Abstract
BackgroundChemokine 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.MethodsIn 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.ResultsBoth 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.ConclusionsOur 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.
Highlights
Chemokine receptor signaling pathways are implicated in the pathobiology of renal cell carcinoma (RCC)
The vast majority of these tumors are associated with the inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene, which leads to the stabilization of hypoxia-inducible factor-1α (HIF-1α) with consequent enhanced transcription of many proangiogenic factors, such as vascular endothelial growth factor (VEGF) [3]
Western blot analysis The expression levels by Western blot in the examined 5 cases were found to correlate with the immunohistochemical expression of IL-6, IL-8, CXCR2, p-signal transducer and activator of transcription (STAT)-3 and suppressors of cytokine signaling (SOCS)-3 (Figure 1; Additional file 1: Figure S1-5)
Summary
Chemokine receptor signaling pathways are implicated in the pathobiology of renal cell carcinoma (RCC). The pleiotropic cytokine interleukin (IL)-6, in particular, is known to induce the expression of VEGF [5], which is considered to be a major endothelial mitogen in RCC. IL-6 signals through a cell surface type I cytokine receptor including the signal transducing component GP130 which activates the tyrosine kinase JAK and the signal transducer and activator of transcription (STAT)-3 [7]. The latter is activated through phosphorylation at Tyr705 in response to growth factors and extracellular signals [8]. STAT-3 translocates to the nucleus where it binds to IFN-γactivated site-like DNA elements [9], inducing the expression of genes promoting abnormal cell cycle progression, angiogenesis, inhibition of apoptosis, tissue invasion and immune evasion [10]
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