title: Lack of association between the functional CX3CR1 polymorphism V249I and hepatocellular carcinoma.
abstract: Chemokine production by cancer cells constitutes a duality. Leukocyte recruitment under the pressure of chemokines may be beneficial for the host or for the tumor. Recently, the chemokine fractalkine and its receptor CX3CR1 have been shown to be expressed in hepatocytes in vivo and in a human hepatocarcinoma cell line in vitro. Therefore, the aim of this study was to analyze the expression of CX3CR1 in hepatocellular carcinoma (HCC) in vivo and to investigate the prevalence of the genetic CX3CR1 polymorphism V249I in HCC patients since this polymorphism has been associated with reduced number of fractalkine binding sites, reduced cell-cell adhesion and decreased signaling and chemotaxis. Genotyping was performed in 183 patients with histologically proven HCC and 99 healthy controls by RFLP-analysis. The frequency of the individual genotypes was similar in HCC patients and controls. The V249I polymorphism revealed no association with tumor grade and stage, the presence of extrahepatic metastasis or the degree of fibrosis in non-tumorous tissue. In addition to genotyping, CX3CR1 mRNA expression was analyzed by quantitative PCR in 9 HCC specimens and in 6 cases in corresponding non-tumorous liver tissues. CX3CR1 mRNA expression levels in HCC showed high variation between individual patients. Similarly, expression in HCC compared to non-tumorous liver varied, from strong downregulation to remarkable upregulation. CX3CR1 mRNA expression levels showed no correlation to the V249I polymorphism. In summary, these results suggest that the patho-physiological role of individual chemokines in carcinogenesis may vary and that the functional CX3CR1 polymorphism V249I is no genetic risk factor for HCC. However, additional independent studies in HCC patients with different ethnic background will be needed to confirm the present study and to elucidate the functional role of CX3CR1 and its polymorphism V249I in chronic liver disease and hepatocarcinogenesis.
authors.affiliation: Department of Internal Medicine I, University of Regensburg, D-93042 Regensburg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Mühlbauer
authors.forename: Susanne
authors.initials: S
authors.lastname: Ringel
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Gertrud
authors.initials: G
authors.lastname: Lallinger
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Weiss
authors.forename: Erwin
authors.initials: E
authors.lastname: Gäbele
authors.forename: Peter H
authors.initials: PH
authors.lastname: Wünsch
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schölmerich
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
mesh_terms: D000368:Aged; D019943:Amino Acid Substitution; D000073883:CX3C Chemokine Receptor 1; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D017931:DNA Primers; D005260:Female; D005838:Genotype; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D019707:Receptors, Chemokine / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D017931:DNA Primers; D008565:Membrane Proteins; D019707:Receptors, Chemokine