染色质免疫沉淀
基因敲除
癌症研究
化学
免疫沉淀
腺癌
车站3
破骨细胞
磷酸化
分子生物学
生物
受体
发起人
基因表达
医学
癌症
细胞凋亡
内科学
基因
生物化学
作者
Lishan Zhang,Ming Liu,Jinglei Liu,Xingkai Li,Ming Yang,Benhua Su,Yen‐Ting Lin
摘要
Abstract 27‐Hydroxycholesterol (27‐HC) has been implicated in the pathological process of estrogen receptor positive breast cancer. However, the role of 27‐HC in lung adenocarcinoma is still unclear. Because bone metastasis is a main reason for the high mortality of lung adenocarcinoma, this study aimed to investigate the effect of 27‐HC on osteoclastogenesis in lung adenocarcinoma microenvironment. The results showed that the conditioned media (CM) from lung adenocarcinoma cells cocultured with macrophages promoted osteoclast differentiation, which was enhanced by 27‐HC. Further investigation showed that CM inhibited miR‐139 expression and promoted c‐Fos expression. Luciferase reporter assay identified c‐Fos as a direct target of miR‐139. CM also induced the expression and nuclear translocation of NFATc1 and STAT3 phosphorylation, which was enlarged by 27‐HC but was attenuated by miR‐139. Coimmunoprecipitation assay demonstrated that 27‐HC increased the interaction between NFATc1 and phosphorylated STAT3, which was restricted by miR‐139. Chromatin immunoprecipitation assay showed that pSTAT3 could bind to the promoter of c‐Fos, c‐Fos could bind to the promoter of NFATc1, and both pSTAT3 and NFATc1 could bind to the promoter of Oscar, which were enlarged by 27‐HC but were blocked by miR‐139. Knockdown of c‐Fos mimicked the effect of miR‐139. These results suggested that CM, especially containing 27‐HC, promoted osteoclastogenesis by inhibiting miR‐139 expression and activating the STAT3/c‐Fos/NFATc1 pathway.
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