17β-estradiol upregulates IL6 expression through the ERβ pathway to promote lung adenocarcinoma progression

Abstract

BackgroundIn non-small cell lung cancer (NSCLC), estrogen (E2) significantly promotes NSCLC cell growth via estrogen receptor beta (ERβ). 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.MethodsExpression of ERβ/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 ERβ/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 ERβ 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 ERβ subtype tumor growth with respect to IL6 expression.ResultsIL6/ERβ expression were significantly increased in lung cancer. Higher IL6/ERβ 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, ERβ 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 ERβ isolation 1/5 is essential for E2 promotion of IL6 expression, while ERβ2 not.ConclusionsOur findings demonstrate that E2 stimulates IL6 expression to promote lung adenocarcinoma progression through the ERβ pathway. We also clarify the difference in each ERβ subtype for E2 promoting IL6 expression, suggesting that ERβ/IL6 might be potential targets for prognostic assessment and therapeutic intervention in lung cancer.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0804-5) contains supplementary material, which is available to authorized users.

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CLPTM1L induces estrogen receptor β signaling-mediated radioresistance in non-small cell lung cancer cells

“…ERβ, an important member of the nuclear receptor protein family as well as a crucial transcription factor, is linked to the survival of breast cancer patients [ 73 – 75 ]. Recently, ERβ was shown to affect the progression of NSCLC by promoting the proliferation, invasion, and metastasis of NSCLC cells [ 38 , 40 , 48 ]. Many studies have focused on the pathological role of ERβ, which can be activated by estrogen or other ligands and coactivators, in the development of lung cancer, especially NSCLC [ 76 – 79 ].…”

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