AI Article Synopsis
- 27-Hydroxycholesterol (27-HC) is linked to breast cancer but its role in lung adenocarcinoma is unclear; this study investigates its impact on osteoclast formation in this cancer type.
- The study found that lung adenocarcinoma cells, when cocultured with macrophages, produced factors that enhanced osteoclast differentiation, and this effect was further increased by 27-HC.
- Results indicated that 27-HC promotes osteoclastogenesis by inhibiting miR-139 and activating the STAT3/c-Fos/NFATc1 signaling pathway, highlighting a potentially critical mechanism in lung cancer metastasis.
Article 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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| http://dx.doi.org/10.1002/jcp.27883 | DOI Listing |
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