The canonical and non-canonical nuclear factor-kappaB (NF-κB) signaling pathways have key roles in cancer, but studies have previously evaluated only the association of canonical transcription factors and ovarian cancer survival. Although a number of in vitro and in vivo studies have demonstrated mechanisms by which non-canonical NF-κB signaling potentially contributes to ovarian cancer progression, a prognostic association has yet to be shown in the clinical context. We assayed p65 and p52 (major components of the canonical and non-canonical NF-κB pathways) by immunohistochemistry in epithelial ovarian tumor samples; nuclear and cytoplasmic staining were semi-quantified by H-scores and dichotomized at median values. Associations of p65 and p52 with progression-free survival (PFS) and overall survival (OS) were quantified by Hazard Ratios (HR) from proportional-hazards regression. Among 196 cases, median p52 and p65 H-scores were higher in high-grade serous cancers. Multivariable regression models indicated that higher p52 was associated with higher hazards of disease progression (cytoplasmic HR: 1.54; nuclear HR: 1.67) and death (cytoplasmic HR: 1.53; nuclear HR: 1.49), while higher nuclear p65 was associated with only a higher hazard of disease progression (HR: 1.40) in unadjusted models. When cytoplasmic and nuclear staining were combined, p52 remained significantly associated with increased hazards of disease progression (HR: 1.91, p = 0.004) and death (HR: 1.70, p = 0.021), even after adjustment for p65 and in analyses among only high-grade serous tumors. This is the first study to demonstrate that p52, a major component of non-canonical NF-κB signaling, may be an independent prognostic factor for epithelial ovarian cancer, particularly high-grade serous ovarian cancer. Approaches to inhibit non-canonical NF-κB signaling should be explored as novel ovarian cancer therapies are needed.

中文翻译：

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p52（一种非经典 NF-kappaB 转录因子）的表达与卵巢癌预后不良相关

经典和非经典核因子-κB (NF-κB) 信号通路在癌症中发挥着关键作用，但之前的研究仅评估了经典转录因子与卵巢癌生存的关联。尽管许多体外和体内研究已经证明非典型 NF-κB 信号传导可能促进卵巢癌进展的机制，但其预后关联尚未在临床环境中得到证实。我们通过免疫组织化学方法在上皮性卵巢肿瘤样本中检测了 p65 和 p52（典型和非典型 NF-κB 通路的主要成分）；核和细胞质染色通过 H 分数半定量并按中值二分。p65 和 p52 与无进展生存期 (PFS) 和总生存期 (OS) 的关联通过比例风险回归的风险比 (HR) 进行量化。在 196 例病例中，高级别浆液性癌症的中位 p52 和 p65 H 分数较高。多变量回归模型表明，较高的 p52 与较高的疾病进展风险（细胞质 HR：1.54；核 HR：1.67）和死亡（细胞质 HR：1.53；核 HR：1.49）相关，而较高的核 p65 仅与较高的风险相关。未经调整的模型中疾病进展的风险（HR：1.40）。当细胞质和核染色相结合时，p52 仍然与疾病进展风险增加（HR：1.91，p = 0.004）和死亡（HR：1.70，p = 0.021）显着相关，即使在对 p65 进行调整后并且仅在高风险人群中进行分析。级浆液性肿瘤。这是第一项研究证明 p52（非经典 NF-κB 信号传导的主要成分）可能是上皮性卵巢癌（尤其是高级别浆液性卵巢癌）的独立预后因素。由于需要新的卵巢癌疗法，因此应探索抑制非经典 NF-κB 信号传导的方法。