摘要 : Lung adenocarcinoma is the most common type of lung cancer in women. Our previous studies demonstrated that 17 beta-estradiol (E2) promoted lung adenocarcinoma cell proliferation and tumor growth through estrogen receptor ER alpha... 展开 Lung adenocarcinoma is the most common type of lung cancer in women. Our previous studies demonstrated that 17 beta-estradiol (E2) promoted lung adenocarcinoma cell proliferation and tumor growth through estrogen receptor ER alpha. Transcriptomic analysis suggested that E2 potentiated TNF alpha-NF kappa B signaling in ER alpha-expressing lung adenocarcinoma cells. This study further demonstrated that E2 increased TNF alpha receptor expression and TNF alpha-triggered NF kappa B activity in ER alpha-expressing cells. E2-activated ER alpha had no physical association with NF kappa B p65/p50 heterodimer but facilitated TNF alpha-initiated I kappa B alpha degradation, NF kappa B nuclear translocation, and S468/S536 phosphorylation of p65 essential for NF kappa B activity. While knockdown of ER alpha prevented E2 from boosting NF kappa B activity, antiestrogen ICI 182,780 stimulated NF kappa B activity like E2. Inhibition of GSK3 beta hampered E2:ER alpha-promoted NF kappa B activity and abolished S468 phosphorylation of p65, suggesting that GSK3 beta played a role in the E2-TNF alpha signaling crosstalk. In ER alpha-expressing cells, E2 and TNF alpha synergistically regulated many genes that were not typically responsive to either E2 or TNF alpha. Functional analysis of microarray data inferred that E2/TNF alpha-induced transcriptomic changes improved cell survival and movement. Viability and colony formation assays validated that E2 and TNF alpha together increased cisplatin tolerance of ER alpha-expressing cells. Wound healing assays also confirmed that E2/TNF alpha cotreatment increased cell migration in an ER alpha-dependent manner. E2/TNF alpha-induced dysregulation of genes such as cell survival and movement-associated genes, pmto-oncogenes, metallothioneins and histone core genes was correlated with poor overall survival in patients. In summary, E2 and TNF alpha engaged in an ER alpha-dependent positive crosstalk in lung adenocarcinoma cells, consequently increasing NF kappa B activation, cisplatin tolerance and cell migration and worsening prognosis. 收起