ADAMTS-1 disrupts HGF/c-MET signaling and HGF-stimulated cellular processes in fibrosarcoma

Autor(es)

Noriega-Guerra, Heydi ^[1] ; Cruz, Mario C. ^[2] ; Ribeiro, Priscilla R. L. ^[1] ; Strnadel, Jan ^{[3, 4]} ; Wan, Huawei ^[3] ; Klemke, Richard L. ^[3] ; Jaeger, Ruy G. ^[1] ; Freitas, Vanessa M. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Biol Celular & Desenvolvimento, Av Prof Lineu Prestes 1524, Predio 1, Sala 428, BR-05508000 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Inst Ciencias Biomed, Ctr Facilidades Pesquisa CEFAP, Av Prof Lineu Prestes 1524, Predio 4, BR-05508000 Sao Paulo, SP - Brazil

^[3] Univ Calif San Diego, Dept Pathol, 9500 Gilman Dr, MC0612, San Diego, CA 92093 - USA

^[4] Comenius Univ, Jessenius Fac Med Martin, Biomed Ctr Martin JFM CU, Dept Mol Med, Mala Hora 4 C, Martin 03601 - Slovakia

• Tipo de documento: Artigo Científico
• Fonte: Experimental Cell Research; v. 363, n. 2, p. 271-282, FEB 15 2018.
• Citações Web of Science: 2

Resumo

Extracellular matrix (ECM) serves as a reservoir for biologically active factors, such as growth factors and proteases that influence the tumor cell behavior. ADAMTS-1 (a disintegrin and metalloprotease with thrombospondin motifs) is a secreted protease that has the ability to modify the ECM during physiological and pathological processes. Here, we analyzed the role played by ADAMTS-1 regulating HGF and TGF-beta 1 activities in the high-grade fibrosarcoma cell line (HT1080). We generated HT1080 and HEK293T cells overexpressing ADAMTS-1. HT1080 cells overexpressing ADAMTS-1 (HT1080-MPA) exhibited a significant decrease in cell proliferation and migration velocity, both in presence of HGF. We obtained similar results with wADAMTS-1-enriched conditioned medium from other cell type. However, ADAMTS-1 overexpression failed to affect TGF-beta 1 activity associated with HT1080 cell proliferation and migration velocity. Immunoblotting showed that ADAMTS-1 overexpression disturbs c-Met activation upon HGF stimulation. Downstream ERK1/2 and FAK signaling pathways are also influenced by this protease. Additionally, ADAMTS-1 decreased the size of the fibrosarcospheres, both under normal conditions and in the presence of HGF. Likewise, in presence of HGF, ADAMTS-1 overexpression in HT1080 disrupted microtumors formation in vivo. These microtumors, including individual cells, presented characteristics of non-invasive lesions (rounded morphology). Our results suggest that ADAMTS-1 is involved in regulating HGF-related functions on fibrosarcoma cells. This protease may then represent an endogenous mechanism in controlling the bioavailability of different growth factors that have a direct influence on tumor cell behavior. (AU)

• Processo FAPESP: 10/07699-1 - Protease ADAMTS-1 influenciando o comportamento e o microambiente do câncer de mama
• Beneficiário: Vanessa Morais Freitas
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 15/02498-1 - Papel do estresse na modulação do fenótipo tronco tumoral
• Beneficiário: Vanessa Morais Freitas
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/24108-2 - Importância da protease ADAMTS-1 na invasão local e sistêmica de células de fibrossarcoma
• Beneficiário: Heydi Noriega Guerra
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto