Study Of ERβ Mediates 17β-estradiol-induced Metastasis Of The Non-small Cell Lung Cancer By Upregulation Of Toll Like Receptor 4 And Activation Of Myd88/NF-κB/MMP2 Pathway

Estrogen promotes non-small cell lung cancer(NSCLC)metastasis via estrogen receptor β(ERβ)-mediated invasiveness-associated metalloproteases 2(MMP2)upregulation.However,how ERβ increases the aggressiveness of NSCLC cells remains unclear.Here,we found that ERβ associated with TLR4 in metastatic lymph nodes,while activated TLR4 is also able to upregulate MMP2 and promote metastasis.Western blot analysis and immunofluorescence revealed that ERβ overexpression upregulated the TLR4 protein and activated downstream targets,myd88/NF-κB/MMP2,enhancing NSCLC cell migration and invasion in vitro.Co-immunoprecipitation and confocal immunofluorescence identified a novel ERβ-TLR4 interaction in cell plasma.The combination of estradiol and specific TLR4 agonist LPS may promote metastatic behaviors in NSCLC cells.In cell culture and murine lung metastasis models,estradiol and LPS treatment induced increased matrix degradation and accelerated invadopodia and metastasis formation in NSCLC cells as compared to cells treated with estradiol or LPS alone.Altogether,we show that estrogen promoted NSCLC metastasis via ERβ by upregulating TLR4 and activating its downstream signaling axis myd88/NF-κB/MMP2.The combined targeting of ERβ and TLR4 may be a novel strategy against advanced metastatic lung cancer.