title: The role of CXC-chemokine receptor CXCR2 and suppressor of cytokine signaling-3 (SOCS-3) in renal cell carcinoma.
abstract: BACKGROUND
  Chemokine receptor signaling pathways are implicated in the pathobiology of renal cell carcinoma (RCC). However, the clinical relevance of CXCR2 receptor, mediating the effects of all angiogenic chemokines, remains unclear. SOCS (suppressor of cytokine signaling)-3 is a negative regulator of cytokine-driven responses, contributing to interferon-α resistance commonly used to treat advanced RCC with limited information regarding its expression in RCC.
  
  
  METHODS
  In this study, CXCR2 and SOCS-3 were immunohistochemically investigated in 118 RCC cases in relation to interleukin (IL)-6 and (IL)-8, their downstream transducer phosphorylated (p-)STAT-3, and VEGF expression, being further correlated with microvascular characteristics, clinicopathological features and survival. In 30 cases relationships with hypoxia-inducible factors, i.e. HIF-1a, p53 and NF-κΒ (p65/RelA) were also examined. Validation of immunohistochemistry and further investigation of downstream transducers, p-JAK2 and p-c-Jun were evaluated by Western immunoblotting in 5 cases.
  
  
  RESULTS
  Both CXCR2 and IL-8 were expressed by the neoplastic cells their levels being interrelated. CXCR2 strongly correlated with the levels of HIF-1a, p53 and p65/RelA in the neoplastic cells. Although SOCS-3 was simultaneously expressed with p-STAT-3, its levels tended to show an inverse relationship with p-JAK-2 and p-c-Jun in Western blots and were positively correlated with HIF-1a, p53 and p65/p65/RelA expression. Neither CXCR2 nor SOCS-3 correlated with the extent of microvascular network. IL-8 and CXCR2 expression was associated with high grade, advanced stage and the presence/number of metastases but only CXCR2 adversely affected survival in univariate analysis. Elevated SOCS-3 expression was associated with progression, the presence/number of metastasis and shortened survival in both univariate and multivariate analysis.
  
  
  CONCLUSIONS
  Our findings implicate SOCS-3 overexpression in RCC metastasis and biologic aggressiveness advocating its therapeutic targeting. IL-8/CXCR2 signaling also contributes to the metastatic phenotype of RCC cells but appears of lesser prognostic utility. Both CXCR2 and SOCS-3 appear to be related to transcription factors induced under hypoxia.
authors.forename: Anastasios
authors.initials: A
authors.lastname: Stofas
authors.affiliation: First Department of Pathology, Laiko Hospital, University of Athens, Medical School, 75 Mikras Asias street, 11527 Athens, Greece. glevidou@yahoo.gr.
authors.forename: Georgia
authors.initials: G
authors.lastname: Levidou
authors.forename: Christina
authors.initials: C
authors.lastname: Piperi
authors.forename: Christos
authors.initials: C
authors.lastname: Adamopoulos
authors.forename: Georgia
authors.initials: G
authors.lastname: Dalagiorgou
authors.forename: Aristotelis
authors.initials: A
authors.lastname: Bamias
authors.forename: Alexandra
authors.initials: A
authors.lastname: Karadimou
authors.forename: George A
authors.initials: GA
authors.lastname: Lainakis
authors.forename: Stefanos
authors.initials: S
authors.lastname: Papadoukakis
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Stravodimos
authors.forename: Meletios-Athanasios
authors.initials: MA
authors.lastname: Dimopoulos
authors.forename: Efstratios
authors.initials: E
authors.lastname: Patsouris
authors.forename: Hariklia
authors.initials: H
authors.lastname: Gakiopoulou
authors.forename: Penelope
authors.initials: P
authors.lastname: Korkolopoulou
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000175:diagnosis* / Q000378:metabolism* / Q000401:mortality; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016130:Immunophenotyping; D007680:Kidney Neoplasms / Q000175:diagnosis* / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D023063:Receptors, Interleukin-8B / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology*; D015996:Survival Rate / Q000639:trends; D015854:Up-Regulation / Q000235:genetics
chemical_list: D023063:Receptors, Interleukin-8B; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins