title: Involvement of the receptor-associated prorenin system in the pathogenesis of human conjunctival lymphoma.
abstract: OBJECTIVE
  Extranodal marginal zone B-cell lymphoma (EMZL) is the most common subtype of conjunctival lymphoma, though its molecular mechanisms of pathogenesis are largely unknown. We attempted to explore the association of the renin-angiotensin system (RAS) and (pro)renin receptor ([P]RR) in the pathogenesis of conjunctival lymphoma.
  
  
  METHODS
  Surgically removed conjunctiva EMZL samples were used for gene expression, and immunohistochemical and immunofluorescence analyses of (P)RR and RAS components. Human B-lymphoblast IM-9 cells were treated with prorenin or angiotensin II (Ang II), and gene expression levels were analyzed using real-time quantitative PCR (qPCR). In addition, immunofluorescence analysis of EMZL samples was used to evaluate the in vivo expression of those components.
  
  
  RESULTS
  Gene expression and immunohistochemical analyses revealed the expression of RAS components, including (P)RR and angiotensin II type 1 receptor (AT1R), in EMZL tissues. Double-labeling analyses demonstrated that (P)RR and AT1R were detected in cells positive for CD20, a marker for B-cells, where they colocalized with prorenin and angiotensinogen, respectively. Prorenin stimulation of human B-lymphoblast IM-9 cells increased mRNA expression levels of fibroblast growth factor 2 (FGF2), while angiotensin II treatment upregulated the expression levels of basigin (BSG), matrix metallopeptidase (MMP)2, 9, and 14, which were abolished by (P)RR and AT1R blockades, respectively. Immunofluorescence analyses of clinical samples showed colocalizations of (P)RR and AT1R with the products of these upregulated genes.
  
  
  CONCLUSIONS
  The present study suggests that activation of (P)RR and AT1R is associated with the pathogenesis of conjunctival EMZL by stimulating the production of FGF2 and MMPs.
authors.affiliation: Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.
authors.forename: Erdal Tan
authors.initials: ET
authors.lastname: Ishizuka
authors.affiliation: Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Kanda
authors.affiliation: Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Kase
authors.affiliation: Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Noda
authors.affiliation: Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Ishida
mesh_terms: D003230:Conjunctival Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008856:Microscopy, Fluorescence; D012334:RNA, Neoplasm / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics*; D012083:Renin; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D025262:Vacuolar Proton-Translocating ATPases / Q000096:biosynthesis / Q000235:genetics*; D000093342:Prorenin Receptor
chemical_list: D012334:RNA, Neoplasm; D011956:Receptors, Cell Surface; D012083:Renin; D025262:Vacuolar Proton-Translocating ATPases; C458319:ATP6AP2 protein, human; D000093342:Prorenin Receptor
keywords: (pro)renin receptor; angiotensin II type 1 receptor; conjunctival lymphoma; receptor-associated prorenin system; renin-angiotensin system