Nuclear factor κB transcription factors are coexpressed and convey a poor outcome in ovarian cancer

Abstract

BACKGROUND: Recent work has suggested a role for nuclear factor jB (NF-jB) in the propagation of ovarian cancer cell lines, but the significance and mechanism of NF-jB in ovarian cancer is unknown. The authors hypothesized that the NF-jB pathway is over activated in aggressive ovarian cancers. METHODS: The levels of 3 NF-jB transcription factors, the activating inhibitors of NF-jB (IjB) kinases, and the NF-jB target matrix metalloproteinase 9 (MMP9) were assessed by immunohistochemistry in specimens of ovarian cancer that were obtained at diagnosis from a cohort of 33 patients who subsequently received combined paclitaxel, cisplatin, and cyclophosphamide. Associations were made between NF-jB pathway proteins and outcome. The validation of coexpression was performed at the gene level in 2 independently collected cohorts of 185 and 153 ovarian cancers. RESULTS: The presence of NF-jB proteins in newly diagnosed advanced ovarian cancers was established, and a potential association with overall survival was identified. Transcription factors p65 and v-rel reticuloendotheliosis viral oncogene homolog B (RelB) were coexpressed with IjB kinase a, 1 component of a key trimolecular regulatory complex. Coexpression of the NF-jB machinery suggested activity of NF-jB signaling in these ovarian tumors. A significant association of p50 with poor overall survival was observed (P ¼ .02). MMP9 expression had the opposite association, in which patients who had tumors without MMP9 staining had the poorest prognosis (P ¼ .01), and this association held true at the gene expression level in an independently collected cohort of 185 ovarian cancers. CONCLUSIONS: The deregulation of NF-jB activity may influence outcome in women who receive standard therapy for advanced ovarian cancer. Modification of the NF-jB pathway may present an opportunity to improve outcome in the subset of women who have pathway activity. Cancer 2010;116:3276-84.

RETRACTED: Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer

“…Uncontrolled activation of NF-kB signaling has been implicated in propagation of a large number of malignancies including ovarian cancer (1,2). Intrinsically or constitutively active NF-kB has been defined critical in the promotion of cell proliferation, angiogenesis, metastasis (3), and development of drug resistance (4) in ovarian cancer.…”

Molecular typing of epithelial ovarian carcinomas using inflammatory markers

“…The authors reported that an increase in cytoplasmic NFj-B transcription factor p50 was significantly associated with poorer patient survival, whereas no association was found between NFj-B transcription factor p65 and patient survival. 24 COX is a key regulatory enzyme in the prostaglandin/eicosanoid synthetic pathway. Two isoforms of COX have been identified, COX-1 and COX-2.…”

Roles of functional NFKB1 and βTrCP insertion/deletion polymorphisms in mRNA expression and epithelial ovarian cancer susceptibility

“…Lin et al (2007) suggested an important role for NF-κB in the propagation of ovarian cancer cell lines. Annunziata et al (2010) found the NF-κB pathway is over-activated in aggressive ovarian cancers. In addition, a recent report by Fan et al (2011) suggested that a functional promoter polymorphism in NFKB1 gene increases the risk of advanced ovarian cancer in a population from northeast China.…”

“…Mammals carry 5 members of the NF-κB family including p50/p105, p65/RelA, c-Rel, RelB, and p52/p100. Although many dimeric forms of NF-κB have been detected, the major form of NF-κB is a heterodimer of the p50 and p65/RelA subunits, encoded by the NFKB1 and RELA genes, respectively (Lin et al, 2007;Annunziata et al, 2010). Recently, NF-κB signaling activation in ovarian cancer development and progression has been studied intensely (Chen et al, 2001;Karin, 2006;Maeda and Omata, 2008).…”