Choi Hyeongjwa, Ignacio Rosa Mistica C, Lee Eun-Sook, Wilson Andrew J, Khabele Dineo, Son Deok-Soo
Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M University, Tallahassee, FL 32301, USA.
Immune Netw. 2017 Apr;17(2):121-127. doi: 10.4110/in.2017.17.2.121. Epub 2017 Apr 20.
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.
肿瘤坏死因子-α（TNF）参与免疫系统和卵巢炎症，这是广为人知的。卵巢癌是一种与炎症相关的恶性肿瘤，缺乏早期筛查策略，导致诊断延迟，随后死亡率很高。基于我们之前的数据，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，我们通过比较人正常卵巢组织和浆液性卵巢肿瘤，研究了TNF与SAA之间的关系。我们发现SAA1/2在肿瘤组织中显著表达，但在正常组织中无表达或表达水平极低。与正常组织相比，TNF在卵巢肿瘤组织中也显著上调。此外，TNF以时间依赖性方式显著增加人卵巢癌细胞系OVCAR-3和SKOV-3中的SAA1/2水平。由于SAA1启动子包含两个核因子（NF）-κB位点，我们研究了TNF是否调节SAA1启动子活性。缺失分析表明，近端NF-κB位点（-95/-85）在调节TNF诱导SAA1启动子活性中起关键作用。腹腔注射已知能刺激TNF释放的脂多糖后2小时内，与颗粒细胞层相比，SAA更倾向于定位于卵巢上皮细胞和卵泡膜-间质层。基于基因表达综合数据库（GEO），SAA1/2和TNF在高级别卵巢癌中占主导表达。综上所述，卵巢癌中SAA1/2的积累可能由TNF诱导的NF-κB激活介导。
