| 880 | 4 | 42 |
| 下载次数 | 被引频次 | 阅读次数 |
肝细胞癌（HCC）是最常见的原发性肝脏恶性肿瘤，其特点是死亡率高，易转移和复发，五年生存率低，临床预后差。目前几乎没有直接靶向肿瘤细胞的治疗方法，最有效的HCC治疗方法是针对肿瘤免疫微环境。肿瘤细胞比较明显的特征是代谢异常，用以满足与肿瘤快速生长相关的高能量和生物合成需求。随着研究的不断深入，发现胆固醇通常富集在肿瘤微环境中，肝脏胆固醇代谢参与HCC的发生发展过程。因此，探索肝脏中胆固醇代谢的分子调控过程，阐明胆固醇在HCC中的作用，并寻求治疗HCC的潜在靶点，是目前备受关注的重要科研问题之一。本文就胆固醇在HCC中的作用及治疗潜在价值作简要综述，为进一步研究和深入探讨胆固醇和HCC之间的关系提供有力证据。
Abstract：Hepatocellular carcinoma(HCC) is the most common primary malignant liver tumor,which is characterized by high mortality,easy metastasis and recurrence,low 5-year survival rate and poor clinical prognosis.At present,there are few treatments that directly target tumor cells.The most effective treatment for HCC is targeting the tumor immune microenvironment.Tumor cells are characterized by metabolic abnormalities to meet the high energy and biosynthesis needs associated with rapid tumor growth.With the deepening of research,it has been found that cholesterol is usually enriched in the tumor microenvironment,and liver cholesterol metabolism is involved in the occurrence and development of HCC.Therefore,exploring the molecular regulation process of cholesterol metabolism in the liver,elucidating the role of cholesterol in HCC,and seeking potential targets for the treatment of HCC is one of the important scientific research issues that have attracted much attention.This article briefly reviews the role of cholesterol in HCC and its potential therapeutic value,and provides strong evidence for further research and in-depth discussion of the relationship between cholesterol and HCC.
1 Asafo-Agyei KO,Sam ant H.Hepatocellular Carcinoma(Hepatoma)[C].2020.
2 Paul B,Lewinska M,Andersen JB.Lipid alterations in chronic liver disease and liver cancer[J].JHEP Rep,2022,4(6):100479.
3 Schade DS,Shey L,Eaton RP.Cholesterol review:A metabolically important molecule[J].Endocrine Practice,2020,26(12):1514-1523.
4 Jung E,Kong SY,Ro YS,et al.Serum cholesterol levels and risk of cardiovascular death:A systematic review and a dose-response meta-analysis of prospective cohort studies[J].Int J Environ Res Public Health,2022,19(14):8272.
5俞静静,杜宇忠,苏洁,等.陈皮对高胆固醇血症大鼠的预防作用及其机制[J].中成药,2021,43(11):2982-2988.Yu JJ,Du YZ,Su J,et al.Preventive effect and mechanism of Citri Reticulatae Pericarp ium on hypercholesterolemia rats[J].Chin Tradit Pat Med,2021,43(11):2982-2988.
6 Yang F,Kou J,Liu Z,et al.MYC enhances cholesterol biosynthesis and supports cell proliferation through SQLE[J].Front Cell Dev Biol,2021,9:655889.
7 Van De Sluis B,Wijers M,Herz J.News on the molecular regulation and function of hepatic LDLR and LRP1[J].Curr Opin Lip idol,2017,28(3):241.
8 Saha P,Shumate JL,Caldwell JG,et al.Inter-domain dynamics drive cholesterol transport by NPC1 and NPC1L1 proteins[J].Elife,2020,9:e57089.
9王佩华,岳珠珠,魏晓彤,等.千金子制霜前后提取物通过肝X受体-腺苷三磷酸结合盒转运体A1信号通路对Caco-2细胞中胆固醇外流的影响[J].中国临床药理学杂志,2023,39(2):201-205.Wang PH,Yue ZZ,Wei XT,et al.Influence of extracts from Euphorbiae Semen before and after frosting on cholesterol efflux in Caco~2 cells through liver X receptor-adenosine triphosphate-binding cassette transporter A1 pathway[J].Chin J Clin Pharmacol,2023,39(2):201-205.
10 Xu H,Zhou S,Tang Q,et al.Cholesterol metabolism:New functions and therapeutic approaches in cancer[J].Biochin Biophys Acta Rev Cancer,2020,1874(1):188394.
11 Cui Y,Liang S,Zhang S,et al.ABCA8 is regulated by miR-374b-5p and inhibits proliferation and metastasis of hepatocellular carcinoma through the ERK/ZEB1 pathway[J].J Exp Clin Cancer Res,2020,39:1-14.
12倪萱.人源诱导型肝样细胞(hiHep)进行胆汁淤积性肝损伤的研究[D].中国科学院大学(中国科学院上海药物研究所),2017.Ni X.Human induced hepatocvtes(hiHep)used in cholestatic liver injury[D].The University of Chinese Academy of Sciences(Shanghai Institutes of Materia Medica,CAS),2017.
13 Chen J,Ding C,Chen Y,et al.ACSL4 reprograms fatty acid metabolism in hepatocellular carcinoma via c-Myc/SREBP1 pathway[J].Cancer Lett,2021,502:154-165.
14 Zhang F,Gao J,Liu X,et al.LATS-regulated nuclearcytoplasmic translocation of SREBP2 inhibits hepatocellular carcinoma cell migration and invasion via epithelialmesenchymal transition[J].Mol Carcinog,2023,62(7):963-974.
15王振兴,杨金梅,张志斌,等.绞股蓝的化学成分及其生物活性研究进展[J].南方农业学报,2023,54(6):1741-1752.Wang ZX,Yang JM,Zhang ZB,et al.Chemical constituents and biological activity of Gynostemma pentaphyllum:A review[J].J South Agric,2023,54(6):1741-1752.
16 Xiao MY,Li FF,Xie P,et al.Gypenosides suppress hepatocellular carcinoma cells by blocking cholesterol biosynthesis through inhibition of MVA pathway enzyme HMGCS1[J].Chem Biol Interact,2023,383:110674.
17 Wei M,Nurjanah U,Herkilini A,et al.Unspliced XBP1 contributes to cholesterol biosynthesis and tumorigenesis by stabilizing SREBP2 in hepatocellular carcinoma[J].Cell Mol Life Sci,2022,79(9):472.
18 Wang S,Zhou Y,Yu R,et al.Loss of hepatic FTCD promotes lipid accumulation and hepatocarcino gene sis by upregulating PPARy and SREBP2[J].JHEP Rep,2023,5(10):100843.
19 Zheng C,Zhu Y,Liu Q,et al.Maprotiline suppresses cholesterol biosynthesis and hepatocellular carcinoma progression through direct targeting of CRABP1[J].Front Pharmacol,2021,12:689767.
20 Mok EHK,Leung CON,Zhou L,et al.Caspase-3-induced activation of SREBP2 drives drug resistance via promotion of cholesterol biosynthesis in hepatocellular carcinoma[J].Cancer Res,2022,82(17):3102-3115.
21 Fasolato S,Pigozzo S,Pontisso P,et al.PCSK9 levels are raised in chronic HCV patients with hepatocellular carcinoma[J].J Clin Med,2020,9(10):3134.
22 Rosoff DB,Bell AS,Wagner J,et al.Assessing the impact of PCSK9 and HMGCR inhibition on liver function:Drug-target mendelian randomization analyses in four ancestries[J].Cell Mol Gastroenterol Hepatol,2023,17(1):29-40.
23 Zhang SZ,Zhu XD,Feng LH,et al.PCSK9 promotes tumor growth by inhibiting tumor cell apoptosis in hepatocellular carcinoma[J].Exp Hematol Oncol,2021,10(1):1-11.
24 Che L,Chi W,Qiao Y,et al.Cholesterol biosynthesis supports the growth of hepatocarcinoma lesions depleted of fatty acid synthase in mice and humans[J].Gut,2020,69(1):177-186.
25 Alannan M,Trézéguet V,Amoêdo N D,et al.Rewiring lipid metabolism by targeting PCSK9 and HMGCR to treat liver cancer[J].Cancers,2022,15(1):3.
26 Sui Z,Zhou J,Cheng Z,et al.Squalene epoxidase(SQLE)promotes the growth and migration of the hepatocellular carcinoma cells[J].Tumor Biol,2015,36:6173-6179.
27 Shen T.Lu Y,Zhang Q.High squalene epoxidase in tumors predicts worse survival in patients with hepatocellular carcinoma:Integrated bioinformatic analysis on NAFLD and HCC[J].Cancer Control,2020,27(1):1073274820914663.
28 Weng W,Zhang D,Li S.Life spae-associated ferroptosis-related genes identification and validation for hepatocellular carcinoma patients as hepatitis B virus carriers[J].J Clin Labor Anal,2023,37(13-14):e24930.
29 Huang W,Yu D,Wang M,et al.ITGBL1 promotes cell migration and invasion through stimulating the TGF-β signalling pathway in hepatocellular carcinoma[J].Cell Prolif,2020,53(7):e12836.
30 Zhang Z,Wu W,Jiao H,et al.Squalene epoxidase promotes hepatocellular carcinoma development by activating STRAP transcription and TGF-β/SMAD signalling[J].Br J Pharmacol,2023,180(12):1562-1581.
31 Lai HH,Hung LY,Yen CJ,et al.NEIL3 promotes hepatoma epithelial-mesenchymal transition by activating the BRAF/IEK/ERK/TWIST signaling pathway[J].J Pathol,2022,258(4):339-352.
32 Chen Z,Chen L,Sun B,et al.LDLR inhibition promotes hepatocellular carcinoma proliferation and metastasis by elevating intracellular cholesterol synthesis through the MEK/ERK signaling pathway[J].Mol Metab,2021,51:101230.
33 Qin WH,Yang ZS,Li M,et al.High serum levels of cholesterol increase antitumor functions of nature killer cells and reduce growth of liver tumors in mice[J].Gastroenterology,2020,158(6):1713-1727.
34 Cao J,Wang Z,Zhu T,et al.Low-density lipoprotein cholesterol and risk of hepatocellular carcinoma:A Mendelian randomization and mediation analysis[J].Lipids Health Dis,2023,22(1):110.
35 Jia Y,Li S,Zhang M,et al.Circ_LDLR knockdown suppresses progression of hepatocellular carcinoma via modulating miR-7/RNF38 axis[Retraction][J],Cancer Manag Res,2022,14:1757-1758.
36 Rodriguez-Gil JL,Bianconi SE,Farhat N,et al.Hepatocellular carcinoma as a complication of Niemann-Pick disease type C1[J].Am J Med Genet Part A,2021,185(10):3111-3117.
37 Hwang S,Choi Y,Lee BH,et al.Pediatric hepatocellular carcinoma associated with Niemann-Pick disease type C:Case report and literature review[J].JIMD Rep,2023,64(1):27-34.
38 Chen K,Zhang X,Peng H,et al.Exploring the diagnos-tic value,prognostic value,and biological functions of NPC gene family members in hepatocellular carcinoma based on a multromics analysis[J].Funct Integr Genom,2023,23(3):264.
39 Wu K,Zou L,Lei X,et al.Roles of ABCA1 in cancer(Review)[J].Oncol Lett,2022,24(4):349.
40 Li Z,Wang Y,Xing R,et al.Cholesterol efflux drives the generation of immunosuppressive macrophages to promote the progression of human hepatocellular carcinoma[J].Cancer Immunol Res,2023,11(10):1400-1413.
41 Al-Maidob ZM,Achour B,Conto N,et al.Mass spectrometry-based abundance atlas of ABC transporters in human liver,gut,kidney,brain and skin[J].FEBS Lett,2020,594(23),4134-4150.
42 Lv C,Yang H,Yu J,et al.ABCA8 inhibits breast cancer cell proliferation by regulating the AMP activated protein kinase/mammalian target of rapamycin signaling pathway[J].Environ Toxicol,2022,37(6):1423-1431.
43 Zhang J,Zhang X,Li J,et al.Systematic analysis of the ABC transporter family in hepatocellular carcinoma reveals the importance of ABCB6 in regulating ferroptosis[J].Life Sci,2020,257:118131.
44 Xiao Y,Wang Y,Liu Y,et al.A nonbile acid farnesoid X receptor agonist tropifexor potently inhibits cholestatic liver injury and fibrosis by modulating the gut-liver axis[J].Liver Int,2021,41(9):2117-2131.
45 MarchianòS,Biagioli M,Roselli R,et al.Atorvastatin protects against liver and vascular damage in a model of diet induced stcatohepatitis by resetting FXR and GPBAR1 signaling[J].FASEB J,2022,36(1):e22060.
46 Liao S,Fu X,Huang J,et al.Suppression of SIRT1/FXR signaling pathway contributes to oleanolic acid-induced liver injury[J].Toxicol Appl Pharmacol,2023,467:116509.
47 Pan L,Yu Z,Liang X,et al.Sodium cholate ameliorates nonalcoholic steatohepatitis by activation of FXR signaling[J].Hepatol Commun,2023,7(2):e0039.
48 Wang X,Shi J,Huang M,et al.TUBB2B facilitates progression of hepatocellular carcinoma by regulating cholesterol metabolism through targeting HNF4A/CYP27A1[J].Cell Death Dis,2023,14(3):179.
49 Chen J,Hao Y,Xu P,et al.CerS5 deficiency promotes liver fibrosis development in non-alcoholic fatty liver disease[J].Biochem Biophysic Res Commun,2023,667:120-126.
50 Lan T,Jiang S,Zhang J,et al.Breviscapine alleviatesNASH by inhibiting TGF-β-activated kinase 1-dependent signaling[J].Hepatology,2022,76(1):155-171.
51徐琪.松杉灵芝多糖降脂机理的研究以及磁性荧光纳米探针的合成在分离膜蛋白中的应用[D].吉林大学,2019.Xu Q.Study on lipid-lowering mechanism of polysaccharides from Ganoderma lucidum and applicatcon of magnetic fluorescent nanoprobe synthesis in separation membrane proteins[D].Jilin University,2019
52刁婷婷.山楂叶总黄酮对高血脂的调节作用[D].湖北科技学院,2019.Diao TT.Regulatory effect of Hawthorn Leaves Flavonoids on hyperlipidemia[D].Hubei University of Science and Technology,2019.
53张夕梅.芹菜素对肝癌增殖和脂代谢的影响及分子机制研究[D].西南大学,2020.Zhang XM.Effect of apigenin on proliferation and lipid metabolism of hepatocellular carcinoma and its molecular mechanism[D].Southwest University,2020.
54 Gong X,Cui HT,Bian YH,et al.Ethanol extract of Ardisiae Japonicae Herba inhibits hepatoma carcinoma cell proliferation in vitro through regulating lipid metabolism[J].Chin Herb Med,2021,13(3):410-415.
55 Fan M,Chen Z,Shao W,et al.SREBP2 inhibitor betulin sensitizes hepatocellular carcinoma to lenvatinib by inhibiting the mTOR/IL-1β pathway:SREBP2 Inhibitor sensitizes HCC to lenvatinib[J].Acta Biochim Biophys Sin(Shanghai),2023,55(9):1479.
56 Zhang S,Shi YN,Gu J,et al.Mechanisms of dihydromyricetin against hepatocellular carcinoma elucidated by network pharmacology combined with experimental vali-dation[J].Pharmaceut Biol,2023,61(1):1108~1119.
57杨莹.茯苓多糖通过SQLE/NLRP3/GSDMD途径调控细胞焦亡对肝癌的影响及分子机制[D].辽宁中医药大学,2023.Yang Y.The effect of Pchymaran on hepatocellular carcinoma by SQLE/NLRP3/GSDMD pathway and its molecular mechanism[D].Liaoning University of Ttaditional Chinese Medicine,2023.
58樊可.蛇床子素增加肝癌对索拉菲尼的敏感性及调节胆固醇代谢机制研究[D].苏州大学,2021.Fan K.Osthole increase sensitivity of hepatocellular carcinoma to sorafenib treatment and its sensitization mechanisms of cholesterol metabolism regulation[D].Soochow University,2021.
59孟嘉伟.香砂六君子汤通过AMPK/Insig-1/SREBP2通路调控胆固醇合成防治血脂异常的机制研究[D].辽宁中医药大学,2023.Meng JW.Study on the mechanism of Xiang Sha Liu Jun Zi hang regulating cholesterol synthesis through AMPK/Insig-1/SREBP2 pathway to prevent dyslipidemia[D].Liaoning University of Traditional Chinese Medicine,2023.
60 Zhang X,Coker O O,Chu E S,et al.Dietary cholesterol dríves fatty liver-associated liver cancer by modulating gut microbiota and metabolites[J].Gut,2021,70(4):761-774.
61 Saito Y,Yin D,Kubota N,et al.A therapeutically targetable TAZ-TEAD2 pathway drives the growth of hepatocellular carcinoma via ANLN and KIF23[J].Gastroenterology,2023,164(7):1279-1292.
基本信息:
DOI：10.13210/j.cnki.jhmu.20231218.001
中图分类号:R735.7
引用信息:
[1]曾阳玲,王运踊,关海梅,等.胆固醇在肝细胞癌中的作用及治疗潜在价值[J].海南医学院学报,2024,30(12):952-960.DOI:10.13210/j.cnki.jhmu.20231218.001.
基金信息:
国家自然科学基金项目（82360912、81960841、82274434）~~
2023-12-19
2023-12-19
2023-12-19