Expression of Nuclear Factor-κB and IκBα Proteins in Prostatic Adenocarcinomas

Abstract

Purpose: The nuclear transcription factor nuclear factor-B (NFB) and its inhibitor, IB, regulate the transcription of various genes involved in cell proliferation, adhesion, and survival. The NFB transcription factor complex plays a role in cancer development and progression through its influence on apoptosis. More recently, NFB has been shown to be activated in human and androgen-independent prostate cancer cells. To our knowledge, this is the first study demonstrating the prognostic significance of NFB immunoreactivity in prostate adenocarcinomas (PACs).Experimental Design: Using prostatectomy specimens, we performed immunohistochemical staining for NFB and IB␣ (Santa Cruz Biotechnology) on formalin-fixed, paraffin-embedded sections obtained from 136 patients with PAC. Cytoplasmic and nuclear immunoreactivity was scored for intensity and distribution, and results were correlated with preoperative serum prostate-specific antigen, tumor grade, stage, DNA ploidy (Feulgen spectroscopy), and biochemical disease recurrence.Results: Forty-nine percent of PACs overexpressed cytoplasmic NFB, and 63% showed decreased IB expression. Cytoplasmic NFB overexpression correlated with advanced tumor stage (P ‫؍‬ 0.048), aneuploidy (P ‫؍‬ 0.022), and biochemical disease recurrence (P ‫؍‬ 0.001). When we compared the means for the NFB-positive and -negative subgroups, NFB overexpression correlated with preoperative serum prostate-specific antigen (P ‫؍‬ 0.04) and DNA index (P ‫؍‬ 0.05). Fifteen percent of PACs expressed nuclear NFB, which correlated with high tumor grade (P ‫؍‬ 0.001) and advanced stage (P ‫؍‬ 0.05). Decreased IB␣ expression correlated with high tumor grade (P ‫؍‬ 0.015). On multivariate analysis, tumor stage (P ‫؍‬ 0.043) and NFB overexpression (P ‫؍‬ 0.006) were independent predictors of biochemical recurrence.Conclusion: These results support a role for NFB pathway proteins in the tumorigenesis of PACs. The findings are also consistent with reported experimental studies suggesting a new strategy of combined chemotherapy and specific NFB blockade in decreasing the rate of disease relapse.

High expression of RelA/p65 is associated with activation of nuclear factor-κB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis

“…The prognostic value of RelA is in concordance with studies on prostate cancer, in which both nuclear and cytoplasmic RelA overexpression were linked to disease progression (Fradet et al, 2004;Ross et al, 2004). In gastric adenocarcinoma, the prognostic impact of RelA expression appears to be somewhat conflictive, as overexpression was reported both to be an indicator of adverse (Sasaki et al, 2001;Yamanaka et al, 2004) and favourable (Lee et al, 2005) patient prognosis.…”

“…Here, we found the NF-kB subunit RelA to be overexpressed in roughly half of a large set of pancreatic adenocarcinomas analysed. Overexpression of cytoplasmic and/or nuclear RelA in tumour tissue has been previously observed in larger study cohorts of gastric (Sasaki et al, 2001;Yamanaka et al, 2004;Cao et al, 2005;Lee et al, 2005), prostate (Fradet et al, 2004;Ismail et al, 2004;Ross et al, 2004; Figure 2 Kaplan -Meier survival curves in dependence of clinicopathological factors and RelA/p65 expression patterns. Overall survival dependent on nodal status (A) and grade (B).…”

“…A well-characterised monoclonal RelA-antibody (sc-8008, Santa Cruz Biotechnology, Santa Cruz, CA, USA) was used on 5 mm paraffin sections (Higashitsuji et al, 2002;Ross et al, 2004). After heat-induced antigen retrieval, slides were incubated with primary antibody (1 : 250) at 41C overnight.…”

Activation of nuclear factor-κB in human prostate carcinogenesis and association to biochemical relapse

“…Furthermore, emerging data obtained from human studies also suggest a potential role of NF-kB in prostate cancer tumorigenesis and/or in its behaviour in a clinical setting (Suh et al, 2002;Lessard et al, 2003;Fradet et al, 2004;Ismail et al, 2004;Ross et al, 2004). In particular, a recent study showed that total overexpression of p65, the best characterised NF-kB protein, was an independent predictor of poor prognosis in prostate cancer patients (Ross et al, 2004). Of note in this study was the fact that nuclear NF-kB expression was not specifically linked with disease relapse.…”

“…Along this line, several preclinical observations have shown that NF-kB plays a role in prostate cancer growth, survival, angiogenesis and metastatic progression (Muenchen et al, 2000;Yu et al, 2000;Catz and Johnson, 2001;Huang et al, 2001;Gasparian et al, 2002;Gunawardena et al, 2002;Gupta et al, 2002;Suh et al, 2002;Zerbini et al, 2003;Suh and Rabson, 2004). Furthermore, emerging data obtained from human studies also suggest a potential role of NF-kB in prostate cancer tumorigenesis and/or in its behaviour in a clinical setting (Suh et al, 2002;Lessard et al, 2003;Fradet et al, 2004;Ismail et al, 2004;Ross et al, 2004). In particular, a recent study showed that total overexpression of p65, the best characterised NF-kB protein, was an independent predictor of poor prognosis in prostate cancer patients (Ross et al, 2004).…”