The estrogen receptor (ER) signaling and the insulin-like growth factor-1 receptor (IGF-1R) signaling are implicated in lung cancer progression. Here, we sought to investigate whether estrogen regulated the IGF-1R signaling in non-small cell lung cancer (NSCLC) and the underlying mechanisms. We examined and analyzed the correlation of the expression of aromatase (Arom), ERβ, ERα, insulin-like growth factor-1 (IGF-1), and IGF-1R in NSCLC. Tissue-microarray and immunohistochemistry analysis of tissue specimens from 162 NSCLC patients and 38 patients with benign pulmonary lesions showed that Arom, ERβ, IGF-1, and IGF-1R were overexpressed while ERα was not expressed in NSCLC. Furthermore, ERβ expression was positively correlated with that of Arom, IGF-1, and IGF-1R (r = 0.554, 0.649, 0.496, respectively, P values are equal to 0.000), while Arom expression was positively associated with that of IGF-1 and IGF-1R (r = 0.657, 0.714, respectively, P values are equal to 0.000). Additionally, ERβ, IGF-1, and phospho-IGF-1R, but not ERα, were expressed in A549 cells. Immunoblotting assays showed that A549 cells treated with E2 showed significantly higher IGF-1 and p-IGF-1R levels than those receiving the combination treatment of 17β-estradiol (E2) and fulvestrant (Ful, ER antagonist) (P = 0.042, 0.002, respectively) or controls (P values are equal to 0.000). The MTT assays further revealed that E2 and IGF-1 synergistically promoted A549 cell proliferation. Together, our study provides the first direct evidence for an interaction between ER and IGF-1R in lung cancer. We showed that estrogen upregulated the IGF-1R signaling through ERβ in lung cancer tissues and A549 cells. These findings shed further light on the mechanisms whereby estrogen promotes lung cancer and highlight the ER and IGF-1R signaling pathways as promising targets for combinational therapy for lung cancer.
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This study was founded by Science and Technology Activity Foundation of Returned Overseas Scholars (Human Resources and Social Security Department of Hubei Province 86, China). The authors thank Research Center of Experimental Medicine for laboratory equipment services and Department of Statistics for the statistical calculations of this study, both coming from Tongji Medical College, Huazhong University of Science and Technology (Wuhan, China).
Conflict of interest
No potential conflicts of interest were disclosed.
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