation of signaling pathways associated with tumor progression in general and in particular of RCC. In normal or tumor cells, two constitutive isoforms and an inducible isoform of NO synthases (NOS2) produce NO. Specifically, NO production by NOS2 has been shown to be an important element in the progression of RCCs. Our laboratory has recently shown that in the cells of CCR lines, in the early stages of tumor development NO * production is reduced and in the following stages, where the tumor cells detach from their primary site and migrate to the sites of metastasis prevail concentrations higher NO levels. NO activation of canonical and oncogenic signaling pathways, EGFR/Ras/Raf/MEK/ERK, Ras-ERK and PI3K-Akt, has also been documented. Several studies report that the activation of these pathways is associated with the induction of the Epithelial-Mesenchimal Transition (EMT), one of the initial and essential steps for tumor progression that will result in metastasis. In order to understand the role of NO/NOS2 in the connections between the activation of canonical and oncogenic signaling pathways mentioned above and the induction of TMS in RCC, we intend to achieve the following objectives: (1) to determine the levels of expression of NOS2 and NO production by cells from the CCR, SW480 (primary tumor tumor cell), SW620 (SW480 cell lymph node metastasis) and SW480 cells that will be transfected permanently with additional copies of the gene encoding the NOS2 enzyme; (2) to determine the occurrence of activation of oncogenic signaling pathways in the three strains and their correlation with: NOS2 expression levels and levels of EMT markers expression: transcription factors: Snail, Slug, Twist1 and Zeb1 and the N-cadherin and vimentin proteins; (3) determine levels of the protein markers of EMT, N-cadherin and vimentin; (4) cking to correlate the events with the levels of NOS2 expression. (AU)