Tumor necrosis factor-α (TNF) is well known to be involved in the immune system and ovarian inflammation. Ovarian cancer is an inflammation-related malignancy that lacks early screening strategies, resulting in late diagnosis followed by high mortality. Based on our previous data, TNF induced abundant serum amyloid A (SAA), an acute phase protein linked to inflammation, in ovarian granulosal cells. To date, the regulation and expression of SAA in ovarian cancer is not fully elucidated. Here, we investigated the relationship between TNF and SAA by comparing human normal ovarian tissues and serous ovarian tumors. We found that SAA1/2 was significantly expressed in tumor tissues, but no or trace expression levels in normal tissues. TNF was also significantly upregulated in ovarian tumor tissues compared to normal tissues. Moreover, TNF significantly increased SAA1/2 levels in human ovarian cancer cell lines, OVCAR-3 and SKOV-3, in a time-dependent manner. Since the SAA1 promoter contains two nuclear factor (NF)-κB sites, we examined whether TNF regulates SAA1 promoter activity. Deletion analysis revealed that the proximal NF-κB site (−95/−85) played a critical role in regulating TNF-induced SAA1 promoter activity. Within 2 h after intraperitoneal injection of lipopolysaccharide, a product known to stimulate release of TNF, SAA preferably localized to ovarian epithelial cells and the thecal-interstitial layers compared to granulosal cell layers. Based on Gene Expression Omnibus (GEO) database, SAA1/2 and TNF were dominantly expressed in advanced grade ovarian cancer. Taken together, the accumulation of SAA1/2 in ovarian cancer could be mediated by TNF-induced NF-κB activation.

中文翻译：

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人浆液性卵巢上皮肿瘤中 TNF 诱导的 NF-κB 介导的血清淀粉样蛋白 A1/2 增加

众所周知，肿瘤坏死因子-α (TNF) 与免疫系统和卵巢炎症有关。卵巢癌是一种与炎症相关的恶性肿瘤，缺乏早期筛查策略，导致诊断较晚，死亡率较高。根据我们之前的数据，TNF 在卵巢颗粒细胞中诱导大量血清淀粉样蛋白 A (SAA)，这是一种与炎症相关的急性期蛋白。迄今为止，SAA在卵巢癌中的调控和表达尚未完全阐明。在这里，我们通过比较人类正常卵巢组织和浆液性卵巢肿瘤来研究 TNF 和 SAA 之间的关系。我们发现SAA1/2在肿瘤组织中显着表达，而在正常组织中无或微量表达。与正常组织相比，卵巢肿瘤组织中 TNF 的表达也显着上调。此外，TNF 以时间依赖性方式显着增加人卵巢癌细胞系 OVCAR-3 和 SKOV-3 中的 SAA1/2 水平。由于SAA1启动子含有两个核因子(NF)-κB位点，我们检查了TNF是否调节SAA1启动子活性。缺失分析显示近端 NF-κB 位点 (−95/−85) 在调节 TNF 诱导的 SAA1 启动子活性中发挥着关键作用。腹腔注射脂多糖（一种已知可刺激 TNF 释放的产品）后 2 小时内，与颗粒细胞层相比，SAA 优选定位于卵巢上皮细胞和鞘间质层。根据基因表达综合（GEO）数据库，SAA1/2和TNF在晚期卵巢癌中占主导地位。综上所述，卵巢癌中 SAA1/2 的积累可能是由 TNF 诱导的 NF-κB 激活介导的。