Prolonged oxidative stress down-regulates Early B cell factor 1 with inhibition of its tumor suppressive function against cholangiocarcinoma genesis.
Prolonged oxidative stress down-regulates Early B cell factor 1 with inhibition of its tumor suppressive function against cholangiocarcinoma genesis.
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DOI：
10.1016/j.redox.2017.11.011
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发表时间：
2018-04
期刊：
影响因子：
11.4
通讯作者：
Thanan R
中科院分区：
文献类型：
--
作者：
Armartmuntree N;Murata M;Techasen A;Yongvanit P;Loilome W;Namwat N;Pairojkul C;Sakonsinsiri C;Pinlaor S;Thanan R
早期B细胞因子1（EBF 1）是一种参与多种干细胞谱系分化的转录因子，并且是雌激素受体的负调节因子。EBF 1在许多肿瘤中下调，并且被认为在癌症促进和进展中发挥抑制作用。然而，EBF 1在肿瘤发生中的功能作用尚不清楚。肝吸虫感染相关性胆管癌（CCA）是一种氧化应激驱动的胆管上皮癌。在这项研究中，我们研究了EBF 1在CCA患者组织，CCA细胞系（KKU-213，KKU-214和KKU-156），胆管细胞（MMNK 1）及其氧化应激抗性（ox-MMNK 1-L）细胞系中的表达。8-氧代-7，8-二氢-2 ′-脱氧鸟苷（8-oxodG）的形成被用作氧化应激标志物。我们的研究结果表明，EBF 1表达抑制癌细胞相比，个别正常胆管细胞在肿瘤附近地区的CCA组织。具有低EBF 1表达和高8-oxodG形成的CCA患者显示与较差的生存相关。此外，与胆管细胞系相比，EBF 1在抗氧化应激细胞系和所有CCA细胞系中被抑制。这表明，长期的氧化应激抑制EBF 1的表达和降低EBF 1水平可能有助于CCA的发生。为了阐明EBF 1抑制在CCA发生中的意义，通过siRNA技术下调MMNK 1细胞系的EBF 1表达，并检查其对干细胞特性（CD 133和Oct 3/4表达）、致瘤特性（细胞增殖、伤口愈合和细胞迁移）、雌激素应答基因（TFF 1）、雌激素刺激的伤口愈合和细胞迁移的影响。结果显示，CD 133、Oct 3/4和TFF 1表达水平、伤口愈合和细胞迁移显著增加。此外，17β-雌二醇处理后，EBF 1敲低细胞的细胞迁移显著增强。我们的研究结果表明，EBF 1下调通过氧化应激诱导干细胞特性，致瘤性和雌激素反应的胆管细胞导致CCA的发生与积极的临床结果。EBF 1在胆管癌组织和细胞系中表达下调。EBF 1水平低、8-oxodG水平高的CCA患者生存率低。氧化应激抑制EBF 1的表达，这可能在CCA的发展中发挥作用。EBF 1沉默增加胆管细胞中的干细胞和致瘤特性。EBF 1沉默增加胆管细胞的氧化应激抗性。
Early B cell factor 1 (EBF1) is a transcription factor involved in the differentiation of several stem cell lineages and it is a negative regulator of estrogen receptors. EBF1 is down-regulated in many tumors, and is believed to play suppressive roles in cancer promotion and progression. However, the functional roles of EBF1 in carcinogenesis are unclear. Liver fluke-infection-associated cholangiocarcinoma (CCA) is an oxidative stress-driven cancer of bile duct epithelium. In this study, we investigated EBF1 expression in tissues from CCA patients, CCA cell lines (KKU-213, KKU-214 and KKU-156), cholangiocyte (MMNK1) and its oxidative stress-resistant (ox-MMNK1-L) cell lines. The formation of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) was used as an oxidative stress marker. Our results revealed that EBF1 expression was suppressed in cancer cells compared with the individual normal bile duct cells at tumor adjacent areas of CCA tissues. CCA patients with low EBF1 expression and high formation of 8-oxodG were shown to correlate with poor survival. Moreover, EBF1 was suppressed in the oxidative stress-resistant cell line and all of CCA cell lines compared to the cholangiocyte cell line. This suggests that prolonged oxidative stress suppressed EBF1 expression and the reduced EBF1 level may facilitate CCA genesis. To elucidate the significance of EBF1 suppression in CCA genesis, EBF1 expression of the MMNK1 cell line was down-regulated by siRNA technique, and its effects on stem cell properties (CD133 and Oct3/4 expressions), tumorigenic properties (cell proliferation, wound healing and cell migration), estrogen responsive gene (TFF1), estrogen-stimulated wound healing, and cell migration were examined. The results showed that CD133, Oct3/4 and TFF1 expression levels, wound healing, and cell migration of EBF1 knockdown-MMNK1 cells were significantly increased. Also, cell migration of EBF1-knockdown cells was significantly enhanced after 17β-estradiol treatment. Our findings suggest that EBF1 down-regulation via oxidative stress induces stem cell properties, tumorigenic properties and estrogen responses of cholangiocytes leading to CCA genesis with aggressive clinical outcomes. EBF1 was down-regulated in cholangiocarcinoma (CCA) tissues and cell lines. CCA patients with low EBF1 and high 8-oxodG levels were related with poor survival. Oxidative stress inhibits EBF1 expression which may play roles in CCA development. EBF1 silencing increases stem cell and tumorigenic properties in cholangiocyte cells. EBF1 silencing increases oxidative stress resistance in cholangiocyte cells.
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