27-hydroxycholesterol linked high cholesterol diet to lung adenocarcinoma metastasis.
27-hydroxycholesterol linked high cholesterol diet to lung adenocarcinoma metastasis.
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DOI：
10.1038/s41388-022-02285-y
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发表时间：
2022-05
期刊：
影响因子：
8
通讯作者：
Lin, Yanliang
中科院分区：
文献类型：
--
作者：
Li, Xingkai;Chen, Hengchi;Zhang, Lizhen;Chen, Li;Wei, Wei;Gao, Shugeng;Xue, Qi;Li, Yue;Wang, Bing;Li, Jiagen;Gao, Yushun;Lin, Yanliang
饮食中的胆固醇被认为是肺癌的诱因。肺腺癌(LAC)是肺癌的一种主要类型，而胆固醇在LAC中的作用机制尚不清楚。在本研究中，我们证实了胆固醇在体外促进LAC细胞的增殖和侵袭，以及在体内促进LAC的转移。Cyp27A1基因敲除降低了胆固醇诱导的LAC细胞的增殖和侵袭。相反，CYP7B1基因敲除增强了胆固醇对LAC细胞增殖和侵袭的影响。此外，Cyp27A1缺乏显著减少了体内高胆固醇诱导的LAC转移。机制研究表明，27-羟基胆固醇可诱导AKT和核因子κB p65的磷酸化，并促进肽基丙酰异构酶B的表达，尤其是在与THP1源巨噬细胞共同培养时。同时，27-羟基胆固醇可诱导细胞分泌FGF2和IL-6，促进蜗牛和波形蛋白的表达。荧光素酶报告实验和芯片实验证实，NFκB p65调控PPIB的转录。抑制核因子κB p65的激活可降低PPIB的表达。抑制PPIB可降低27-羟基胆固醇诱导的蜗牛和波形蛋白的表达。这些结果表明，27-羟基胆固醇通过调节NFGFB/κ轴以及FGF2和IL-6的分泌与高胆固醇和LAC转移有关。
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 NFκB 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 NFκB p65 controlled the transcription of PPIB. Inhibiting NFκB 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 NFκB/PPIB axis and the secretion of FGF2 and IL-6.
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影响因子：
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DOI：
10.1016/j.bbrc.2015.01.035
发表时间：
2015-02-20
影响因子：
3.1
作者：
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