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Analysis of laminin cleavage, generating putative bioactive peptides.

Grant number: 15/03393-9
Support type:Regular Research Grants
Duration: February 01, 2016 - January 31, 2018
Field of knowledge:Biological Sciences - Morphology - Cytology and Cell Biology
Principal researcher:Ruy Gastaldoni Jaeger
Grantee:Ruy Gastaldoni Jaeger
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Breast cancer is a major public health problem with significant morbidity and mortality. The microenvironment plays an important role in tumorigenesis and tumor progression. Extracellular matrix (ECM) is a crucial component of microenvironment. Our laboratory studies the effect of laminin, a major ECM glycoprotein, in tumor biology. We have systematically investigated the in vitro effect of laminin-derived peptides in cancer. We have discovered that laminin-derived peptides are responsible for important steps in tumor biology, such as migration, invasion, invadopodia formation and protease secretion. We have also elucidated receptors and signaling pathways related to peptide effects. However, a fundamental point to be addressed and clarified is to determine the presence of laminin peptides in tumor sites in vivo. This aspect yet remains speculative. This project has as major objective to detect in vivo peptides derived from the proteolytic cleavage of laminin. We will study by immunohistochemistry the distribution of laminin chains in human tumors. In parallel we will analyze the biochemical profile of laminin in tumor samples in vivo, compared with normal tissues. This profile would reveal bands resulting from laminin cleavage, exposing fragments containing bioactive peptides. These bands resulting from proteolytic cleavage will be sequenced by proteomic methods. Proteomic analysis will determine whether the peptides we have previously investigated in vitro (Freitas & Jaeger 2002; Capuano & Jaeger 2004; Freitas et al. 2004a; Freitas et al. 2007; Morais Freitas et al. 2007; Gama-de-Souza et al. 2008; Nascimento et al. 2010; Siqueira et al. 2010; Nascimento et al. 2011; Caires dos Santos 2014; De Siqueira 2014) are present in the tumors. Furthermore, this approach may yield the discovery of new bioactive sequences, to be further investigated. We will also investigate in vitro laminin cleavage, with release of bioactive peptides. Normal and tumor cells will be cultured on laminin. Electrophoresis and proteomics will be carried out to identify bioactive peptides from laminin cleavage. Finally, tumor cells will be treated by the peptides identified, addressing their role on adhesion, invasion, invadopodia formation and tumorigenesis. (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)
CAIRES-DOS-SANTOS, LIVIA; DA SILVA, SUELY V.; SMUCZEK, BASILIO; DE SIQUEIRA, ADRIANE S.; CRUZ, KAREN S. P.; BARBUTO, JOSE ALEXANDRE M.; AUGUSTO, TAIZE M.; FREITAS, VANESSA M.; CARVALHO, HERNANDES F.; JAEGER, RUY G. Laminin-derived peptide C16 regulates Tks expression and reactive oxygen species generation in human prostate cancer cells. Journal of Cellular Physiology, v. 235, n. 1 JUN 2019. Web of Science Citations: 1.
SMUCZEK, BASILIO; SANTOS, EMERSON DE S.; SIQUEIRA, ADRIANE S.; PINHEIRO, JOAO J. V.; FREITAS, VANESSA M.; JAEGER, RUY G. The laminin-derived peptide C16 regulates GPNMB expression and function in breast cancer. Experimental Cell Research, v. 358, n. 2, p. 323-334, SEP 15 2017. Web of Science Citations: 4.

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