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-a 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-kappa B
(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