title: Pro-inflammation NF-κB signaling triggers a positive feedback via enhancing cholesterol accumulation in liver cancer cells.
abstract: 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.
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
authors.forename: Mingyan
authors.initials: M
authors.lastname: He
authors.affiliation: Cancer Hospital of Baotou City, Inner Monggolia, 014030, China.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
authors.forename: Yinying
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Minhang Hospital, Fudan University, Shanghai, 201100, China.
authors.forename: Lishun
authors.initials: L
authors.lastname: Wang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Fang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Tang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
authors.forename: Bei
authors.initials: B
authors.lastname: Lv
authors.affiliation: Minhang Hospital, Fudan University, Shanghai, 201100, China.
authors.forename: Guanglang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
authors.forename: Biwei
authors.initials: B
authors.lastname: Yang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
authors.forename: Peixin
authors.initials: P
authors.lastname: Huang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. xiajinglin@fudan.edu.cn.|Minhang Hospital, Fudan University, Shanghai, 201100, China. xiajinglin@fudan.edu.cn.
authors.forename: Jinglin
authors.initials: J
authors.lastname: Xia
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects; D008113:Liver Neoplasms / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D000071449:Proprotein Convertase 9 / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism
chemical_list: C573412:LDLR protein, human; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011973:Receptors, LDL; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
keywords: Cholesterol accumulation; Hepatocellular carcinoma; Lipopolysaccharide; Nuclear factor-kappa B; microRNA-195