Oncotarget

Research Papers:

Relevance of CCL3/CCR5 axis in oral carcinogenesis

Janine Mayra da Silva, Tálita Pollyanna Moreira dos Santos, Lays Martin Sobral, Celso Martins Queiroz-Junior, Milene Alvarenga Rachid, Amanda E.I. Proudfoot, Gustavo Pompermaier Garlet, Aline Carvalho Batista, Mauro Martins Teixeira, Andréia Machado Leopoldino, Remo Castro Russo and Tarcília Aparecida Silva _

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Oncotarget. 2017; 8:51024-51036. https://doi.org/10.18632/oncotarget.16882

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Abstract

Janine Mayra da Silva1,2, Tálita Pollyanna Moreira dos Santos3, Lays Martin Sobral3, Celso Martins Queiroz-Junior2, Milene Alvarenga Rachid4, Amanda E.I. Proudfoot5, Gustavo Pompermaier Garlet6, Aline Carvalho Batista7, Mauro Martins Teixeira8, Andréia Machado Leopoldino3, Remo Castro Russo9 and Tarcília Aparecida Silva1

1Department of Oral Surgery and Pathology, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

2Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

3Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, Universidade de São Paulo, São Paulo, Bauru, Brazil

4Department of General Pathology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

5Merck Serono Geneva Research Centre, Geneva, Switzerland

6Department of Biological Sciences, School of Dentistry, Universidade de São Paulo, São Paulo, Bauru, Brazil

7Department of Stomatology, School of Dentistry, Universidade Federal de Goiás, Goiânia, Goiás, Brazil

8Laboratory of Immunopharmacology, Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

9Laboratory of Pulmonary Immunology and Mechanics, Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

Correspondence to:

Tarcília Aparecida Silva, email: tarcilia@ufmg.br

Keywords: chemokines, CCL3, CCR1, CCR5, OSCC

Received: August 15, 2016    Accepted: February 20, 2017    Published: April 06, 2017

ABSTRACT

The chemokine CCL3 is a chemotactic cytokine crucial for inflammatory cell recruitment in homeostatic and pathological conditions. CCL3 might stimulate cancer progression by promoting leukocyte accumulation, angiogenesis and tumour growth. The expression of CCL3 and its receptors CCR1 and CCR5 was demonstrated in oral squamous cell carcinoma (OSCC), but their role was not defined. Here, the functions of CCL3 were assessed using a model of chemically induced tongue carcinogenesis with 4-nitroquinoline-1-oxide (4NQO). Lineages of OSCC were used to analyse the effects of CCL3 in vitro. The 4NQO-induced lesions exhibited increased expression of CCL3, CCR1 and CCR5. CCL3-/- and CCR5-/- mice presented reduced incidence of tongue tumours compared to wild-type (WT) and CCR1-/- mice. Consistently, attenuated cytomorphological atypia and reduced cell proliferation were observed in lesions of CCL3-/- and CCR5-/- mice. OSCC from CCL3-/- mice exhibited lower infiltration of eosinophils and reduced expression of Egf, Fgf1, Tgf-β1, Vegfa, Vegfb, Itga-4, Vtn, Mmp-1a, Mmp-2 and Mmp-9 than WT mice. In vitro, CCL3 induced invasion and production of CCL5, IL-6, MMP -2, -8, -9. Blockage of CCL3 in vitro using α-CCL3 or Evasin-1 (a CCL3-binding protein) impaired tumour cell invasion. In conclusion, CCL3/CCR5 axis has pro-tumourigenic effects in oral carcinogenesis. The induction of inflammatory and angiogenic pathways and eosinophils recruitment appear to be the underlying mechanism explaining these effects. These data reveal potential protective effects of CCL3 blockade in oral cancer.


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