Role of syndecan-4 in extracellular matrix remodeling in anoikis-resistant endothelial cells

• Grant number: 19/19739-2
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2020
• End date: September 30, 2023
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Carla Cristina Lopes de Azevedo
• Grantee: Carla Cristina Lopes de Azevedo
• Host Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil
• Associated researchers: Helena Bonciani Nader

Abstract

During cancer progression, some events are important to trigger the metastasis process, such as extracellular matrix remodeling for survival after the absence of cell-extracellular matrix interaction, in a process denominated anoikis resistance. Previous work from our group has shown that anoikis-resistant endothelial cells show an increased in the sindecan-4 expression, a heparan sulfate proteoglycan that, together with integrins, can act as a co-receptor in the interaction between extracellular matrix and cytoskeleton. Also, anoikis-resistant endothelial cells exhibit alterations in the expression of genes and proteins involved in extracellular matrix remodeling, leading to a decrease in cell adhesion and an increase in cell invasion and proliferation. Although syndecam-4 and other extracellular matrix molecules play important roles in cancer progression, the cellular and molecular mechanisms of interaction of these molecules during extracellular matrix remodeling and consequently in the loss of cell adhesion, are not yet defined. Thus, this paper aims to study the role of syndecan-4 in extracellular matrix remodeling and to clarify its interactions with other molecules. For this purpose, anoikis-resistant rabbit aortic endothelial cells submitted to syndecan-4 gene silencing (Adh-shRNA-Syn4-EC) will be studied by comparing with parental anoikis-resistant rabbit aortic endothelial cells (Adh-EC), wild rabbit aortic endothelial cells (EC) and EJ-ras oncogene transfected rabbit aortic endothelial cells (EJ-ras EC) in relation to: cell migration, angiogenesis, biosynthesis of sulfated glycosaminoglycans in the cell cycle, gene and protein expression of extracellular matrix macromolecules (integrins, fibronectin, vitronectin, collagen IV and perlecan), as well as enzymes responsible for their regulation, such as metalloproteinases 2 and 9 and heparanase. In addition, we will analyze the expression of cell signaling molecules: focal adhesion kinase (FAK) and SRC, production of nitric oxide (NO) and expression of the enzyme endothelial nitric oxide synthase (eNOS). These data will provide insights into the role of syndecan-4 in the extracellular matrix remodeling of anoikis-resistant endothelial cells and thus help in the development of new therapeutic targets against cancer. (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)

ONYEISI, JESSICA OYIE SOUSA; FERREIRA, BIANCA ZAIA FRANCO; NADER, HELENA BONCIANI; LOPES, CARLA CRISTINA. Heparan sulfate proteoglycans as targets for cancer therapy: a review. CANCER BIOLOGY & THERAPY, v. 21, n. 12, NOV 2020. (19/19739-2)

MESQUITA, A. P. S.; MATSUOKA, M.; LOPES, S. A.; PERNAMBUCO FILHO, P. C. A.; CRUZ, A. S.; NADER, H. B.; LOPES, C. C.. itric oxide regulates adhesiveness, invasiveness, and migration of anoikis-resistant endothelial cell. Brazilian Journal of Medical and Biological Research, v. 55, n. 1, 2022. (19/19739-2)