Relationship Between Vascular Endothelial Growth Factor and Nuclear Factor-κB in Renal Cell Tumors

Abstract

Aim To assess the relationship between protein and messenger RNA (mRNA) levels of vascular endothelial growth factor (VEGF) and subcellular localization of nuclear factor-kappa B (NF-κB), proliferation rate of tumor cells, and clinicopathological characteristics of renal cell tumors.Methods We analyzed 31 one renal cell tumors -22 clear cell renal cell carcinomas (CCRCC) and 9 other histologic types (non-CCRCC). VEGF expression and subcellular localization of p65 member of NF-κB and Ki67 were immunohistochemically evaluated for the proliferation rate of tumor cells. Expression of VEGF mRNA was assessed using quantitative real-time polymerase chain reaction after total RNA extraction from snap-frozen tumor tissue samples.Results Cytoplasmic localization of VEGF protein in renal cell tumors showed a perimembranous and diffuse pattern, the former being more evident in CCRCC (27.1 ± 18.9 vs 3.3 ± 10 % tumors, P<0.001) and the latter in non-CCRCC type (71.7 ± 23.2 vs 31.1 ± 22.1 % tumors, P < 0.001). Heterogeneity in VEGF gene expression was more pronounced in CCRCC type than in non-CCRCC type (P = 0.004). In addition, perimembranous VEGF pattern was associated with higher VEGF mRNA levels (P = 0.006) and diffuse VEGF pattern with lower VEGF mRNA levels (P < 0.001). Nuclear and cytoplasmic staining of NF-κB/ p65 was observed in the majority of tumor cells. A significant association was recorded between cytoplasmic NK-κB/65 staining and VEGF staining of diffuse pattern (P = 0.026). Association between NF-κB/65 and proliferation rate of tumor cells was significant for cytoplasmic staining (P = 0.039) but not for nuclear NFkB/p65 staining (P = 0.099). ConclusionHigher but inhomogeneous expression of VEGF in tumor cells, especially in CCRCCs, is associated with NF-κB/65 activity. This indicates that both VEGF and NF-κB/65 may be important in renal carcinogenesis, representing a possible molecular target in the treatment of renal cell carcinoma.

NFκB-mediated cyclin D1 expression by microRNA-21 influences renal cancer cell proliferation

“…Many renal cancer cells including the one used in this study are known to express increased levels of canonical NFκB subunits [48, 49, 53]. Additionally, nuclear localization of NFκB was observed in majority of the renal tumors, which was associated with rate of proliferation of tumor cells [51]. We show a correlation between increased miR-21 and phosphorylated active NFκB due to upregulated active IKKβ.…”

“…Recently Sourbier et al reported significant increase in levels of p65 and phosphorylated p65 in a cohort of patients with renal cell carcinoma [49]. Using renal tumor tissue, two more studies also showed increased expression of NFκB subunits that was associated with increased growth factors and anti-apoptotic proteins [50, 51]. Furthermore, a more recent study demonstrated that 70% of renal tumors possess activated NFκB [52].…”

A Functional Insertion/Deletion Polymorphism (-94 ins/del ATTG) in the Promoter Region of the <b><i>NFKB1</i></b> Gene Is Related to the Risk of Renal Cell Carcinoma

“…Besides, the ins allele played an important role in the susceptibility to ulcerative colitis, oral squamous cell carcinoma and psoriasis [30,33,34]. Accumulating evidence suggested that NF-ĸB was constitutively activated in RCC tumors [35,36,37]. Konda et al [38] reported that overexpression of NF-ĸB may be involved in the development of renal cysts and their subsequent transformation into tumors.…”

Differential behavior of NF‑κB, IκBα and EGFR during the renal carcinogenic process in an experimental model in�vivo

“…The expression of numerous genes related to various events such as cell proliferation, inflammation and inhibition of apoptosis, is under the influence of this transcription factor (7), its deregulation being associated with almost all types of cancer (11,12). Particularly, different authors have reported an NF-κB overexpression in RCC tumors and cell lines (12)(13)(14)(15), and in certain publications this overexpression has been correlated to tumor grade, invasion and metastasis, proposing the factor as a target for RCC treatment (2,3,14,16). In fact, apoptosis-induction and/or growth-repression of different RCC cell lines have been demonstrated by using a specific inhibitor of NF-κB activation (Bay- or by blocking tyrosine kinases involved in NF-κB activation signaling (17,18).…”