鞘磷脂酶在肝细胞癌中的作用

姚春; 张广发; 乐滢玉; 毛德文; 张荣臻; 刘茵

doi:10.3969/j.issn.1001-5256.2022.02.042

鞘磷脂酶在肝细胞癌中的作用

DOI: 10.3969/j.issn.1001-5256.2022.02.042

1.
广西中医药大学研究生院，南宁 530222
2.
广西中医药大学第一附属医院肝病一区，南宁 530023

基金项目:

国家自然科学基金面上项目 (81774236);

国家自然科学基金项目 (81960841)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：姚春、张广发负责拟定写作思路，撰写文章；毛德文负责研究选题，指导文章撰写和修改；张荣臻、刘茵负责设计论文框架；乐滢玉负责起草论文。

详细信息

通信作者:
毛德文, mdwboshi2005@163.com

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- 被引次数: 0
出版历程
- 收稿日期: 2021-06-29
- 录用日期: 2021-07-30
- 出版日期: 2022-02-20

Role of sphingomyelinases in hepatocellular carcinoma

1.
Graduate School, Guangxi University of Chinese Medicine, Nanning 530222, China
2.
First Ward of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, China

Research funding:

General Project of National Natural Science Foundation of China (81774236);

National Natural Science Foundation of China (81960841)

More Information

Corresponding author: MAO Dewen, mdwboshi2005@163.com

摘要

摘要: 鞘磷脂酶(SMase)是调节鞘磷脂类信号通路及其相关产物代谢的主要酶类，参与了鞘磷脂复杂代谢过程中的关键步骤。近年来，许多研究表明SMase参与了细胞周期停滞、细胞迁移和炎症等生物学过程，并通过调节肿瘤干细胞的凋亡和增殖来促进肝细胞癌的发生发展。SMase在肝细胞癌的发生发展及诊疗中具有重要潜在生物学价值。就SMase在肝细胞癌发生发展中的作用进行归纳和探讨，以期为其临床治疗和新型药物的开发提供新的思路和策略。
- 癌, 肝细胞 /
- 鞘脂类 /
- 神经酰胺类
Abstract: Sphingomyelinases (SMase) are the main enzymes that regulate the signaling pathway of sphingomyelin and the metabolism of related products, and they are involved in the key steps of the complex metabolic process of sphingomyelin. In recent years, many studies have shown that SMase is involved in the biological processes such as cell cycle arrest, cell migration, and inflammation and promotes the development and progression of hepatocellular carcinoma by regulating the apoptosis and proliferation of tumor stem cells. SMase has an important potential biological value in the development, progression, diagnosis, and treatment of hepatocellular carcinoma. This article summarizes the exact role of SMase in the development and progression of hepatocellular carcinoma, in order to provide new ideas and strategies for the clinical treatment of hepatocellular carcinoma and the development of new drugs.
- Carcinoma, Hepatocellular /
- Sphingolipids /
- Ceramides

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参考文献(49)

[1]	LE YY, ZHANG RZ, WANG TS, et al. Expression mechanism and clinical significance of absent in melanoma 2 in liver diseases[J]. J Clin Hepatol, 2021, 37(10): 2488-2492. DOI: 10.3969/j.issn.1001-5256.2021.10.049. 乐滢玉, 张荣臻, 王挺帅, 等. 黑色素瘤缺乏因子2在肝脏疾病中的作用机制及临床意义[J]. 临床肝胆病杂志, 2021, 37(10): 2488-2492. DOI: 10.3969/j.issn.1001-5256.2021.10.049.
[2]	Professional Committee for Prevention and Control of Hepatobiliary and Pancreatic Diseases of Chinese Preventive Medicine Association; Professional Committee for Hepatology, Chinese Research Hospital Association; Chinese Society of Hepatology, Chinese Medical Association, et al. Guideline for stratified screening and surveillance of primary liver cancer (2020 edition)[J]. J Clin Hepatol, 2021, 37(2): 286-295. DOI: 10.3969/j.issn.1001-5256.2021.02.009. 中华预防医学会肝胆胰疾病预防与控制专业委员会, 中国研究型医院学会肝病专业委员会, 中华医学会肝病学分会, 等. 原发性肝癌的分层筛查与监测指南(2020版)[J]. 临床肝胆病杂志, 2021, 37(2): 286-295. DOI: 10.3969/j.issn.1001-5256.2021.02.009.
[3]	HANNUN YA, OBEID LM. Sphingolipids and their metabolism in physiology and disease[J]. Nat Rev Mol Cell Biol, 2018, 19(3): 175-191. DOI: 10.1038/nrm.2017.107.
[4]	PONNUSAMY S, MEYERS-NEEDHAM M, SENKAL CE, et al. Sphingolipids and cancer: Ceramide and sphingosine-1-phosphate in the regulation of cell death and drug resistance[J]. Future Oncol, 2010, 6(10): 1603-1624. DOI: 10.2217/fon.10.116.
[5]	BIENIAS K, FIEDOROWICZ A, SADOWSKA A, et al. Regulation of sphingomyelin metabolism[J]. Pharmacol Rep, 2016, 68(3): 570-581. DOI: 10.1016/j.pharep.2015.12.008.
[6]	PARK MH, JIN HK, BAE JS. Potential therapeutic target for aging and age-related neurodegenerative diseases: The role of acid sphingomyelinase[J]. Exp Mol Med, 2020, 52(3): 380-389. DOI: 10.1038/s12276-020-0399-8.
[7]	SIMONIS A, SCHUBERT-UNKMEIR A. The role of acid sphingomyelinase and modulation of sphingolipid metabolism in bacterial infection[J]. Biol Chem, 2018, 399(10): 1135-1146. DOI: 10.1515/hsz-2018-0200.
[8]	LIU SS, YANG JH, WANG A. Research progress in regulation of acid sphingomyelinase activity and its related drugs[J]. Chin J Pharmacol Toxicol, 2020, 34(3): 232-240. DOI: 10.3867/j.issn.1000-3002.2020.03.009. 刘思思, 杨嘉辉, 王安. 酸性鞘磷脂酶活性调控及相关药物研究进展[J]. 中国药理学与毒理学杂志, 2020, 34(3): 232-240. DOI: 10.3867/j.issn.1000-3002.2020.03.009.
[9]	XIANG H, JIN S, TAN F, et al. Physiological functions and therapeutic applications of neutral sphingomyelinase and acid sphingomyelinase[J]. Biomed Pharmacother, 2021, 139: 111610. DOI: 10.1016/j.biopha.2021.111610.
[10]	THAYYULLATHIL F, CHERATTA AR, ALAKKAL A, et al. Acid sphingomyelinase-dependent autophagic degradation of GPX4 is critical for the execution of ferroptosis[J]. Cell Death Dis, 2021, 12(1): 26. DOI: 10.1038/s41419-020-03297-w.
[11]	AIROLA MV, HANNUN YA. Sphingolipid metabolism and neutral sphingomyelinases[J]. Handb Exp Pharmacol, 2013, (215): 57-76. DOI: 10.1007/978-3-7091-1368-4_3.
[12]	WU BX, CLARKE CJ, HANNUN YA. Mammalian neutral sphingomyelinases: Regulation and roles in cell signaling responses[J]. Neuromolecular Med, 2010, 12(4): 320-330. DOI: 10.1007/s12017-010-8120-z.
[13]	TANI M, HANNUN YA. Analysis of membrane topology of neutral sphingomyelinase 2[J]. FEBS Lett, 2007, 581(7): 1323-1328. DOI: 10.1016/j.febslet.2007.02.046.
[14]	de PALMA C, MEACCI E, PERROTTA C, et al. Endothelial nitric oxide synthase activation by tumor necrosis factor alpha through neutral sphingomyelinase 2, sphingosine kinase 1, and sphingosine 1 phosphate receptors: A novel pathway relevant to the pathophysiology of endothelium[J]. Arterioscler Thromb Vasc Biol, 2006, 26(1): 99-105. DOI: 10.1161/01.ATV.0000194074.59584.42.
[15]	DUAN RD. Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied[J]. World J Hepatol, 2018, 10(2): 246-253. DOI: 10.4254/wjh.v10.i2.246.
[16]	WANG X, WANG LQ, ZHANG P. Inhibitory effect of basic sphingolipase on inflammatory bowel disease[J]. Chin J Gastroenterol Hepatol, 2020, 29(9): 975-978. DOI: 10.3969/j.issn.1006-5709.2020.09.004. 王旭, 王凌琪, 张萍. 碱性鞘磷脂酶抑制炎症性肠病的研究[J]. 胃肠病学和肝病学杂志, 2020, 29(9): 975-978. DOI: 10.3969/j.issn.1006-5709.2020.09.004.
[17]	TONNETTI L, VERÍ MC, BONVINI E, et al. A role for neutral sphingomyelinase-mediated ceramide production in T cell receptor-induced apoptosis and mitogen-activated protein kinase-mediated signal transduction[J]. J Exp Med, 1999, 189(10): 1581-1589. DOI: 10.1084/jem.189.10.1581.
[18]	YABU T, IMAMURA S, YAMASHITA M, et al. Identification of Mg²⁺-dependent neutral sphingomyelinase 1 as a mediator of heat stress-induced ceramide generation and apoptosis[J]. J Biol Chem, 2008, 283(44): 29971-29982. DOI: 10.1074/jbc.M805402200.
[19]	FILOSTO S, FRY W, KNOWLTON AA, et al. Neutral sphingomyelinase 2 (nSMase2) is a phosphoprotein regulated by calcineurin (PP2B)[J]. J Biol Chem, 2010, 285(14): 10213-10222. DOI: 10.1074/jbc.M109.069963.
[20]	ITO H, MURAKAMI M, FURUHATA A, et al. Transcriptional regulation of neutral sphingomyelinase 2 gene expression of a human breast cancer cell line, MCF-7, induced by the anti-cancer drug, daunorubicin[J]. Biochim Biophys Acta, 2009, 1789(11-12): 681-690. DOI: 10.1016/j.bbagrm.2009.08.006.
[21]	MARCHESINI N, OSTA W, BIELAWSKI J, et al. Role for mammalian neutral sphingomyelinase 2 in confluence-induced growth arrest of MCF7 cells[J]. J Biol Chem, 2004, 279(24): 25101-25111. DOI: 10.1074/jbc.M313662200.
[22]	YANG YG, HU YH, ZHANG GH, et al. Analysis of knowledge graph of endoplasmic reticulum stress research based on VOSviewer and CiteSpace[J]. China Med Herald, 2021, 18 (7): 13-17. https://www.cnki.com.cn/Article/CJFDTOTAL-YYCY202107005.htm 杨一格, 胡元会, 张广辉, 等. 基于VOSviewer与CiteSpace对内质网应激研究的知识图谱分析[J]. 中国医药导报, 2021, 18(7): 13-17. https://www.cnki.com.cn/Article/CJFDTOTAL-YYCY202107005.htm
[23]	MALHI H, KAUFMAN RJ. Endoplasmic reticulum stress in liver disease[J]. J Hepatol, 2011, 54(4): 795-809. DOI: 10.1016/j.jhep.2010.11.005.
[24]	HENKEL A, GREEN RM. The unfolded protein response in fatty liver disease[J]. Semin Liver Dis, 2013, 33(4): 321-329. DOI: 10.1055/s-0033-1358522.
[25]	FERNANDEZ A, MATIAS N, FUCHO R, et al. ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading[J]. J Hepatol, 2013, 59(4): 805-813. DOI: 10.1016/j.jhep.2013.05.023.
[26]	CZAJA MJ, DING WX, DONOHUE TM Jr, et al. Functions of autophagy in normal and diseased liver[J]. Autophagy, 2013, 9(8): 1131-1158. DOI: 10.4161/auto.25063.
[27]	QUAN M, DUAN Y, XING HC. Research progress on alcoholic fatty liver disease and autophagy[J/CD]. Chin J Liver Dis: Electronic Edition, 2021, 13(3): 25-29. DOI: 10.3969/j.issn.1674-7380.2021.03.004. 全敏, 段英, 邢卉春. 酒精性脂肪性肝病与细胞自噬研究进展[J/CD]. 中国肝脏病杂志(电子版), 2021, 13(3): 25-29. DOI: 10.3969/j.issn.1674-7380.2021.03.004.
[28]	FUCHO R, MARTÍNEZ L, BAULIES A, et al. ASMase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage non-alcoholic steatohepatitis[J]. J Hepatol, 2014, 61(5): 1126-1134. DOI: 10.1016/j.jhep.2014.06.009.
[29]	BOYA P, KROEMER G. Lysosomal membrane permeabilization in cell death[J]. Oncogene, 2008, 27(50): 6434-6451. DOI: 10.1038/onc.2008.310.
[30]	WU YF, ZHANG JG, LI Q. Progress in pharmacokinetic mechanism of drug resistance in hepatocellular carcinoma[J]. Chin Pharmacol J, 2020, 55(19): 1578-1584. DOI: 10.11669/cpj.2020.19.005. 吴亚菲, 张吉刚, 李琴. 肝细胞癌药物治疗耐药的药动学机制研究进展[J]. 中国药学杂志, 2020, 55(19): 1578-1584. DOI: 10.11669/cpj.2020.19.005.
[31]	CHEN GX, ZHOU M, CHEN S, et al. The role of non-coding RNA in drug resistance of hepatocellular carcinoma treated with sorafenib[J]. J Clin Hepatol, 2021, 37(3): 699-703. DOI: 10.3969/j.issn.1001-5256.2021.03.040. 陈国想, 周茉, 陈圣, 等. 非编码RNA在索拉非尼治疗肝细胞癌耐药中的作用机制[J]. 临床肝胆病杂志, 2021, 37(3): 699-703. DOI: 10.3969/j.issn.1001-5256.2021.03.040.
[32]	KRAUTBAUER S, MEIER EM, REIN-FISCHBOECK L, et al. Ceramide and polyunsaturated phospholipids are strongly reduced in human hepatocellular carcinoma[J]. Biochim Biophys Acta, 2016, 1861(11): 1767-1774. DOI: 10.1016/j.bbalip.2016.08.014.
[33]	MAENG HJ, SONG JH, KIM GT, et al. Celecoxib-mediated activation of endoplasmic reticulum stress induces de novo ceramide biosynthesis and apoptosis in hepatoma HepG2 cells mobilization[J]. BMB Rep, 2017, 50(3): 144-149. DOI: 10.5483/bmbrep.2017.50.3.197.
[34]	LIN M, LIAO W, DONG M, et al. Exosomal neutral sphingomyelinase 1 suppresses hepatocellular carcinoma via decreasing the ratio of sphingomyelin/ceramide[J]. FEBS J, 2018, 285(20): 3835-3848. DOI: 10.1111/febs.14635.
[35]	REVILL K, WANG T, LACHENMAYER A, et al. Genome-wide methylation analysis and epigenetic unmasking identify tumor suppressor genes in hepatocellular carcinoma[J]. Gastroenterology, 2013, 145(6): 1424-1435. e1-25. DOI: 10.1053/j.gastro.2013.08.055.
[36]	ZHONG L, KONG JN, DINKINS MB, et al. Increased liver tumor formation in neutral sphingomyelinase-2-deficient mice[J]. J Lipid Res, 2018, 59(5): 795-804. DOI: 10.1194/jlr.M080879.
[37]	YOO SW, AGARWAL A, SMITH MD, et al. Inhibition of neutral sphingomyelinase 2 promotes remyelination[J]. Sci Adv, 2020, 6(40): eaba5210. DOI: 10.1126/sciadv.aba5210.
[38]	AL-RASHED F, AHMAD Z, THOMAS R, et al. Neutral sphingomyelinase 2 regulates inflammatory responses in monocytes/macrophages induced by TNF-α[J]. Sci Rep, 2020, 10(1): 16802. DOI: 10.1038/s41598-020-73912-5.
[39]	LEONETTI D, ESTÉPHAN H, RIPOCHE N, et al. Secretion of acid sphingomyelinase and ceramide by endothelial cells contributes to radiation-induced intestinal toxicity[J]. Cancer Res, 2020, 80(12): 2651-2662. DOI: 10.1158/0008-5472.CAN-19-1527.
[40]	van HELL AJ, HAIMOVITZ-FRIEDMAN A, FUKS Z, et al. Gemcitabine kills proliferating endothelial cells exclusively via acid sphingomyelinase activation[J]. Cell Signal, 2017, 34: 86-91. DOI: 10.1016/j.cellsig.2017.02.021.
[41]	GRAMMATIKOS G, TEICHGRÄBER V, CARPINTEIRO A, et al. Overexpression of acid sphingomyelinase sensitizes glioma cells to chemotherapy[J]. Antioxid Redox Signal, 2007, 9(9): 1449-1456. DOI: 10.1089/ars.2007.1673.
[42]	SMITH EL, SCHUCHMAN EH. Acid sphingomyelinase overexpression enhances the antineoplastic effects of irradiation in vitro and in vivo[J]. Mol Ther, 2008, 16(9): 1565-1571. DOI: 10.1038/mt.2008.145.
[43]	SAXTON RA, SABATINI DM. mTOR signaling in growth, metabolism, and disease[J]. Cell, 2017, 169(2): 361-371. DOI: 10.1016/j.cell.2017.03.035.
[44]	XU Z, XU M, LIU P, et al. The mTORC2-Akt1 Cascade is crucial for c-Myc to promote hepatocarcinogenesis in mice and humans[J]. Hepatology, 2019, 70(5): 1600-1613. DOI: 10.1002/hep.30697.
[45]	WU WK, COFFELT SB, CHO CH, et al. The autophagic paradox in cancer therapy[J]. Oncogene, 2012, 31(8): 939-953. DOI: 10.1038/onc.2011.295.
[46]	PAN H, WANG Z, JIANG L, et al. Autophagy inhibition sensitizes hepatocellular carcinoma to the multikinase inhibitor linifanib[J]. Sci Rep, 2014, 4: 6683. DOI: 10.1038/srep06683.
[47]	QIU DM, WANG GL, CHEN L, et al. The expression of beclin-1, an autophagic gene, in hepatocellular carcinoma associated with clinical pathological and prognostic significance[J]. BMC Cancer, 2014, 14: 327. DOI: 10.1186/1471-2407-14-327.
[48]	PARK MA, ZHANG G, MARTIN AP, et al. Vorinostat and sorafenib increase ER stress, autophagy and apoptosis via ceramide-dependent CD95 and PERK activation[J]. Cancer Biol Ther, 2008, 7(10): 1648-1662. DOI: 10.4161/cbt.7.10.6623.
[49]	SAVIĆ R, HE X, FIEL I, et al. Recombinant human acid sphingomyelinase as an adjuvant to sorafenib treatment of experimental liver cancer[J]. PLoS One, 2013, 8(5): e65620. DOI: 10.1371/journal.pone.0065620.