Pro-inflammation NF-κB signaling triggers a positive feedback via enhancing cholesterol accumulation in liver cancer cells.
Pro-inflammation NF-κB signaling triggers a positive feedback via enhancing cholesterol accumulation in liver cancer cells.
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促炎症 NF-κB 信号传导通过增强肝癌细胞中胆固醇的积累来触发正反馈。
DOI：
10.1186/s13046-017-0490-8
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发表时间：
2017-01-18
期刊：
影响因子：
--
通讯作者：
Xia J
中科院分区：
文献类型：
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作者：
He M;Zhang W;Dong Y;Wang L;Fang T;Tang W;Lv B;Chen G;Yang B;Huang P;Xia J
肝细胞癌（HCC）是在以慢性炎症为特征的复杂微环境中发生的。近年来，胆固醇代谢异常在肿瘤细胞生理学中的重要性日益受到重视.本研究旨在探讨肝癌细胞中炎症与胆固醇积聚之间的关系。培养人肝癌细胞HepG 2和Huh 7，用脂多糖（LPS）刺激24 h。比较分析肝癌细胞内胆固醇浓度、胆固醇摄取以及胆固醇相关基因3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）、低密度脂蛋白受体（LDLR）、固醇调节元件结合转录因子2（SREBF 2）和前蛋白转化酶枯草杆菌蛋白酶/kexin 9（PCSK 9）的表达变化。同时，通过RNAi和microRNA（miR）-195敲低核因子-κ B激酶α亚基（IKKα）和TGF-β激活的激酶1和MAP 3 K7结合蛋白3（TAB 3），阐明核因子-κ B（NF-κB）信号通路对胆固醇代谢的影响。随后，进一步研究了胆固醇积累在LPS诱导的促炎作用中的作用。促炎因子LPS通过上调HMGCR、LDLR和SREBF 2的表达，同时下调PCSK 9的表达，显著增加细胞内胆固醇蓄积。这些作用依赖于NF-κB信号通路，通过敲低和过表达IKKα和TAB 3来实现。此外，直接靶向IKKα和TAB 3的调节剂miR-195阻断了胆固醇蓄积的作用，进一步支持了促炎症NF-κB信号传导在调节胆固醇蓄积中的关键作用。有趣的是，胆固醇的积累反过来通过进一步激活NF-κB信号通路而增强了促炎症作用。这些结果表明，NF-κB信号通路的促炎作用可能通过促进肝癌细胞胆固醇的积累而被正反馈增强。
Hepatocellular carcinoma (HCC) develops in a complex microenvironment characterized by chronic inflammation. In recent years, cholesterol metabolic abnormalities have been implicated the importance in cancer cell physiology. This study was designed to investigate the relationship between inflammation and cholesterol accumulation in HCC cells. Human HCC cells HepG2 and Huh7 were cultured and stimulated with lipopolysaccharide (LPS) for 24 h. The changes of HCC cells related to cholesterol metabolism including intracellular cholesterol concentrations, cholesterol uptake, and the expression of cholesterol-related genes 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), LDL receptor (LDLR), sterol regulatory element-binding transcription factor 2 (SREBF2), and proprotein convertase subtilisin/kexin 9 (PCSK9) were comparatively analyzed. Simultaneously, the effects of nuclear factor-kappa B (NF-κB) signaling pathway on cholesterol metabolism were clarified by knocking-down of nuclear factor kappa-B kinase subunit alpha (IKKα) and TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 (TAB3) via RNAi and microRNA (miR)-195. Subsequently, the roles of cholesterol accumulation in LPS induced pro-inflammatory effects were further investigated. Pro-inflammatory factor LPS significantly increased intracellular cholesterol accumulation by upregulating the expression of HMGCR, LDLR, and SREBF2, while downregulating the expression of PCSK9. These effects were revealed to depend on NF-κB signaling pathway by knocking-down and overexpression of IKKα and TAB3. Additionally, miR-195, a regulator directly targeting IKKα and TAB3, blocked the effects of cholesterol accumulation, further supporting the critical role of pro-inflammation NF-κB signaling in regulating cholesterol accumulation. Intriguingly, the accumulation of cholesterol conversely exerted an augmented pro-inflammation effects by further activating NF-κB signaling pathway. These results indicated that pro-inflammation effects of NF-κB signaling could be augmented by a positive feedback via enhancing the cholesterol accumulation in liver cancer cells.