Estrogen promotes non-small cell lung cancer (NSCLC) metastasis via estrogen receptor β (ERβ)-mediated invasiveness-associated matrix metalloprotease 2 (MMP2) upregulation. However, how ERβ increases the aggressiveness of NSCLC cells remains unclear. Recently, MMP2 was found to be upregulated by Toll-like receptor 4 (TLR4) signaling activation and to promote NSCLC metastasis. Our present study aimed to examine the role of ERβ in the activation of TLR4 signaling and in tumor progression and metastasis, and to explore the synergistic metastatic effect of a combination of ERβ and TLR4 activation on human NSCLC cells in vitro and in vivo. Here, we found that ERβ is associated with TLR4 in metastatic lymph nodes. Western blot analysis and immunofluorescence revealed that ERβ overexpression upregulated TLR4 protein expression and activated downstream targets, myeloid differentiation primary response 88 (myd88)/nuclear factor (NF)-κB/MMP2, enhancing NSCLC cell migration and invasion in vitro. A novel ERβ-TLR4 interaction in cell plasma was identified by co-immunoprecipitation and confocal immunofluorescence. The combination of estradiol and specific TLR4 agonist lipopolysaccharide (LPS) synergistically promoted metastatic behaviors in NSCLC cells. In cell culture and murine lung metastasis models, exposure to estradiol and LPS induced increased matrix degradation and accelerated invadopodia and metastasis formation in NSCLC cells compared with that in cells treated with estradiol or LPS alone. Together, we showed 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 therapeutic strategy against advanced metastatic lung cancer.
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disorder characterized by high autoantibodies levels and multiorgan tissue damage. The current study investigated the role of CD64 in SLE patients and animal models. According to a flow cytometry study, SLE patients showed an increase in CD64 expression in circulating monocytes. There was a correlation between CD64 and SLEDAI, blood urea nitrogen levels, and anti-Sm antibodies. In skin lesions of lupus MRL/lpr mice, there was high IgG deposition and CD64 expression. In vitro, cytokines IL-10 and IFN-γ upregulated CD64 expression in monocytes/macrophages that was inhibited by glucocorticoids. In CD64-deficient mice, skin inflammation induced by lupus serum was reduced. Furthermore, activation of spleen tyrosine kinase (Syk), Akt, and extracellular signal-regulated kinase (Erk) was inhibited in CD64-deficient monocytes. The results suggest that CD64 could be a biomarker for observing SLE progression, as well as a mechanistic checkpoint in lupus pathogenesis.
Systemic lupus erythematosus (SLE), often known simply as lupus, is a severe chronic autoimmune disease that is characterized by multi-organ and tissue damage and high levels of autoantibodies in serum. We have recently investigated, using animal models, the role of organ-deposited IgG autoantibodies in the pathogenesis of organ and tissue damage in SLE. We found that intra-organ injection of serum from mice with lupus (i.e., lupus mice) into healthy mice triggered inflammation in tissue and organs but that serum from other healthy mice did not, and that the severity of inflammation was related to the dose of serum injected. Immunohistochemistry showed that a large number of IgG molecules are deposited at the site of organ and tissue damage in lupus mice, and that IgG is a major contributor to the development of tissue inflammation triggered by serum from lupus mice or patients. The development of tissue inflammation induced by IgG in serum from lupus mice requires the presence of monocytes/macrophages, but not of lymphocytes or neutrophils; tumor necrosis factor (TNF)/tumor necrosis factor receptor 1 (TNFR1) and interleukin 1 (IL-1) also play essential roles in the development of tissue inflammation triggered by IgG. In addition, it has been found that TNFR1 inhibitors can suppress skin injury in lupus mice and that spleen tyrosine kinase (Syk) inhibitors, which can block the signaling transduction of IgG/Fc gamma receptors (FcγRs), can prevent and treat skin injury and kidney damage in lupus mice. We have also observed that lupus IgG might protect against bone erosion. Based on these results, we conclude that IgG plays a crucial role in the development of organ and tissue damage in SLE and in protecting bone erosion and arthritis, and we suggest that the IgG/FcγR signaling pathway is an important therapeutic target in SLE.
In a previous study, our research group observed that estrogen promotes the metastasis of non‐small cell lung cancer (NSCLC) through the estrogen receptor β (ERβ). Invadopodia are key structures involved in tumor metastasis. However, it is unclear whether ERβ is involved in the promotion of NSCLC metastasis through invadopodia. In our study, we used scanning electron microscopy to observe the formation of invadopodia following the overexpression of ERβ and treatment with E2. In vitro experiments using multiple NSCLC cell lines demonstrated that ERβ can increase the formation of invadopodia and cell invasion. Mechanistic studies revealed that ERβ can upregulate the expression of ICAM1 by directly binding to estrogen‐responsive elements (EREs) located on the ICAM1 promoter, which in turn can enhance the phosphorylation of Src/cortactin. We also confirmed these findings in vivo using an orthotopic lung transplantation mouse model, which validated the results obtained from the in vitro experiments. Finally, we examined the expressions of ERβ and ICAM1 using immunohistochemistry in both NSCLC tissue and paired metastatic lymph nodes. The results confirmed that ERβ promotes the formation of invadopodia in NSCLC cells through the ICAM1/p‐Src/p‐Cortactin signaling pathway.
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