NF-kB Expression and Outcomes in Solid Tumors

Nuclear factor-kappaB (NF-kB) is a key inflammatory transcription factor expressed frequently in tumors. Numerous studies have investigated the correlation between NF-kB expression and prognosis in solid tumors, but the conclusions are still in contradiction. Here, we conduct a meta-analysis to explore the overall association of NF-kB overexpression and survival in human solid tumors. Pubmed and EBSCO databases were searched for studies evaluating expression of NF-kB (as measured by immunohistochemistry) and overall survival (OS) and disease-free survival (DFS) in solid tumors. Published data were extracted and computed into odds ratios (ORs) for death at 3, 5, and 10 years. Data were pooled using the Mantel–Haenszel random-effect model. All statistical tests were two-sided. Forty-four studies with a total of 4418 patients were included in this meta-analysis. NF-kB overexpression was associated with worse OS at 3 years (OR1⁄4 3.40, 95% confidence interval [CI]1⁄4 2.41–4.79, P< 0.00001), 5 years (OR1⁄4 2.72, 95% CI1⁄4 1.92–3.85, P< 0.00001), and 10 years (OR1⁄4 2.63, 95% CI1⁄4 1.34–5.16, P1⁄4 0.005) of solid tumors. Results for 3and 5-year DFS were similar. NF-kB expression was associated with poor 3-year OS in both Tumor, Lymph Node, Metastasis stage I-II (OR1⁄4 9.11, 95% CI1⁄4 2.90–28.68, P1⁄4 0.0002) and III-IV (OR1⁄4 2.59, 95% CI1⁄4 1.61–4.15, P< 0.0001). There is no correlation between cellular localization of NF-kB overexpression and OS of solid tumors. Among the tumor types, NF-kB was o, MD, Lijian Hua ng Zhang, MD, an Huang, MD, PhD (OR1⁄4 2.72, 95% CI1⁄4 1.92–3.85, P< 0.00001), esophageal carcinoma (OR1⁄4 5.96, 95% CI1⁄4 3.48–10.18, P1⁄4 0.03), and nonsmall cell lung cancer (OR1⁄4 1.69, 95% CI1⁄4 1.20–2.38, P1⁄4 0.002). Expression of NF-kB is associated with worse survival in most solid tumors irrespective of NF-kB localization. (Medicine 94(40):e1687) Abbreviations: CI = confidence interval, DFS = disease-free survival, IHC = immunohistochemistry, NF-kB = nuclear factorkappaB, NOS = Newcastle–Ottawa Scale, ORs = odds ratios, OS = overall survival. INTRODUCTION C ancer is an extremely complex fatal disease with accumulation of abnormal genetic/epigenetic and inflammatory alterations during multistep development. Inflammatory transcriptional factors, such as signal transducer and activator of transcription 3 and nuclear factor-kappaB (NF-kB), are considered to play a pivotal role in tumor initiation and progression. Accumulating evidence has demonstrated that persistent activation of inflammatory transcriptional factors facilitate tumor development through various mechanisms, such as providing proliferation and survival advantages, and promoting tumor-related inflammation. NF-kB, a transcriptional factor involved in multicellular biology response, was first discovered by Sen and Baltimore in 1986. The mammalian NF-kB family consists of 5 protein members: NF-kB1 (p50 and its precursor p105), NF-kB2 (p52 and its precursor p100), RelA (p65), RelB, and c-Rel. NF-kB transcriptional factor, as an inactive complex with inhibitory proteins called I-kB in the cytoplasm in normal resting cells, can be activated to enter the nucleus where it regulates the expression of diverse genes encoding cytokines, growth factors, cell adhesion molecules, and apoptotic-related proteins. Aberrant activation of NF-kB has been linked to inflammatory and autoimmune diseases, infection and cancer. The first hint to a link between NF-kB and cancer has emerged with the discovery of RelA/p65, and the realization of the close kinship to c-Rel and its oncogenic avian homolog v-Rel. Following studies reported that NF-kB was constitutively activated in various malignancies such as lymphoma, gastrointestinal tumor, genitourinary, gynecological, thoracic, head, and neck tumors. Notably, the presence of activated NF-kB in a tumor is not necessarily causal. NF-kB is involved in most if not all cellular processes in tumor evolution including inflammation, transformation, proliferation, angiogenesis, invasion, metastasis, chemoresistance, and radioresistance. Given the tumor promoting role of NF-kB, targeting NF-kB for tumor might be beneficial. A myriad of studies correlation between NF-kB overexpressolid tumors. However, the prognostic www.md-journal.com | 1 value of NF-kB overexpression across different solid tumors is still in contradiction. We therefore conducted an exhaustive meta-analysis combining evidence to evaluate the prognostic impact of NF-kB overexpression in solid tumors. We also evaluated whether the outcome differs between nuclear and cytoplasmic NF-kB expression and between different tumor types. This metaanalysis aimed to evaluate the role of NF-kB in relation to survival in solid tumors, thereby supporting more rational development of therapeutic strategies against NF-kB. MATERIAL AND METHODS This meta-analysis was conducted according to preferred reporting items for systematic reviews and meta-analyses statement. This study based on summary and analysis of the results of previous studies, so the ethical approval was not necessary. Identification and Selection of Studies Pubmed and EBSCO were searched for studies evaluating the correlation between NF-kB expression and survival in solid tumors from 2004 to January 2015. The search terms ‘‘NF-kB’’ and ‘‘neoplasms’’ were used and only human studies of solid tumors were included. In addition, the entry ‘‘NF-kB’’ and the name of each specific solid tumor were used to screen additional studies. We identified a total of 9168 and 13,092 entries, respectively. The inclusion criteria for selecting articles were the measurement of NF-kB by immunohistochemistry (IHC), availability of survival data for at least 3 years, and publication in English. Studies evaluating gene expression of NF-kB measured by real-time polymerase chain reaction were excluded. We screened the citation lists of retrieved articles to ensure sensitivity of the search strategy. Interreviewer agreement was evaluated using Cohen kappa coefficient. Disagreement was resolved by discussion and a final consensus was achieved. Endpoints of Interest Overall survival (OS) at 3, 5, and 10 years were the primary endpoints. Where not available, data for disease-free survival (DFS) at 3 and 5 years were collected. Tumors were classified by NF-kB expression status using cut-off value as defined by each study. Data Collection Process and Quality Assessment Two authors (DW and PW) independently reviewed and extracted data using predefined data abstraction forms from each eligible studies. Extracted information included first author’s name, publication year, country, type of cancer, number of patients, median age, gender, Tumor, Lymph Node, Metastasis (TNM) stage, time of follow-up, antibody used for the evaluation, technique used to quantify NF-kB, and cut-off value to determine NF-kB positivity. OS and DFS data were extracted from the text, tables, or Kaplan–Meier curves for both NF-kB negative and NF-kB positive group. The studies included in this meta-analysis were cohort studies. The quality of each included cohort study was evaluated using Newcastle–Ottawa Scale (NOS) by 2 independent authors. The studies with 6 scores or more were classified as high quality studies. A consensus NOS score for each item was achieved. Wu et al Data Synthesis The relative frequency of 3-, 5-, and 10-year OS or DFS between NF-kB negative and NF-kB positive group was 2 | www.md-journal.com expressed as an odds ratio (OR) and its 95% confidence interval (CI). Sensitivity analyses were carried out for different analytical methods and cut-offs for defining NF-kB expression and NOS scores for quality assessment of included studies. Statistical Analysis Data were extracted, computed into ORs, and pooled using the Mantel–Haenszel random-effect model by RevMan 5.3 analysis software (Cochrane Collaboration, Copenhagen, Denmark). Heterogeneity was evaluated with the Cochran’s Q and I statistics. Statistical differences between subgroups were assessed using the methods described in Cochrane Handbook for Systematic Reviews of Interventions. Meta-regression analysis was conducted using Stata 12.0 software (StataCorp LP, College Station, TX). All statistical tests were 2-sided, and P values less than.05 were defined statistically significant.