title: The formyl peptide receptor 1 exerts a tumor suppressor function in human gastric cancer by inhibiting angiogenesis.
abstract: N-formyl peptide receptors (FPR1, FPR2 and FPR3) are involved in innate immunity, inflammation and cancer. FPR expression, initially described in immune cells, was later observed in non-hematopoietic cell populations and tissues. Several studies suggested a role for FPRs in the progression of various tumor histotypes, including gastric cancer (GC), for which a positive association with a specific FPR1 polymorphism has recently been described. We previously showed that FPRs are expressed on gastric epithelium and are required for wound repair and restitution of barrier integrity. Here we assess the role of FPRs in GC. We characterized the functions of FPRs in GC epithelial cells (MKN28, AGS and MKN45) cultured in vitro by assessing migration, proliferation, resistance to apoptosis and activation of the epithelial-to-mesenchymal transition. Activation of each FPR induced the epithelial-to-mesenchymal transition, proliferation, resistance to apoptosis and migration of GC cells in culture. Blocking compounds or RNA interference of each FPR reverted these effects. We also defined the in vivo tumorigenic potential of GC epithelial cells silenced for FPRs by xenograft experiments in immunocompromised mice. Interestingly, FPR1 silencing in GC cells (shFPR1) significantly enhanced xenograft growth with respect to shCTR, shFPR2 and shFPR3 xenografts, because of augmented vessel density and cell proliferation. Accordingly, HIF-1α and VEGF mRNA levels were higher in shFPR1 xenografts than in controls. Moreover, the in vitro production of proangiogenic factors in response to FPR2/3 agonists (WKYMVm, LL-37, uPA, uPAR84-95, AnxA1) or to other proinflammatory mediators (IL-1α) was higher in shFPR1 GC cells than in shCTR, shFPR2 and shFPR3 cells, suggesting that FPR1 functions as an inhibitor of CG angiogenesis. Thus, we propose that FPR1 stimulation may represent a novel therapeutic approach to counteract tumor angiogenesis.
authors.affiliation: Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI) - University of Naples Federico II, Naples, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Prevete
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology - University of Naples and CNR Institute of Experimental Oncology and Endocrinology (IEOS), Naples, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Liotti
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology - University of Naples and CNR Institute of Experimental Oncology and Endocrinology (IEOS), Naples, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Visciano
authors.affiliation: Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI) - University of Naples Federico II, Naples, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Marone
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology - University of Naples and CNR Institute of Experimental Oncology and Endocrinology (IEOS), Naples, Italy.
authors.forename: R M
authors.initials: RM
authors.lastname: Melillo
authors.affiliation: Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI) - University of Naples Federico II, Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: de Paulis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016513:Mice, SCID; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D034622:RNA Interference; D044042:Receptors, Formyl Peptide / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: C469986:FPR1 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009842:Oligopeptides; D044042:Receptors, Formyl Peptide; C113617:Trp-Lys-Tyr-Met-Val-Met; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D009240:N-Formylmethionine Leucyl-Phenylalanine