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Study of regulation of ADAMs in oral cancer

Grant number: 10/19278-0
Support type:Research Grants - Young Investigators Grants
Duration: September 01, 2011 - October 31, 2016
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Adriana Franco Paes Leme
Grantee:Adriana Franco Paes Leme
Home Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brasil). Campinas , SP, Brazil
Assoc. researchers:Annelize Zambon Barbosa Aragão ; Francisco Humberto Nociti Junior ; Michelle Agostini ; Ricardo Della Coletta
Associated grant(s):16/50005-7 - The role of ADAM 17-containing exosomes in sculpting metastatic niche in oral cancer, AP.R
Associated scholarship(s):13/16483-0 - Study of protein composition in the invasion area of squamous cell carcinoma by proteomics based on mass spectrometry, BP.DR
14/06485-9 - Investigation of the ADAM17 metalloproteinase regulation mechanism by the interaction with Trx-1, BP.PD
13/02257-9 - Search of Syndecan- 1 binders using quantitative proteomic approach, BP.DR
11/22421-2 - Determination of cleavage sites of recombinant ADAM-17 in human cells, BP.DD
11/02267-9 - Identifying ADAM17 partners and mapping the domains responsible for its interaction with other proteins, BP.PD

Abstract

Oral squamous cell carcinoma is highly invasive cancer and this invasion occurs mainly due to the proteolytic activity of metalloproteinases on basal membrane and extracellular matrix. The proteinases are key regulators of both cell-cell and cell-extracellular matrix (ECM) interactions that are associated with all aspects of tumorigenesis and metastasis, and the interest in their potential as targets for the development of anticancer agents dates back many decades. ADAMs, a family of membrane proteinase, have been considered critical in this process due to the high expression in tumors, showing strong correlation with disease progression and development. ADAMs are characterized as sheddases, proteinases that are involved in the regulation of physiological and development processes by the release of surface ectodomain proteins. In addition, there is a triple cross-talk among EGFR, GPCR and ADAMs, and ADAMs function as signaling effectors of GPCR and EGFR, which could determine the regulation of several processes, including cell proliferation and migration. Recently, novel extracellular targets resulting from proteolytic activity of ADAMs have been revealed, indicating that little is known about these molecules considering the vast pathways that could be coordinate by these proteinases. Indeed only a few studies increased knowledge about the ligands and the mechanism they are involved to activate ADAMs. To gain insight into the mechanism of action of ADAM-17, the aim of this project is to elucidate the regulation of ADAM-17 in vitro model of tumorigenic and non-tumorigenic cells, animal model and human tissue using molecular and cellular biology, proteomic and mass spectrometry tools. Different strategies will be performed to modulate ADAM-17 expression to determine novel targets, its cleavage sites, the cytoplasmatic domain ligands, the phosphorylation sites in the cytoplasmatic domain and the phosphorylation sites of membrane proteins. The effect of ADAM-17 modulation in keratinocytes and oral squamous cell carcinoma (CEC) will be evaluated by migration, proliferation, adhesion, invasion and apoptosis assays. To validate and improve the in vitro experiments, the protein and peptide composition will be also evaluated in tumor induced by cell lines with modulated ADAM-17 and in human tissue samples. The gene expression of specific targets will be evaluated in all the models used in this study. The results of this project could improve the knowledge of ligands the signaling pathways of ADAM-17 to elucidate subproteome targets to peptides and inhibitors design that could modulate the ligand binding as well as to reveal potential candidates involved in the initiation and progression of oral cancer, and thus, could aid to the development of novel diagnostic and treatment options for this disease. (AU)

Articles published in Agência FAPESP Newsletter about the research grant
Oral cancer prognostic signature identified 

Scientific publications (19)
(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)
CARNIELLI, CAROLINA MORETTO; SOARES MACEDO, CAROLINA CARNEIRO; DE ROSSI, TATIANE; GRANATO, DANIELA CAMPOS; RIVERA, CESAR; DOMINGUES, ROMENIA RAMOS; PAULETTI, BIANCA ALVES; YOKOO, SAMI; HEBERLE, HENRY; BUSSO-LOPES, ARIANE FIDELIS; CERVIGNE, NILVA KARLA; SAWAZAKI-CALONE, IRIS; MEIRELLES, GABRIELA VAZ; MARCHI, FABIO ALBUQUERQUE; TELLES, GUILHERME PIMENTEL; MINGHIM, ROSANE; PRADO RIBEIRO, ANA CAROLINA; BRANDAO, THAIS BIANCA; CASTRO, JR., GILBERTO DE; ALEJANDRO GONZALEZ-ARRIAGADA, WILFREDO; GOMES, ALEXANDRE; PENTEADO, FABIO; SANTOS-SILVA, ALAN ROGER; LOPES, MARCIO AJUDARTE; RODRIGUES, PRISCILA CAMPIONI; SUNDQUIST, ELIAS; SALO, TUULA; DA SILVA, SABRINA DANIELA; ALAOUI-JAMALI, MOULAY A.; GRANER, EDGARD; FOX, JAY W.; DELLA COLETTA, RICARDO; PAES LEME, ADRIANA FRANCO. Combining discovery and targeted proteomics reveals a prognostic signature in oral cancer. NATURE COMMUNICATIONS, v. 9, SEP 5 2018. Web of Science Citations: 9.
RIVERA, CESAR; ZANDONADI, FLAVIA SILVA; SANCHEZ-ROMERO, CELESTE; SOARES, CIRO DANTAS; GRANATO, DANIELA CAMPOS; ALEJANDRO GONZALEZ-ARRIAGADA, WILFREDO; PAES LEME, ADRIANA FRANCO. Agrin has a pathological role in the progression of oral cancer. BRITISH JOURNAL OF CANCER, v. 118, n. 12, p. 1628-1638, JUN 2018. Web of Science Citations: 1.
GRANATO, DANIELA C.; P. E COSTA, RUTE A.; KAWAHARA, REBECA; YOKOO, SAMI; ARAGAO, ANNELIZE Z.; DOMINGUES, ROMENIA R.; PAULETTI, BIANCA A.; HONORATO, RODRIGO V.; FATTORI, JULIANA; FIGUEIRA, ANA CAROLINA M.; OLIVEIRA, PAULO S. L.; CONSONNI, SILVIO R.; FERNANDES, DENISE; LAURINDO, FRANCISCO; HANSEN, HINRICH P.; LEME, ADRIANA F. PAES. Thioredoxin-1 Negatively Modulates ADAM17 Activity Through Direct Binding and Indirect Reductive Activity. Antioxidants & Redox Signaling, v. 29, n. 8 FEB 2018. Web of Science Citations: 0.
SCHAEFER, MIRIAM; GRANATO, DANIELA C.; KROSSA, SEBASTIAN; BARTELS, ANNE-KATHRIN; YOKOO, SAMI; DUSTERHOFT, STEFAN; KOUDELKA, TOMAS; SCHEIDIG, AXEL J.; THOLEY, ANDREAS; PAES LEME, ADRIANA F.; GROETZINGER, JOACHIM; LORENZEN, INKEN. GRP78 protects a disintegrin and metalloprotease 17 against protein-disulfide isomerase A6 catalyzed inactivation. FEBS Letters, v. 591, n. 21, p. 3567-3587, NOV 2017. Web of Science Citations: 4.
KAWAHARA, REBECA; GRANATO, DANIELA CAMPOS; YOKOO, SAMI; DOMINGUES, ROMENIA RAMOS; TRINDADE, DANIEL MARAGNO; PAES LEME, ADRIANA FRANCO. Mass spectrometry-based proteomics revealed Glypican-1 as a novel ADAM17 substrate. JOURNAL OF PROTEOMICS, v. 151, n. SI, p. 53-65, JAN 16 2017. Web of Science Citations: 3.
TAVARES, RAPHAEL; WAJNBERG, GABRIEL; SCHERER, NICOLE DE MIRANDA; PAULETTI, BIANCA ALVES; CASSOLI, JULIANA S.; FERREIRA, CARLOS GIL; PAES LEME, ADRIANA FRANCO; DE ARAUJO-SOUZA, PATRICIA SAVIO; MARTINS-DE-SOUZA, DANIEL; PASSETTI, FABIO. Unveiling alterative splice diversity from human oligodendrocyte proteome data. JOURNAL OF PROTEOMICS, v. 151, n. SI, p. 293-301, JAN 16 2017. Web of Science Citations: 2.
KORVALA, JOHANNA; MOSAKHANI, NEDA; ZANDONADI, FLAVIA S.; MEIRELLES, GABRIELA V.; PAES LEME, ADRIANA FRANCO; COLETTA, RICARDO D.; LEIVO, ILMO; SALO, TUULA. . Experimental Cell Research, v. 350, n. 1, p. 9-18, JAN 1 2017. Web of Science Citations: 9.
FLORES, ISADORA L.; KAWAHARA, REBECA; MIGUEL, MARCIA C. C.; GRANATO, DANIELA C.; DOMINGUES, ROMENIA R.; MACEDO, CAROLINA C. S.; CARNIELLI, CAROLINA M.; YOKOO, SAMI; RODRIGUES, PRISCILA C.; MONTEIRO, BARBARA V. B.; OLIVEIRA, CARINE E.; SALMON, CRISTIANE R.; NOCITI, FRANCISCO H.; LOPES, MARCIO A.; SANTOS-SILVA, ALAN; WINCK, FLAVIA V.; COLETTA, RICARDO D.; PAES LEME, ADRIANA F. EEF1D modulates proliferation and epithelial-mesenchymal transition in oral squamous cell carcinoma. Clinical Science, v. 130, n. 10, p. 785-799, MAY 1 2016. Web of Science Citations: 12.
KAWAHARA, REBECA; MEIRELLES, GABRIELA V.; HEBERLE, HENRY; DOMINGUES, ROMENIA R.; GRANATO, DANIELA C.; YOKOO, SAMI; CANEVAROLO, RAFAEL R.; WINCK, FLAVIAV.; RIBEIRO, ANA CAROLINA P.; BRANDAO, THAIS BIANCA; FILGUEIRAS, PAULO R.; CRUZ, KAREN S. P.; BARBUTO, JOSE ALEXANDRE; POPPI, RONEI J.; MINGHIM, ROSANE; TELLES, GUILHERME P.; FONSECA, FELIPE PAIVA; FOX, JAY W.; SANTOS-SILVA, ALAN R.; COLETTA, RICARDO D.; SHERMAN, NICHOLAS E.; PAES LEME, ADRIANA F. Integrative analysis to select cancer candidate biomarkers to targeted validation. ONCOTARGET, v. 6, n. 41, p. 43635-43652, DEC 22 2015. Web of Science Citations: 5.
WINCK, FLAVIA V.; PRADO RIBEIRO, ANA CAROLINA; DOMINGUES, ROMENIA RAMOS; LING, LIU YI; RIANO-PACHON, DIEGO MAURICIO; RIVERA, CESAR; BRANDAO, THAIS BIANCA; GOUVEA, ADRIELE FERREIRA; SANTOS-SILVA, ALAN ROGER; COLETTA, RICARDO D.; PAES LEME, ADRIANA F. Insights into immune responses in oral cancer through proteomic analysis of saliva and salivary extracellular vesicles. SCIENTIFIC REPORTS, v. 5, NOV 5 2015. Web of Science Citations: 27.
CARNIELLI, CAROLINA M.; WINCK, FLAVIA V.; LEME, ADRIANA F. PAES. Functional annotation and biological interpretation of proteomics data. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, v. 1854, n. 1, p. 46-54, JAN 2015. Web of Science Citations: 19.
KAWAHARA, REBECA; GRANATO, DANIELA C.; CARNIELLI, CAROLINA M.; CERVIGNE, NILVA K.; OLIVERIA, CARINE E.; MARTINEZ, CESAR A. R.; YOKOO, SAMI; FONSECA, FELIPE P.; LOPES, MARCIO; SANTOS-SILVA, ALAN R.; GRANER, EDGARD; COLETTA, RICARDO D.; PAES LEME, ADRIANA FRANCO. Agrin and Perlecan Mediate Tumorigenic Processes in Oral Squamous Cell Carcinoma. PLoS One, v. 9, n. 12 DEC 15 2014. Web of Science Citations: 23.
GRANATO, DANIELA C.; ZANETTI, MARIANA R.; KAWAHARA, REBECA; YOKOO, SAMI; DOMINGUES, ROMENIA R.; ARAGAO, ANNELIZE Z.; AGOSTINI, MICHELLE; CARAZZOLLE, MARCELO F.; VIDAL, RAMON O.; FLORES, ISADORA L.; KORVALA, JOHANNA; CERVIGNE, NILVA K.; SILVA, ALAN R. S.; COLETTA, RICARDO D.; GRANER, EDGARD; SHERMAN, NICHOLAS E.; PAES LEME, ADRIANA F. Integrated Proteomics Identified Up-Regulated Focal Adhesion-Mediated Proteins in Human Squamous Cell Carcinoma in an Orthotopic Murine Model. PLoS One, v. 9, n. 5 MAY 23 2014. Web of Science Citations: 5.
KAWAHARA, REBECA; LIMA, RENATO NIYAMA; DOMINGUES, ROMENIA R.; PAULETTI, BIANCA ALVES; MEIRELLES, GABRIELA V.; ASSIS, MICHELLE; MIGLIORINI FIGUEIRA, ANA CAROLINA; PAES LEME, ADRIANA FRANCO. Deciphering the Role of the ADAM17-Dependent Secretome in Cell Signaling. JOURNAL OF PROTEOME RESEARCH, v. 13, n. 4, p. 2080-2093, APR 2014. Web of Science Citations: 20.
SIMABUCO, FERNANDO MOREIRA; KAWAHARA, REBECA; YOKOO, SAMI; GRANATO, DANIELA C.; MIGUEL, LUCAS; AGOSTINI, MICHELLE; ARAGAO, ANNELIZE Z. B.; DOMINGUES, ROMENIA R.; FLORES, ISADORA L.; MACEDO, CAROLINA C. S.; DELLA COLETTA, RICARDO; GRANER, EDGARD; PAES LEME, ADRIANA FRANCO. ADAM17 mediates OSCC development in an orthotopic murine model. Molecular Cancer, v. 13, FEB 5 2014. Web of Science Citations: 10.
WINCK, FLAVIA V.; BELLONI, MARILIA; PAULETTI, BIANCA A.; ZANELLA, JACKELINE DE LIMA; DOMINGUES, ROMENIA R.; SHERMAN, NICHOLAS E.; PAES LEME, ADRIANA F. Phosphoproteome analysis reveals differences in phosphosite profiles between tumorigenic and non-tumorigenic epithelial cells. JOURNAL OF PROTEOMICS, v. 96, p. 67-81, JAN 16 2014. Web of Science Citations: 9.
MASSON, N.; DOMINGUES, R. R.; CURY, J. A.; PAES LEME, A. F. Acidulated Phosphate Fluoride Application Changes the Protein Composition of Human Acquired Enamel Pellicle. Caries Research, v. 47, n. 3, p. 251-258, 2013. Web of Science Citations: 6.
ARAGAO, ANNELIZE Z. B.; NOGUEIRA, MARIA LUIZA C.; GRANATO, DANIELA C.; SIMABUCO, FERNANDO M.; HONORATO, RODRIGO V.; HOFFMAN, ZAIRA; YOKOO, SAMI; LAURINDO, FRANCISCO R. M.; SQUINA, FABIO M.; ZERI, ANA CAROLINA M.; OLIVEIRA, PAULO S. L.; SHERMAN, NICHOLAS E.; PAES LEME, ADRIANA F. Identification of Novel Interaction between ADAM17 (a Disintegrin and Metalloprotease 17) and Thioredoxin-1. Journal of Biological Chemistry, v. 287, n. 51, p. 43071-43082, DEC 14 2012. Web of Science Citations: 22.
ARAGAO, ANNELIZE Z. B.; BELLONI, MARILIA; SIMABUCO, FERNANDO M.; ZANETTI, MARIANA R.; YOKOO, SAMI; DOMINGUES, ROMENIA R.; KAWAHARA, REBECA; PAULETTI, BIANCA A.; GONCALVES, ANDERSON; AGOSTINI, MICHELLE; GRANER, EDGARD; COLETTA, RICARDO D.; FOX, JAY W.; PAES LEME, ADRIANA F. Novel Processed Form of Syndecan-1 Shed from SCC-9 Cells Plays a Role in Cell Migration. PLoS One, v. 7, n. 8 AUG 15 2012. Web of Science Citations: 27.

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