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27-羟胆固醇与高胆固醇饮食相关，促进肺腺癌转移。

27-hydroxycholesterol linked high cholesterol diet to lung adenocarcinoma metastasis.

机构信息

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.

出版信息

Oncogene. 2022 May;41(19):2685-2695. doi: 10.1038/s41388-022-02285-y. Epub 2022 Apr 4.

DOI:10.1038/s41388-022-02285-y
PMID:35379924
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9076535/
Abstract

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.

摘要

膳食胆固醇被认为可促进肺癌的发生。肺腺癌（LAC）是肺癌的主要类型，而胆固醇在 LAC 中的功能机制在很大程度上尚不清楚。在本研究中，我们证明胆固醇可促进 LAC 细胞在体外的增殖和侵袭以及体内的转移。Cyp27A1 敲低可减少胆固醇诱导的 LAC 细胞增殖和侵袭。相比之下，Cyp7B1 敲低增强了胆固醇对 LAC 细胞增殖和侵袭的作用。此外，Cyp27A1 缺乏可显著减少高胆固醇诱导的 LAC 体内转移。机制研究表明，暴露于 27-羟胆固醇可诱导 LAC 细胞中 AKT 和 NFκB p65 的磷酸化，并促进肽基脯氨酰异构酶 B（PPIB）的表达，尤其是在与 THP1 衍生的巨噬细胞共培养时。同时，27-羟胆固醇诱导 FGF2 和 IL-6 的分泌，这有助于 snail 和波形蛋白的表达。荧光素酶报告测定和 ChIP 测定证实 NFκB p65 控制 PPIB 的转录。抑制 NFκB p65 的激活可降低 PPIB 的表达。PPIB 抑制可降低 27-羟胆固醇诱导的 snail 和波形蛋白的表达。这些结果表明，27-羟胆固醇通过调节 NFκB/PPIB 轴和 FGF2 和 IL-6 的分泌将高胆固醇与 LAC 转移联系起来。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664b/9076535/6b1fc1ae134a/41388_2022_2285_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664b/9076535/cb9acc61eb90/41388_2022_2285_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664b/9076535/b2e1af365fd4/41388_2022_2285_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664b/9076535/2962bc1d2fb3/41388_2022_2285_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664b/9076535/7c271b5b0869/41388_2022_2285_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664b/9076535/039d7bb8e09e/41388_2022_2285_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664b/9076535/d8bec3f91d93/41388_2022_2285_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664b/9076535/6491b916ace5/41388_2022_2285_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664b/9076535/6b1fc1ae134a/41388_2022_2285_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664b/9076535/cb9acc61eb90/41388_2022_2285_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664b/9076535/b2e1af365fd4/41388_2022_2285_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664b/9076535/2962bc1d2fb3/41388_2022_2285_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664b/9076535/7c271b5b0869/41388_2022_2285_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664b/9076535/039d7bb8e09e/41388_2022_2285_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664b/9076535/d8bec3f91d93/41388_2022_2285_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664b/9076535/6491b916ace5/41388_2022_2285_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/664b/9076535/6b1fc1ae134a/41388_2022_2285_Fig8_HTML.jpg

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