Journal
ONCOGENE
Volume 41, Issue 19, Pages 2685-2695Publisher
SPRINGERNATURE
DOI: 10.1038/s41388-022-02285-y
Keywords
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Funding
- National Natural Science Foundation of China [81572272, 81972177]
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In this study, it was found that cholesterol promotes cell proliferation and invasion of lung adenocarcinoma (LAC), and also enhances LAC metastasis. The mechanism involves the regulation of NF kappa B/PPIB axis and the secretion of FGF2 and IL-6 by 27-hydroxycholesterol.
Dietary cholesterol has been implicated to promote lung cancer. Lung adenocarcinoma (LAC) is a main type of lung cancer, whereas the functional mechanism of cholesterol in LAC remained largely unknown. In the present study, we evidenced that cholesterol promoted cell proliferation and invasion of LAC in vitro as well as LAC metastasis in vivo. Cyp27A1 knockdown reduced the cholesterol-induced LAC cells proliferation and invasion. In contrast, Cyp7B1 knockdown enhanced the effect of cholesterol on LAC cells proliferation and invasion. Furthermore, Cyp27A1 deficiency remarkably reduced high cholesterol-induced LAC metastasis in vivo. Mechanism investigation demonstrated that exposure of LAC cells to 27-hydroxycholesterol induced the phosphorylation of AKT and NF kappa B p65, and promoted the expression of peptidylprolyl isomerase B (PPIB), especially in the coculture with THP1-derived macrophage. Meanwhile, 27-hydroxycholesterol induced the secretion of FGF2 and IL-6, which contributed to the expression of snail and vimentin. Luciferase report assay and ChIP assay confirmed that NF kappa B p65 controlled the transcription of PPIB. Inhibiting NF kappa B p65 activation reduced PPIB expression. PPIB inhibition reduced 27-hydroxycholesterol-induced expression of snail and vimentin. These results indicated that 27-hydroxycholesterol linked high cholesterol and LAC metastasis by regulating NF kappa B/PPIB axis and the secretion of FGF2 and IL-6.
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