title: Inflammation and cancer: role of annexin A1 and FPR2/ALX in proliferation and metastasis in human laryngeal squamous cell carcinoma.
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.
authors.affiliation: From the Post-graduation in Structural and Functional Biology, Federal University of São Paulo (UNIFESP), Paulista School of Medicine (EPM), São Paulo, SP, Brazil.
authors.forename: Thaís Santana
authors.initials: TS
authors.lastname: Gastardelo
authors.affiliation: Department of Molecular Biology, Faculty of Medicine (FAMERP), São José do Rio Preto, SP, Brazil.
authors.forename: Bianca Rodrigues
authors.initials: BR
authors.lastname: Cunha
authors.affiliation: Department of Otorhinolaringology, Faculty of Medicine (FAMERP), São José do Rio Preto, SP, Brazil.
authors.forename: Luís Sérgio
authors.initials: LS
authors.lastname: Raposo
authors.affiliation: Department of Otorhinolaringology, Faculty of Medicine (FAMERP), São José do Rio Preto, SP, Brazil.
authors.forename: José Victor
authors.initials: JV
authors.lastname: Maniglia
authors.affiliation: Department of Pathology, Faculty of Medicine (FAMERP), São José do Rio Preto, SP, Brazil.
authors.forename: Patrícia Maluf
authors.initials: PM
authors.lastname: Cury
authors.affiliation: Department of Biology and Zootechny, São Paulo State University (UNESP), Ilha Solteira, SP, Brazil.
authors.forename: Flávia Cristina Rodrigues
authors.initials: FC
authors.lastname: Lisoni
authors.affiliation: Department of Molecular Biology, Faculty of Medicine (FAMERP), São José do Rio Preto, SP, Brazil; Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo (USP), São Paulo, SP, Brazil.
authors.forename: Eloiza Helena
authors.initials: EH
authors.lastname: Tajara
authors.affiliation: From the Post-graduation in Structural and Functional Biology, Federal University of São Paulo (UNIFESP), Paulista School of Medicine (EPM), São Paulo, SP, Brazil; Department of Biology, Instituto de Biociências, Letras e Ciências Exatas (IBILCE), São Paulo State University (UNESP), São José do Rio Preto, SP, Brazil.
authors.forename: Sonia Maria
authors.initials: SM
authors.lastname: Oliani
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D017305:Annexin A1 / Q000737:chemistry / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D015550:Cell Degranulation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007822:Laryngeal Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects; D045726:Metalloproteases / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000378:metabolism*; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D017305:Annexin A1; C105101:FPR2 protein, human; D010446:Peptide Fragments; D011453:Prostaglandins; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D045726:Metalloproteases