17β-estradiol upregulates IL6 expression through the ERβ pathway to promote lung adenocarcinoma progression
17β-estradiol upregulates IL6 expression through the ERβ pathway to promote lung adenocarcinoma progression
复制标题
17β-雌二醇通过 ERbeta 途径上调 IL6 表达，促进肺腺癌进展。
DOI：
10.1186/s13046-018-0804-5
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发表时间：
2018-07-03
影响因子：
11.3
通讯作者：
Xiong, Jing
中科院分区：
文献类型：
--
作者：
Huang, Quanfu;Zhang, Zheng;Xiong, Jing
背景：在非小细胞肺癌（NSCLC）中，雌激素（E2）通过雌激素受体β（ER β）显著促进NSCLC细胞生长。发现和阐明雌激素促进NSCLC进展的机制对于有效的预防干预至关重要。IL 6参与多种肿瘤的发生、发展和转移，IL 6过表达与NSCLC预后不良有关。然而，IL 6在雌激素促进的NSCLC进展中发挥的确切作用仍然未知。在这里，我们评估了IL 6在NSCLC细胞中的表达和生物学效应时，E2和探讨IL 6在E2促进NSCLC progress.Methods的潜在机制：ER β/IL 6在289例肺癌标本中的表达进行了评估。使用转移性淋巴结和原发性肿瘤组织的匹配样品通过蛋白质印迹定量ER β/IL 6的表达。通过Western印迹、ELISA和免疫荧光染色定量NSCLC细胞中IL 6的表达水平。采用CCK-8、集落形成、伤口愈合和transwell等方法评价E2刺激的IL-6对细胞恶性的影响。此外，构建过表达和敲低ER β构建体以测量IL 6的表达。使用乳腺癌诱导的腺癌模型评价E2刺激的IL 6对肿瘤生长的影响。结果：肺癌组织中IL 6/ER β的表达明显增高，IL 6/ER β的表达与肺癌组织中ER β的表达呈负相关。IL 6/ER β高表达与分化程度降低或转移增加相关。IL 6是影响总生存率的独立预后因素，IL 6高表达与总生存率降低相关。ER β在E2刺激下通过MAPK/ERK和PI 3 K/AKT途径调节IL 6的表达，并在体外促进细胞恶性化，在体内诱导肿瘤生长。最后，我们证实，ER β隔离1/5是必不可少的E2促进IL 6的表达，而ER β 2没有。结论：我们的研究结果表明，E2刺激IL 6的表达，促进肺腺癌的进展，通过ER β途径。我们还阐明了E2促进IL 6表达的每个ER β亚型的差异，表明ER β/IL 6可能是肺癌预后评估和治疗干预的潜在靶点。
Background: In non-small cell lung cancer (NSCLC), estrogen (E2) significantly promotes NSCLC cell growth via estrogen receptor beta (ER beta). Discovery and elucidation of the mechanism underlying estrogen-promoted NSCLC progression is critical for effective preventive interventions. IL6 has been demonstrated to be involved in the development, progression and metastasis in several cancers and IL6 overexpression is associated with poor prognosis in NSCLC. However, the exact role played by IL6 in estrogen-promoted NSCLC progress remain unknown. Here, we evaluated the expression and biological effects of IL6 in NSCLC cells when treated with E2 and explored the underlying mechanism of IL6 in E2-promoted NSCLC progression.Methods: Expression of ER beta/IL6 in 289 lung cancer samples was assessed by immunohistochemistry. Matched samples of metastatic lymph node and primary tumor tissues were used to quantify the expression of ER beta/IL6 by western blot. Expression levels of IL6 in NSCLC cells were quantified by western blotting, ELISA, and immunofluorescence staining. The effects of IL6 stimulated by E2 on cell malignancy were evaluated using CCK8, colony formation, wound healing and transwell. Furthermore, overexpression and knockdown ER beta constructs were constructed to measure the expression of IL6. The effects of IL6 stimulated by E2 on tumor growth were evaluated using a urethane-induced adenocarcinoma model. In addition, a xenograft mouse model was used to observe differences in ER beta subtype tumor growth with respect to IL6 expression.Results: IL6/ER beta expression were significantly increased in lung cancer. Higher IL6/ER beta expression was associated with decreased differentiation or increased metastasis. IL6 was an independent prognostic factor for overall survival (OS), higher IL6 expression was associated with decreased OS. Furthermore, ER beta regulates IL6 expression via MAPK/ERK and PI3K/AKT pathways when stimulated by E2 and promotes cell malignancy in vitro and induced tumor growth in vivo. Finally we confirm that ER beta isolation 1/5 is essential for E2 promotion of IL6 expression, while ER beta 2 not.Conclusions: Our findings demonstrate that E2 stimulates IL6 expression to promote lung adenocarcinoma progression through the ER beta pathway. We also clarify the difference in each ER beta subtype for E2 promoting IL6 expression, suggesting that ER beta/IL6 might be potential targets for prognostic assessment and therapeutic intervention in lung cancer.