Estrogen induces CXCR4 overexpression and CXCR4/CXL12 pathway activation in lung adenocarcinoma cells in vitro.
PURPOSE
This study was designed to investigate whether estradiol is related to the expression of the chemokine receptor CXCR4 and its activation in lung adenocarcinoma in vitro, since lung adenocarcinomas from premenopausal women have shown high levels of CXCR4, and this expression has been associated with worse prognosis and poor survival.


METHODS
The effect of 17-β-estradiol (E2) (0.03 nM-10 nM) on CXCR4 expression was analyzed in lung adenocarcinoma cell lines (SK-LU-1, H1435, H23, A549) by immunofluorescence after 24 and 72-h poststimulation. Tamoxifen treatment was applied to corroborate the estrogenic effect. The wound-healing assay was performed to investigate whether E2 treatment increased CXCR4/CXL12 pathway activity. A549 and SK-LU-1 cells were stimulated with E2, CXCL12, and CXCL12 combined with E2. Tamoxifen and AMD3100 were applied to corroborate estrogen and chemokine pathway activation.


RESULTS
Estradiol stimulated significantly CXCR4 overexpression in all the cell lines analyzed in a dose- and a time-dependent manner. Tamoxifen treatment inhibited the CXCR4 overexpression observed in estrogen-treated groups, demonstrating that estrogen strongly influences CXCR4 expression in lung adenocarcinoma cells. Cells treated with E2, CXCL12 and E2 combined with CXCL12 exhibited significant cell migration, which was suppressed when tamoxifen and AMD3100 were present.


CONCLUSION
Overexpression of CXCR4 induced by estrogen and the activity of CXCL12/CXCR4 pathway could be a new mechanism by which this hormone supports tumor progression and metastasis. These findings may partly explain the worse prognosis observed in premenopausal women and suggest considering the role of estrogen in lung cancer for the design of more specific treatment schemes.
['Rodriguez-Lara|Vianey|V|', 'Ignacio|González-Sánchez|GS|', 'Cerbón Cervantes|Marco A|MA|']
D000230:Adenocarcinoma D000077192:Adenocarcinoma of Lung D018931:Antineoplastic Agents, Hormonal D045744:Cell Line, Tumor D054377:Chemokine CXCL12 D004958:Estradiol D005260:Female D006801:Humans D008175:Lung Neoplasms D008297:Male D008875:Middle Aged D019718:Receptors, CXCR4 D015398:Signal Transduction D013629:Tamoxifen
estrogen CXCR4 lung adenocarcinoma women tamoxifen