核因子 κB 转录因子在卵巢癌中共同表达并预示不良预后。
Nuclear factor kappaB transcription factors are coexpressed and convey a poor outcome in ovarian cancer.
机构信息
Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1906, USA.
出版信息
Cancer. 2010 Jul 1;116(13):3276-84. doi: 10.1002/cncr.25190.
BACKGROUND
Recent work has suggested a role for nuclear factor kappaB (NF-kappaB) in the propagation of ovarian cancer cell lines, but the significance and mechanism of NF-kappaB in ovarian cancer is unknown. The authors hypothesized that the NF-kappaB pathway is over activated in aggressive ovarian cancers.
METHODS
The levels of 3 NF-kappaB transcription factors, the activating inhibitors of NF-kappaB (IkappaB) kinases, and the NF-kappaB 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-kappaB 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-kappaB 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 IkappaB kinase alpha, 1 component of a key trimolecular regulatory complex. Coexpression of the NF-kappaB machinery suggested activity of NF-kappaB signaling in these ovarian tumors. A significant association of p50 with poor overall survival was observed (P = .02). MMP9 expression had the opposite association, in which patients who had tumors without MMP9 staining had the poorest prognosis (P = .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-kappaB activity may influence outcome in women who receive standard therapy for advanced ovarian cancer. Modification of the NF-kappaB pathway may present an opportunity to improve outcome in the subset of women who have pathway activity.
背景
最近的研究表明核因子 kappaB（NF-κB）在卵巢癌细胞系的传播中起作用，但 NF-κB 在卵巢癌中的意义和机制尚不清楚。作者假设 NF-κB 途径在侵袭性卵巢癌中过度激活。
方法
作者通过免疫组织化学方法检测了 33 名接受紫杉醇、顺铂和环磷酰胺联合治疗的患者的卵巢癌诊断标本中 3 种 NF-κB 转录因子、NF-κB 激活抑制剂（IkappaB）激酶和 NF-κB 靶标基质金属蛋白酶 9（MMP9）的水平。NF-κB 通路蛋白与预后之间存在相关性。在两个独立收集的 185 例和 153 例卵巢癌队列中，对共表达进行了基因水平的验证。
结果
在新诊断的晚期卵巢癌中确定了 NF-κB 蛋白的存在，并发现与总生存期存在潜在关联。转录因子 p65 和 v-rel 网状内皮增生病毒癌基因同源物 B（RelB）与关键三聚体调节复合物的 1 个成分 IkappaB 激酶α共表达。NF-κB 机制的共表达表明这些卵巢肿瘤中 NF-κB 信号的活性。观察到 p50 与总体生存率差显著相关（P=0.02）。MMP9 的表达呈相反的相关性，即没有 MMP9 染色的肿瘤患者预后最差（P=0.01），并且这一相关性在一个独立收集的 185 例卵巢癌队列的基因表达水平上也是成立的。
结论
NF-κB 活性的失调可能会影响接受标准治疗的晚期卵巢癌妇女的预后。NF-κB 途径的修饰可能为具有途径活性的妇女提供改善预后的机会。
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