鞘磷脂酶在消化道恶性肿瘤中的研究进展

doi:10.3969/j.issn.1009-976X.2023.03.010

摘要/Abstract

摘要： 鞘磷脂酶（SMPD）是一种可以将鞘磷脂水解为神经酰胺和磷酸胆碱的水解酶,在鞘磷脂代谢中起主要作用。相关研究显示,SMPD家族在多种类型肿瘤中异常表达,并且在肿瘤发生、发展、耐药等方面发挥重要调控作用。因此SMPD有望成为肿瘤诊断和预后预测的标志物及治疗靶点,具有重要的临床转化价值。本文集中阐述了SMPD全家族分子的结构和功能特点,并综述SMPD在消化道恶性肿瘤中的作用及其机制研究进展,从而为消化道恶性肿瘤的靶向治疗及患者预后评估提供新的研究思路和策略。

关键词: 消化道恶性肿瘤, 鞘磷脂酶, 靶向治疗

Abstract: SMPD protein family is a kind of hydrolase that plays a major role in sphingomyelin metabolism. At present, relative researches have found that the members of SMPD are abnormally expressed in different types of tumors, and play a key role in the occurrence, development and drug resistance of cancer. Thus, SMPD family is expected to be a potential predictor for tumor diagnosis, prognosis and treatment. Therefore, this review summarizes the structure and function of SMPD gene and protein, and elucidates the research finding of SMPD in gastrointestinal cancers, which provides new ways and strategies into precision medicine and prognosis evaluation.

Key words: sphingomyelinase, gastrointestinal cancers, targeted therapy

中图分类号:

R735

王荣悦, 苏延泽, 陈二宝, 刘吉奎. 鞘磷脂酶在消化道恶性肿瘤中的研究进展[J]. 岭南现代临床外科, 2023, 23(03): 263-268.

WANG Rong-yue, SU Yan-ze, CHEN Er-bao, LIU Ji-kui. Research progress of sphingomyelinase in gastrointestinal cancers[J]. Lingnan Modern Clinics In Surgery, 2023, 23(03): 263-268.

参考文献

[1] Airola MV, Hannun YA.Sphingolipid metabolism and neutral sphingomyelinases[J]. Handb Exp Pharmacol, 2013,(215):57-76.
[2] Lv Y, Zhang CD, Wang YL, et al.Synergism of rMV-Hu191 with cisplatin to treat gastric cancer by acid sphingomyelinase-mediated apoptosis requiring integrity of lipid raft microdomains[J]. Gastric Cancer, 2021, 24(6):1293-1306.
[3] Chen Y, Ma Z, Min L, et al.Biomarker identification and pathway analysis by serum metabolomics of lung cancer[J]. Biomed Res Int, 2015, 2015:183624.
[4] Hertervig E, Nilsson A, Nyberg L, Duan RD.Alkaline sphingomyelinase activity is decreased in human colorectal carcinoma[J]. Cancer, 1997, 79(3):448-453.
[5] Sung H, Ferlay J, Siegel RL, et al.Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249.
[6] Magini P, Smits DJ, Vandervore L, et al.Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis[J]. Am J Hum Genet, 2019, 105(4):689-705.
[7] Barnholz Y, Roitman A, Gatt S.Enzymatic hydrolysis of sphingolipids. II. Hydrolysis of sphingomyelin by an enzyme from rat brain[J]. J Biol Chem, 1966, 241(16):3731-3737.
[8] Ferranti CS, Cheng J, Thompson C, et al.Fusion of lysosomes to plasma membrane initiates radiation-induced apoptosis[J]. J Cell Biol, 2020, 219(4): e201903176.
[9] Peña LA, Fuks Z, Kolesnick RN.Radiation-induced apoptosis of endothelial cells in the murine central nervous system: protection by fibroblast growth factor and sphingomyelinase deficiency[J]. Cancer Res, 2000, 60(2):321-327.
[10] Paris F, Fuks Z, Kang A, et al.Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice[J]. Science, 2001, 293(5528):293-297.
[11] El Kaffas A, Al-Mahrouki A, Hashim A, et al.Role of Acid Sphingomyelinase and Ceramide in Mechano-Acoustic Enhancement of Tumor Radiation Responses[J]. J Natl Cancer Inst,2018,110(9):1009-1018.
[12] Rana S, Espinosa-Diez C, Ruhl R, et al.Differential regulation of microRNA-15a by radiation affects angiogenesis and tumor growth via modulation of acid sphingomyelinase[J]. Sci Rep, 2020, 10(1):5581.
[13] Zhang CD, Wang YL, Zhou DM, et al.A recombinant Chinese measles virus vaccine strain rMV-Hu191 inhibits human colorectal cancer growth through inducing autophagy and apoptosis regulating by PI3K/AKT pathway[J]. Transl Oncol, 2021,14(7):101091.
[14] Chakraborty P, Vaena SG, Thyagarajan K, et al. Pro-Survival Lipid Sphingosine-1-Phosphate Metabolically Programs T Cells to Limit Anti-tumor Activity [J]. Cell Rep, 2019, 28(7):1879-1893.e7.
[15] Montfort A, Bertrand F, Rochotte J, et al.Neutral Sphingomyelinase 2 Heightens Anti-Melanoma Immune Responses and Anti-PD-1 Therapy Efficacy[J]. Cancer Immunol Res, 2021, 9(5):568-582.
[16] 简心韵,邓子新,孙宇辉.氨基糖苷抗生素庆大霉素:基础研究的新进展及应用研究的新潜力[J].生物工程学报,2015,31(6):829-844.
[17] Albi E, Cataldi S, Ceccarini MR, et al.Gentamicin Targets Acid Sphingomyelinase in Cancer: The Case of the Human Gastric Cancer NCI-N87 Cells[J]. Int J Mol Sci, 2019, 20(18):4375.
[18] 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.
[19] 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.
[20] Osawa Y, Suetsugu A, Matsushima-Nishiwaki R, et al.Liver acid sphingomyelinase inhibits growth of metastatic colon cancer[J]. J Clin Invest, 2013,123(2):834-843.
[21] Ordoñez R, Fernández A, Prieto-Domínguez N, et al.Ceramide metabolism regulates autophagy and apoptotic cell death induced by melatonin in liver cancer cells[J]. J Pineal Res, 2015, 59(2):178-189.
[22] 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.
[23] Antoon JW, White MD, Burow ME, et al.Dual inhibition of sphingosine kinase isoforms ablates TNF-induced drug resistance[J]. Oncol Rep, 2012, 27(6):1779-1786.
[24] Jung JH, Taniguchi K, Lee HM, et al.Comparative lipidomics of 5-Fluorouracil-sensitive and -resistant colorectal cancer cells reveals altered sphingomyelin and ceramide controlled by acid sphingomyelinase (SMPD1)[J]. Sci Rep, 2020, 10(1):6124.
[25] Zhang L, Dai J, Zeng Z, et al.Nitric oxide induces HepG2 cell death via extracellular signal-regulated protein kinase activation by regulating acid sphingomyelinase[J]. Mol Biol Rep, 2020, 47(10):8353-8359.
[26] Clarke CJ, Wu BX, Hannun YA.The neutral sphingomyelinase family: identifying biochemical connections[J]. Adv Enzyme Regul, 2011, 51(1):51-58.
[27] Momchilova A, Nikolaev G, Pankov S, et al.Effect of Quercetin and Fingolimod, Alone or in Combination, on the Sphingolipid Metabolism in HepG2 Cells[J]. Int J Mol Sci, 2022, 23(22): 13916.
[28] Tomiuk S, Zumbansen M, Stoffel W.Characterization and subcellular localization of murine and human magnesium-dependent neutral sphingomyelinase[J]. J Biol Chem, 2000, 275(8):5710-5717.
[29] 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.
[30] 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.
[31] 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):1424-35. e1-25.
[32] Nemoto S, Nakamura M, Osawa Y, et al.Sphingosine kinase isoforms regulate oxaliplatin sensitivity of human colon cancer cells through ceramide accumulation and Akt activation[J]. J Biol Chem, 2009, 284(16):10422-10432.
[33] Liu X, Wu J, Zhang D, et al.Identification of Potential Key Genes Associated With the Pathogenesis and Prognosis of Gastric Cancer Based on Integrated Bioinformatics Analysis[J]. Front Genet, 2018, 9:265.
[34] Shen Y, Takahashi M, Byun HM, et al.Boswellic acid induces epigenetic alterations by modulating DNA methylation in colorectal cancer cells[J]. Cancer Biol Ther, 2012, 13(7):542-552.
[35] Datta A, Kim H, McGee L, et al. High-throughput screening identified selective inhibitors of exosome biogenesis and secretion: A drug repurposing strategy for advanced cancer[J]. Sci Rep, 2018, 8(1): 8161.
[36] Richards KE, Zeleniak AE, Fishel ML, et al.Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells[J]. Oncogene, 2017, 36(13): 1770-1778.
[37] Moloudizargari M, Hekmatirad S, Gharaghani S, et al.Virtual screening reveals aprepitant to be a potent inhibitor of neutral sphingomyelinase 2: implications in blockade of exosome release in cancer therapy[J]. J Cancer Res Clin Oncol, 2023.
[38] Wang L, Chen X, Meng F, et al.α2,6-Sialylation promotes hepatocellular carcinoma cells migration and invasion via enhancement of nSmase2-mediated exosomal miRNA sorting[J]. J Physiol Biochem, 2023, 79(1): 19-34.
[39] Wu BX, Clarke CJ, Hannun YA.Mammalian neutral sphingomyelinases: regulation and roles in cell signaling responses[J]. Neuromolecular Med, 2010, 12(4): 320-330.
[40] Atilla-Gokcumen GE, Muro E, Relat-Goberna J, et al.Dividing cells regulate their lipid composition and localization[J]. Cell, 2014, 156(3): 428-439.
[41] Hu B, Yang XB, Sang XT.Construction of a lipid metabolism-related and immune-associated prognostic signature for hepatocellular carcinoma[J]. Cancer Med, 2020, 9(20): 7646-7662.
[42] Wu BX, Rajagopalan V, Roddy PL, et al.Identification and characterization of murine mitochondria-associated neutral sphingomyelinase (MA-nSMase), the mammalian sphingomyelin phosphodiesterase 5[J]. J Biol Chem, 2010, 285(23): 17993-18002.
[43] Nilsson A.The presence of sphingomyelin-and-ceramide-cleaving enzymes in the small intestinal tract[J]. Biochim Biophys Acta, 1969, 176(2): 339-347.
[44] Duan RD, Bergman T, Xu N, et al.Identification of human intestinal alkaline sphingomyelinase as a novel ecto-enzyme related to the nucleotide phosphodiesterase family[J]. J Biol Chem, 2003, 278(40): 38528-38536.
[45] Wu J, Cheng Y, Palmberg C, et al.Cloning of alkaline sphingomyelinase from rat intestinal mucosa and adjusting of the hypothetical protein XP_221184 in GenBank[J]. Biochim Biophys Acta, 2005, 1687(1-3): 94-102.
[46] Duan RD, Nilsson A.Metabolism of sphingolipids in the gut and its relation to inflammation and cancer development[J]. Prog Lipid Res, 2009, 48(1): 62-72.
[47] Chen Y, Zhang P, Xu SC, et al.Enhanced colonic tumorigenesis in alkaline sphingomyelinase (NPP7) knockout mice[J]. Mol Cancer Ther, 2015, 14(1): 259-267.
[48] 张萍, 袁丽杰, 赵蕾, 等. 鞘磷脂水解产物对结肠癌细胞中碱性鞘磷脂酶的影响[J]. 癌变.畸变.突变, 2009,21(6): 418-421.
[49] Cheng Y, Wu J, Hertervig E, et al.Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis[J]. Br J Cancer, 2007, 97(10): 1441-1448.
[50] Duan RD, Hindorf U, Cheng Y, et al.Changes of activity and isoforms of alkaline sphingomyelinase (nucleotide pyrophosphatase phosphodiesterase 7) in bile from patients undergoing endoscopic retrograde cholangiopancreatography[J]. BMC Gastroenterol, 2014, 14: 138.