Lung adenocarcinoma is the most common type of lung cancer in women. Our previous studies demonstrated that 17β-estradiol (E2) promoted lung adenocarcinoma cell proliferation and tumor growth through estrogen receptor ERα. Transcriptomic analysis suggested that E2 potentiated TNFα-NFκB signaling in ERα-expressing lung adenocarcinoma cells. This study further demonstrated that E2 increased TNFα receptor expression and TNFα-triggered NFκB activity in ERα-expressing cells. E2-activated ERα had no physical association with NFκB p65/p50 heterodimer but facilitated TNFα-initiated IκBα degradation, NFκB nuclear translocation, and S468/S536 phosphorylation of p65 essential for NFκB activity. While knockdown of ERα prevented E2 from boosting NFκB activity, antiestrogen ICI 182,780 stimulated NFκB activity like E2. Inhibition of GSK3β hampered E2:ERα-promoted NFκB activity and abolished S468 phosphorylation of p65, suggesting that GSK3β played a role in the E2-TNFα signaling crosstalk. In ERα-expressing cells, E2 and TNFα synergistically regulated many genes that were not typically responsive to either E2 or TNFα. Functional analysis of microarray data inferred that E2/TNFα-induced transcriptomic changes improved cell survival and movement. Viability and colony formation assays validated that E2 and TNFα together increased cisplatin tolerance of ERα-expressing cells. Wound healing assays also confirmed that E2/TNFα cotreatment increased cell migration in an ERα-dependent manner. E2/TNFα-induced dysregulation of genes such as cell survival and movement-associated genes, proto-oncogenes, metallothioneins and histone core genes was correlated with poor overall survival in patients. In summary, E2 and TNFα engaged in an ERα-dependent positive crosstalk in lung adenocarcinoma cells, consequently increasing NFκB activation, cisplatin tolerance and cell migration and worsening prognosis.

肺腺癌是女性最常见的肺癌类型。我们之前的研究表明，17β-雌二醇 (E2)通过雌激素受体ERα促进肺腺癌细胞增殖和肿瘤生长。转录组学分析表明，E2 增强了表达 ERα 的肺腺癌细胞中的 TNFα-NFκB 信号传导。该研究进一步证明，E2 增加了 ERα 表达细胞中 TNFα 受体的表达和 TNFα 触发的 NFκB 活性。E2 激活的 ERα 与 NFκB p65/p50 异二聚体没有物理联系，但促进了 TNFα 启动IκBα 降解、NFκB 核易位和对 NFκB 活性至关重要的 p65 的 S468/S536 磷酸化。虽然 ERα 的敲低阻止了 E2 增强 NFκB 活性，但抗雌激素 ICI 182,780 像 E2 一样刺激了 NFκB 活性。GSK3β 的抑制阻碍了 E2:ERα 促进的 NFκB 活性并消除了 p65 的 S468 磷酸化，表明 GSK3β 在 E2-TNFα 信号串扰中发挥了作用。在表达 ERα 的细胞中，E2 和 TNFα 协同调节许多通常对 E2 或 TNFα 没有反应的基因。微阵列数据的功能分析推断 E2/TNFα 诱导的转录组变化改善了细胞存活和运动。活力和集落形成分析证实 E2 和 TNFα 一起增加顺铂ERα 表达细胞的耐受性。伤口愈合试验还证实 E2/TNFα 协同处理以 ERα 依赖性方式增加细胞迁移。E2/TNFα 诱导的基因失调，例如细胞存活和运动相关基因、原癌基因、金属硫蛋白和组蛋白核心基因，与患者的总体存活率较差相关。总之，E2 和 TNFα 在肺腺​​癌细胞中参与 ERα 依赖性阳性串扰，从而增加 NFκB 活化、顺铂耐受性和细胞迁移并恶化预后。