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1.
PLoS One ; 9(12): e111317, 2014.
Article in English | MEDLINE | ID: mdl-25490767

ABSTRACT

The anti-inflammatory protein annexin A1 (ANXA1) has been associated with cancer progression and metastasis, suggesting its role in regulating tumor cell proliferation. We investigated the mechanism of ANXA1 interaction with formylated peptide receptor 2 (FPR2/ALX) in control, peritumoral and tumor larynx tissue samples from 20 patients, to quantitate the neutrophils and mast cells, and to evaluate the protein expression and co-localization of ANXA1/FPR2 in these inflammatory cells and laryngeal squamous cells by immunocytochemistry. In addition, we performed in vitro experiments to further investigate the functional role of ANXA1/FPR2 in the proliferation and metastasis of Hep-2 cells, a cell line from larynx epidermoid carcinoma, after treatment with ANXA1(2-26) (annexin A1 N-terminal-derived peptide), Boc2 (antagonist of FPR) and/or dexamethasone. Under these treatments, the level of Hep-2 cell proliferation, pro-inflammatory cytokines, ANXA1/FPR2 co-localization, and the prostaglandin signalling were analyzed using ELISA, immunocytochemistry and real-time PCR. An influx of neutrophils and degranulated mast cells was detected in tumor samples. In these inflammatory cells of peritumoral and tumor samples, ANXA1/FPR2 expression was markedly exacerbated, however, in laryngeal carcinoma cells, this expression was down-regulated. ANXA1(2-26) treatment reduced the proliferation of the Hep-2 cells, an effect that was blocked by Boc2, and up-regulated ANXA1/FPR2 expression. ANXA1(2-26) treatment also reduced the levels of pro-inflammatory cytokines and affected the expression of metalloproteinases and EP receptors, which are involved in the prostaglandin signalling. Overall, this study identified potential roles for the molecular mechanism of the ANXA1/FPR2 interaction in laryngeal cancer, including its relationship with the prostaglandin pathway, providing promising starting points for future research. ANXA1 may contribute to the regulation of tumor growth and metastasis through paracrine mechanisms that are mediated by FPR2/ALX. These data may lead to new biological targets for therapeutic intervention in human laryngeal cancer.


Subject(s)
Annexin A1/metabolism , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Laryngeal Neoplasms/metabolism , Laryngeal Neoplasms/pathology , Receptors, Formyl Peptide/metabolism , Receptors, Lipoxin/metabolism , Aged , Aged, 80 and over , Amino Acid Sequence , Annexin A1/chemistry , Carcinoma, Squamous Cell/immunology , Cell Degranulation/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Laryngeal Neoplasms/immunology , Male , Mast Cells/cytology , Mast Cells/drug effects , Metalloproteases/metabolism , Middle Aged , Molecular Sequence Data , Neoplasm Metastasis , Neutrophils/drug effects , Neutrophils/immunology , Peptide Fragments/chemistry , Peptide Fragments/pharmacology , Prostaglandins/metabolism , Receptors, Prostaglandin E, EP3 Subtype/metabolism , Receptors, Prostaglandin E, EP4 Subtype/metabolism , Signal Transduction/drug effects , Tumor Microenvironment/drug effects , Up-Regulation/drug effects
2.
Am J Pathol ; 174(1): 177-83, 2009 Jan.
Article in English | MEDLINE | ID: mdl-19095957

ABSTRACT

The purpose of this study was twofold: to reveal cellular events associated with the protective role of endogenous annexin A1 (AnxA1) in inflammation and to highlight the potential involvement of members of the formyl peptide receptor (Fpr) family in this process. We found that wild-type, AnxA1-null, and Fpr1-null mice all displayed an intense neutrophil recruitment into the peritoneal cavity as assessed 4 hours after carrageenin injection, and that this recruitment was most pronounced in AnxA1-null mice. In addition, this cell influx could be inhibited by the AnxA1 pharmacophore peptide, Ac2-26, in wild-type, AnxA1-null, and Fpr1-null mice, but was restored when co-treated with the pan-receptor antagonist Boc2. Using the LacZ gene reporter assay, an enhancement of AnxA1 gene promoter activity in extravasated neutrophils was evident in AnxA1-null mice; again this response was reduced after peptide treatment. The lack of functional involvement of Fpr1 prompted us to monitor the structurally related receptor Fpr2. We report, for the first time, the ultrastructural immunocytochemical co-localization of Fpr2 with AnxA1 in neutrophils that migrate into the mesenteric microcirculation and extravasate into the peritoneal fluid. Collectively, these data provide in vivo support to the hypothesis that endogenous AnxA1 is an essential effector of endogenous anti-inflammation and provide an ultrastructural indication that this mediator interacts with Fpr2 in murine neutrophils. We believe that these findings could significantly affect the development of novel therapeutics, which are modeled after the anti-migratory actions of AnxA1.


Subject(s)
Annexin A1/metabolism , Chemotaxis, Leukocyte/immunology , Inflammation/metabolism , Neutrophils/metabolism , Animals , Annexin A1/ultrastructure , Gene Expression , Immunohistochemistry , Inflammation/immunology , Male , Mice , Mice, Mutant Strains , Neutrophils/immunology , Neutrophils/ultrastructure , Receptors, Formyl Peptide/immunology , Receptors, Formyl Peptide/metabolism , Receptors, Formyl Peptide/ultrastructure , Reverse Transcriptase Polymerase Chain Reaction
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