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      Call for Papers: Beyond Biology: The Crucial Role of Sex and Gender in Oncology

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      Expression of Platelet-Activating Factor Receptor: A Novel Prognosticator in Patients with Hepatocellular Carcinoma following Hepatectomy

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          Abstract

          Backgrounds and Aims: Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a phospholipid mediator and acts by binding to a specific G-protein-coupled receptor. Though various functions of PAF have been associated with tumor activities, the mechanism of PAF-PAF receptor signaling in the development of hepatocellular carcinoma (HCC) remains to be elucidated. Methods: In this study, PAF receptor (PAFR) expression was examined in hepatoma cell lines (Huh7, PLC/PRF/5 and HepG2) and clinical samples of HCC (n = 60) using immunohistochemical staining. The relationships between the expression of PAFR and clinicopathological parameters were also investigated. Results: An immunohistochemical study showed that 24 HCC cases (40%) showed a lower PAFR expression than non-cancerous hepatocytes. The patients were divided into two groups according to the degree of PAFR expression: the high (n = 36) and low PAFR groups (n = 24). Lower expression of PAFR was correlated with poor differentiation, portal vein invasion, high levels of serum α-fetoprotein and poor prognosis after surgery. In the low PAFR group, multiple recurrences and distant metastases were more often observed than in the high PAFR group. Multivariate analysis revealed that lower PAFR expression in addition to portal vein invasion is significantly related to survival after hepatectomy. Conclusions: A lower expression of PAFR correlated with poor differentiation and a poor prognosis, and may therefore be used as a prognostic marker in HCC after hepatectomy.

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          Platelet-activating factor (PAF) receptor and genetically engineered PAF receptor mutant mice

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            Platelet-activating factor mediates MMP-2 expression and activation via phosphorylation of cAMP-response element-binding protein and contributes to melanoma metastasis.

            Overexpression of cAMP-response element (CRE)-binding protein (CREB) and activating transcription factor (ATF) 1 contributes to melanoma progression and metastasis at least in part by promoting tumor cell survival and stimulating matrix metalloproteinase (MMP) 2 expression. However, little is known about the regulation of CREB and ATF-1 activities and their phosphorylation within the tumor microenvironment. We analyzed the effect of platelet-activating factor (PAF), a potent phospholipid mediator of inflammation, for its ability to activate CREB and ATF-1 in eight cultured human melanoma cell lines, and we found that PAF receptor (PAFR) was expressed in all eight lines. In metastatic melanoma cell lines, PAF induced CREB and ATF-1 phosphorylation via a PAFR-mediated signal transduction mechanism that required pertussis toxin-insensitive Galphaq protein and adenylate cyclase activity and was antagonized by a cAMP-dependent protein kinase A and p38 MAPK inhibitors. Addition of PAF to metastatic A375SM cells stimulated CRE-dependent transcription, as observed in a luciferase reporter assay, without increasing the CRE DNA binding capacity of CREB. Furthermore, PAF stimulated the gelatinase activity of MMP-2 by activating transcription and MMP-2 expression. MMP-2 activation correlated with the PAF-induced increase in the expression of an MMP-2 activator, membrane type 1 MMP. PAF-induced expression of pro-MMP-2 was causally related to PAF-induced CREB and ATF-1 phosphorylation; it was prevented by PAFR antagonist and inhibitors of p38 MAPK and protein kinase A and was abrogated upon quenching of CREB and ATF-1 activities by forced overexpression of a dominant-negative form of CREB. PAF-induced MMP-2 activation was also down-regulated by p38 MAPK and protein kinase A inhibitors. Finally, PAFR antagonist PCA4248 inhibited the development of A375SM lung metastasis in nude mice. This result indicated that PAF acts as a promoter of melanoma metastasis in vivo. We proposed that metastatic melanoma cells overexpressing CREB/ATF-1 are better equipped than nonmetastatic cells to respond to PAF within the tumor microenvironment.
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              Trafficking, ubiquitination, and down-regulation of the human platelet-activating factor receptor.

              Platelet-activating factor (PAF) is a potent phospholipid mediator involved in various disease states such as allergic asthma, atherosclerosis and psoriasis. The human PAF receptor (PAFR) is a member of the G protein-coupled receptor family. Following PAF stimulation, cells become rapidly desensitized; this refractory state can be maintained for hours and is dependent on PAFR phosphorylation, internalization, and down-regulation. In this report, we characterized ligand-induced, long term PAFR desensitization, and pathways leading to its degradation. Some GPCRs are known to be targeted to proteasomes for degradation while others traffic via the early/late endosomes toward lysosomes. Specific inhibitors of lysosomal proteases and inhibitors of the proteasome were effective in reducing the ligand-induced PAFR down-regulation by 40 and 25%, respectively, indicating the importance of receptor targeting to both lysosomes and proteasomes in long term cell desensitization to PAF. The effects of the proteasome and lysosomal protease inhibitors were additive and, together, completely blocked ligand-induced degradation of PAFR. Using dominant-negative Rab5 and 7 and colocalization of the PAFR with the early endosome autoantigen I (EEAI) or transferrin, we confirmed that ligand-induced PAFR down-regulation was Rab5/7-dependent and involved lysosomal degradation. In addition, we also demonstrated that PAFR was ubiquitinated in an agonist-independent manner. However, a dominant negative ubiquitin ligase (NCbl) reduced PAFR ubiquitination and inhibited ligand-induced but not basal receptor degradation. Our results indicate that PAFR degradation can occur via both the proteasome and lysosomal pathways and ligand-stimulated degradation is ubiquitin-dependent.
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                Author and article information

                Journal
                OCL
                Oncology
                10.1159/issn.0030-2414
                Oncology
                S. Karger AG
                0030-2414
                1423-0232
                2007
                February 2008
                14 January 2008
                : 72
                : 5-6
                : 381-387
                Affiliations
                Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
                Article
                113149 Oncology 2007;72:381–387
                10.1159/000113149
                18187960
                d3773186-59df-411e-b31d-0c642388bf66
                © 2008 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 16 July 2007
                : 18 July 2007
                Page count
                Figures: 3, Tables: 3, References: 38, Pages: 7
                Categories
                Laboratory/Clinical Translational Research

                Oncology & Radiotherapy,Pathology,Surgery,Obstetrics & Gynecology,Pharmacology & Pharmaceutical medicine,Hematology
                Hepatocellular carcinoma,Platelet activating factor,Prognosticator,Platelet activating factor receptor,Portal vein invasion

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