Breast cancer is one of the most prevalent malignancies among women and comprises a heterogeneous spectrum of molecular subtypes with distinct biological behaviors.Among various regulatory molecules,sphingolipids play...Breast cancer is one of the most prevalent malignancies among women and comprises a heterogeneous spectrum of molecular subtypes with distinct biological behaviors.Among various regulatory molecules,sphingolipids play pivotal roles in dynamically modulating fundamental cellular processes such as proliferation,apoptosis,and metastasis through metabolic interconversions,including phosphorylation,glycosylation,and the generation of sphingosine-1-phosphate.This review aims to elucidate the mechanisms through which sphingolipid metabolism orchestrates cancer cell fate and drives breast cancer progression.Particular emphasis is placed on the balance between proapoptotic ceramides and pro-survival metabolites,such as sphingosine-1-phosphate,which collectively influence tumor growth and the therapeutic response.Additional sphingolipid species,including glucosylceramide and gangliosides(GD2,GD3,GM1,and GM3),have also been implicated in promoting breast cancer development.Furthermore,sphingolipid-based therapeutic strategies,including immunotherapy and antibody therapy,are discussed.By providing a comprehensive overview of sphingolipid metabolism,this review aims to identify novel therapeutic targets that may help overcome treatment resistance and improve clinical outcomes in breast cancer.展开更多
Myalgic encephalomyelitis/chronic fatigue syndrome-an insidious disease:The recent COVID-19 pandemic has brought substantial attention to the overlapping symptoms between long COVID and myalgic encephalomyelitis/chron...Myalgic encephalomyelitis/chronic fatigue syndrome-an insidious disease:The recent COVID-19 pandemic has brought substantial attention to the overlapping symptoms between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS),a chronic and poorly understood neurological disorder(Shankar et al.,2024).展开更多
A set of three sphingolipids, N-2′-hydroxyplmitoyl-1-O-β-D-glucopyranosyl-9-methyl-4E, 8E-sphingadiene （A）, N-2′-hydroxyl-3′E-octadecenoyl-1-O-β-D-glucopyranosyl-9-methyl-4E, 8E-sphingediene （B） and N-palmito...A set of three sphingolipids, N-2′-hydroxyplmitoyl-1-O-β-D-glucopyranosyl-9-methyl-4E, 8E-sphingadiene （A）, N-2′-hydroxyl-3′E-octadecenoyl-1-O-β-D-glucopyranosyl-9-methyl-4E, 8E-sphingediene （B） and N-palmitoyldihydrosphingosine （C）, were isolated from two marine-derived mangrove endophytic fungal strains （strains No. 1924 and 3893） from the South China Sea. Their structures were elucidated by 2D NMR and FABMS methods. It is the first time that these sphingolipids were separated and obtained from marine-derived mangrove endophytic fungus from the South China Sea.展开更多
Sphingolipids not only exert structural roles in cellular membranes,but also act as signaling molecules in various physiological and pathological processes.A myriad of studies have shown that abnormal levels of sphing...Sphingolipids not only exert structural roles in cellular membranes,but also act as signaling molecules in various physiological and pathological processes.A myriad of studies have shown that abnormal levels of sphingolipids and their metabolic enzymes are associated with a variety of human diseases.Moreover,blood sphingolipids can also be used as biomarkers for disease diagnosis.This review summarizes the biosynthesis,metabolism,and pathological roles of sphingolipids,with emphasis on the biosynthesis of ceramide,the precursor for the biosynthesis of complex sphingolipids with different fatty acyl chains.The possibility of using sphingolipids for disease prediction,diagnosis,and treatment is also discussed.Targeting endogenous ceramides and complex sphingolipids along with their specific fatty acyl chain to promote future drug development will also be discussed.展开更多
8-Sphingolipid desaturase is the key enzyme that catalyses desaturation at the C8 position of the long-chain base of sphingolipids in higher plants. There have been no previous studies on the genes encoding AS-sphingo...8-Sphingolipid desaturase is the key enzyme that catalyses desaturation at the C8 position of the long-chain base of sphingolipids in higher plants. There have been no previous studies on the genes encoding AS-sphingolipid desaturases in Brassica rapa. In this study, four genes encoding AS-sphingolipid desaturases from B. rapa were isolated and characterised. Phylogenetic analyses indicated that these genes could be divided into two groups： BrD8A, BrD8C and BrD8D in group I, and BrD8B in group II. The two groups of genes diverged before the separation of Arabidopsis and Brassica. Though the four genes shared a high sequence similarity, and their coding desaturases all located in endoplasmic reticulum, they exhibited distinct expression patterns. Heterologous expression in Saccharomyces cerevisiae revealed that BrD8A/B/C/D were functionally diverse AS-sphingolipid desaturases that catalyse different ratios of the two products 8（Z）- and 8（E）-C18-phytosphingenine. The aluminium tolerance of transgenic yeasts expressing BrD8A/B/C/D was enhanced compared with that of control cells. Expression of BrD8A in Arabidopsis changed the ratio of 8（Z）：8（E）-C 18-phytosphingenine in transgenic plants. The information reported here provides new insights into the biochemical functional diversity and evolutionary relationship of AS-sphingolipid desaturase in plants and lays a foundation for further investigation of the mechanism of 8（Z）- and 8（E）-C18- phytosphingenine biosynthesis.展开更多
The sphingolipid (SL) signaling pathways are induced by reactive oxygen species and proin-flammatory molecules, which are shown to be upregulated in the obese state. The present work was conducted to determine if an a...The sphingolipid (SL) signaling pathways are induced by reactive oxygen species and proin-flammatory molecules, which are shown to be upregulated in the obese state. The present work was conducted to determine if an altered SL pathway exists, and contributes to the pathogenesis of hepatic steatosis associated with obesity. Steatotic and non-steatotic livers were procured from Zucker Obese female rats and their lean counterparts in this pre-clinical study, and assessed for enzymes involved in degradation as well as in phos-phorylation of proapoptotic SLs. The expression of enzymes [sphingo-myelinase (SMase), ceramidase, and sphingosine kinase-1 (SK1)] and apoptotic proteins (Bax and Bcl-2) was quantified by ELISA and by Western Blot. Sphingomyelin (SM), ceramide, ceramide-1 phosphate (C1P), sphingosine (SPH), and sphingosine-1-phosphate (S1P) levels were quantified by high-performance liquid chroma-tography (HPLC)-tandem mass spectroscopy (MS). Obese steatotic livers exhibited significantly upregulated ceramidase and down-regulated SK1 and C1P levels (P < 0.05), as well as significantly lower levels of SM and higher levels of ceramide species containing long chain fatty acids, compared to their lean counterparts. These findings demonstrate that obese liver harbours SLs that favour a proapoptotic environment. Moreover, accumulation of ceramides containing long chain fatty acids could be involved in the pathogenesis of hepatic steatosis.展开更多
The sphingolipid metabolites ceramide,sphingosine,and sphingosine-1-phosphate(S1P) and its enzyme sphingosine kinase(SphK) play an important role in the regulation of cell proliferation,survival,inflammation,and cell ...The sphingolipid metabolites ceramide,sphingosine,and sphingosine-1-phosphate(S1P) and its enzyme sphingosine kinase(SphK) play an important role in the regulation of cell proliferation,survival,inflammation,and cell death.Ceramide and sphingosine usually inhibit proliferation and promote apoptosis,while its metabolite S1P phosphorylated by SphK stimulates growth and suppresses apoptosis.Because these metabolites are interconvertible,it has been proposed that it is not the absolute amounts of these metabolites but rather their relative levels that determine cell fate.The relevance of this "sphingolipid rheostat" and its role in regulating cell fate has been borne out by work in many labs using many different cell types and experimental manipulations.A central finding of these studies is that SphK is a critical regulator of the sphingolipid rheostat,as it not only produces the pro-growth,anti-apoptotic messenger S1P,but also decreases levels of pro-apoptotic ceramide and sphingosine.Activation of bioactive sphingolipid S1P signaling has emerged as a critical protective pathway in response to acute ischemic injury in both cardiac and cerebrovascular disease,and these observations have considerable relevance for future potential therapeutic targets.展开更多
Lipidomics approach by UPLC-Q-Exactive-MS was used for the identification,quantification,comparison,and characterization of sphingolipids in virus infected marine Emiliania huxleyi BOF92 cells.The results show that 16...Lipidomics approach by UPLC-Q-Exactive-MS was used for the identification,quantification,comparison,and characterization of sphingolipids in virus infected marine Emiliania huxleyi BOF92 cells.The results show that 16 significantly changed sphingolipids(including Cer,CerG1,and SPHm)were identified during viral infection.Our data confirmed previously recognized facts that viral infection led to a shift toward virus-specific sphingolipids,which is consistent with the down-regulation of genes involved in the host de novo sphingolipid biosynthesis.Moreover,we revealed the upregulation of virusencoded homologous genes participating in de novo sphingolipids biosynthesis and virus-specific hydroxylated long chain bases(LCBs)as phytoCer,suggesting the competitive inhibition of host sphingolipid synthesis to produce the required building blocks for viral production,replication,and assembly.Additionally,Cer 40꞉1;2,Cer 40꞉2;2 isomer,and CerG139꞉0;2,Cer 39꞉0;2 as novel metabolite markers might indicate the general dysfunctions in E.huxleyi in response to viral infection.Our results show that viral infection led to a profound remodeling of host sphingolipidome,by which viruses depend on the hijacking of host sphingolipid metabolism to support the viral life cycle.展开更多
The sphingosine kinases, SK1 and SK2, produce the potent signaling lipid sphingosine-1-phosphate (S1P). These enzymes have garnered increasing interest for their roles in tumorigenesis, inflammation, vascular diseases...The sphingosine kinases, SK1 and SK2, produce the potent signaling lipid sphingosine-1-phosphate (S1P). These enzymes have garnered increasing interest for their roles in tumorigenesis, inflammation, vascular diseases, and immunity, as well as other functions. The sphingosine kinases are considered signaling enzymes by producing S1P, and their activity is acutely regulated by a variety of agonists. However, these enzymes are also key players in the control of sphingolipid metabolism. A variety of sphingolipids, such as sphingosine and the ceramides, are potent signaling molecules in their own right. The role of sphingosine kinases in regulating sphingolipid metabolism is potentially a critical aspect of their signaling function. A central aspect of signaling lipids is that their hydrophobic nature constrains them to membranes. Most enzymes of sphingolipid metabolism, including the enzymes that degrade S1P, are membrane enzymes. Therefore the localization of the sphingosine kinases and S1P is likely to be important in S1P signaling. Sphingosine kinase localization affects sphingolipid signaling in several ways. Translocation of SK1 to theplasma membrane promotes extracellular secretion of S1P. SK1 and SK2 localization to specific sites appears to direct S1P to intracellular protein effectors. SK localization also determines the access of these enzymes to their substrates. This may be an important mechanism for the regulation of ceramide biosynthesis by diverting dihydrosphingosine, a precursor in the ceramide biosynthetic pathway, from the de novo production of ceramide.展开更多
Objective:Cholangiocarcinoma(CCA)is a rare but highly malignant hepatobiliary cancer with a very poor prognosis and limited treatment options.CCA is commonly associated with chronic cholestasis and significantly eleva...Objective:Cholangiocarcinoma(CCA)is a rare but highly malignant hepatobiliary cancer with a very poor prognosis and limited treatment options.CCA is commonly associated with chronic cholestasis and significantly elevated levels of primary and conjugated bile acids(CBAs),which are correlated with bile duct obstruction.展开更多
Background:The specific impact of sphingolipid metabolism on developing hepatocellular Carcinoma(HCC)remains unclear.This study aims to explore the relationship between sphingolipid metabolism and HCC prognosis,immune ...Background:The specific impact of sphingolipid metabolism on developing hepatocellular Carcinoma(HCC)remains unclear.This study aims to explore the relationship between sphingolipid metabolism and HCC prognosis,immune response,and drug sensitivity.Methods:Data were obtained from The Cancer Genome Atlas(TCGA)-Hepatocellular Carcinoma(LIHC)and Gene Expression Omnibus(GEO,GSE14520 datasets).47 sphingolipid metabolism genes were obtained from the Kyoto Encyclopedia of Genes and Genomes(KEGG)database.After classifying HCC samples using the Non-negative Matrix Factorization(NMF)clustering method,differentially expressed genes were screened.Then,8 risk genes were obtained by univariate analysis,survival random forest reduction and lasso analysis.The expression of 8 risk genes was verified in vitro.Results:8 risk genes were used to construct the Sphingolipid score model.High-Sphingolipid score predicted poor prognosis of HCC patients.Sphingolipid score was associated with immune checkpoints(IL-1B,TLR4,TGFB1,and IL-10),immune cells(Th2,Treg,MDSC,Neutrophil,Fibroblasts and macrophage),and MAPK Cascade.In the High-Sphingolipid score group,a significantly higher proportion of patients with TP53(p53)mutations was significantly higher(56%).Furthermore,patients with a high-Sphingolipid score were predicted to have a higher sensitivity to chemotherapy drugs.In vitro validation showed that compared with normal liver cells LX-2,TRIM47,and S100A9 significantly increased in liver cancer cells Hep G2,MHCC-97H,and Hep3B2.1-7,while SLC1A7,LPCAT1,and CFHR4 significantly decreased.Silencing TRIM47 reduced the proliferation and promoted apoptosis.The levels of ceramide synthesis-related indexes(CERS1,CERS6,CERS5,and SPTLC2)increased,and the ACER3 related to catalytic hydrolysis decreased.Conclusion:We constructed a sphingolipid metabolism-related prognostic signature(Sphingolipid score)based on 8 risk genes.TRIM47 may affect the development of liver cancer by regulating the relevant indicators of ceramide synthesis and catalytic hydrolysis.展开更多
Cisplatin,a DNA crosslinking agent,is widely used for the treatment of a variety of solid tumors.Numerous studies have demonstrated that sphingolipid metabolism,which acts as a target for cisplatin treatment,is a high...Cisplatin,a DNA crosslinking agent,is widely used for the treatment of a variety of solid tumors.Numerous studies have demonstrated that sphingolipid metabolism,which acts as a target for cisplatin treatment,is a highly complex network that consists of sphingolipid signaling molecules and related catalytic enzymes.Ceramide(Cer),which is the central molecule of this network,has been established to induce apoptosis.However,another molecule,sphingosine-1-phosphate(S1P),exerts the opposite function,i.e.,serves as a regulator of pro-survival.Other sphingolipid molecules,including dihydroceramide,ceramide-1-phosphate,glucosylceramide(Glu Cer),and sphingosine(Sph),or sphingolipid catalytic enzymes such as Sph kinase(Sph K),Cer synthase(Cer S),and S1 P lyase,have also attracted considerable attention,particularly Cer,Glu Cer,Sph K,Cer S,and S1 P lyase,which have been implicated in cisplatin resistance.This review summarizes specific molecules involved in sphingolipid metabolism and related catalytic enzymes affecting the anticancer effect of cisplatin,particularly in relation to induction of apoptosis and drug resistance.展开更多
Background:Renal osteodystrophy(ROD)is a skeletal pathology associated with chronic kidney disease-mineral and bone disorder(CKD-MBD)that is characterized by aberrant bone mineralization and remodeling.ROD increases t...Background:Renal osteodystrophy(ROD)is a skeletal pathology associated with chronic kidney disease-mineral and bone disorder(CKD-MBD)that is characterized by aberrant bone mineralization and remodeling.ROD increases the risk of fracture and mortality in CKD patients.The underlying mechanisms of ROD remain elusive,partially due to the absence of an appropriate animal model.To address this gap,we established a stable mouse model of ROD using an optimized adenine-enriched diet and conducted exploratory analyses through ribonucleic acid sequencing(RNA-seq).Methods:Eight-week-old male C57BL/6J mice were randomly allocated into three groups:control group(n=5),adenine and high-phosphate(HP)diet group(n=20),and the optimized adenine-containing diet group(n=20)for 12 weeks.We assessed the skeletal characteristics of model mice through blood biochemistry,microcomputed tomography(micro-CT),and bone histomorphometry.RNA-seq was utilized to profile gene expression changes of ROD.We elucidated the functions of differentially expressed genes(DEGs)using gene ontology(GO)analysis,Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis,and gene set enrichment analysis(GSEA).DEGs were validated via quantitative real-time polymerase chain reaction(qRT-PCR).Results:By the fifth week,adenine followed by an HP diet induced rapid weight loss and high mortality rates in the mouse group,precluding further model development.Mice with optimized adenine diet-induced ROD displayed significant abnormalities in serum creatinine and blood urea nitrogen levels,accompanied by pronounced hyperparathyroidism and hyperphosphatemia.The femur bone mineral density(BMD)of the model mice was lower than that of control mice,with substantial bone loss and cortical porosity.ROD mice exhibited substantial bone turnover with an increase in osteoblast and osteoclast markers.Transcriptomic profiling revealed 1907 genes with upregulated expression and 723 genes with downregulated expression in the femurs of ROD mice relative to those of control mice.Pathway analyses indicated significant enrichment of upregulated genes in the sphingolipid metabolism pathway.The significant upregulation of alkaline ceramidase 1(Acer1),alkaline ceramidase 2(Acer2),prosaposin-like 1(Psapl1),adenosine A1 receptor(Adora1),and sphingosine-1-phosphate receptor 5(S1pr5)were successfully validated in mouse femurs by qRT-PCR.Conclusions:Optimized adenine diet mouse model may be a valuable proxy for studying ROD.RNA-seq analysis revealed that the sphingolipid metabolism pathway is likely a key player in ROD pathogenesis,thereby providing new avenues for therapeutic intervention.展开更多
Plant sphingolipids are not only structural components of the plasma membrane and other endomembrane systems but also act as signaling molecules during biotic and abiotic stresses.However,the roles of sphingolipids in...Plant sphingolipids are not only structural components of the plasma membrane and other endomembrane systems but also act as signaling molecules during biotic and abiotic stresses.However,the roles of sphingolipids in plant signal transduction in response to environmental cues are yet to be investigated in detail. In this review,we discuss the signaling roles of sphingolipid metabolites with a focus on plant sphingolipids.We also mention some microbial sphingolipids that initiate signals during their interaction with plants, because of the limited literatures on their plant analogs.The equilibrium of nonphosphorylated and phosphorylated sphingolipid species determine the destiny of plant cells,whereas molecular connections among the enzymes responsible for this equilibrium in a coordinated signaling network are poorly understood.A mechanistic link between the phytohormone-sphingolipid interplay has also not yet been fully understood and many key participants involved in this complex interaction operating under stress conditions await to be identified.Future research is needed to fill these gaps and to better understand the signal pathways of plant sphingolipids and their interplay with other signals in response to environmental stresses.展开更多
Synapses are key structures involved in transmitting information in the nervous system,and their functions rely on the regulation of various lipids.Lipids play important roles in synapse formation,neurotransmitter rel...Synapses are key structures involved in transmitting information in the nervous system,and their functions rely on the regulation of various lipids.Lipids play important roles in synapse formation,neurotransmitter release,and signal transmission,and dysregulation of lipid metabolism is closely associated with various neurodegenerative diseases.The complex roles of lipids in synaptic function and neurological diseases have recently garnered increasing attention,but their specific mechanisms remain to be fully understood.This review aims to explore how lipids regulate synaptic activity in the central nervous system,focusing on their roles in synapse formation,neurotransmitter release,and signal transmission.Additionally,it discusses the mechanisms by which glial cells modulate synaptic function through lipid regulation.This review shows that within the central nervous system,lipids are essential components of the cell membrane bilayer,playing critical roles in synaptic structure and function.They regulate presynaptic vesicular trafficking,postsynaptic signaling pathways,and glial-neuronal interactions.Cholesterol maintains membrane fluidity and promotes the formation of lipid rafts.Glycerophospholipids contribute to the structural integrity of synaptic membranes and are involved in the release of synaptic vesicles.Sphingolipids interact with synaptic receptors through various mechanisms to regulate their activity and are also involved in cellular processes such as inflammation and apoptosis.Fatty acids are vital for energy metabolism and the synthesis of signaling molecules.Abnormalities in lipid metabolism may lead to impairments in synaptic function,affecting information transmission between neurons and the overall health of the nervous system.Therapeutic strategies targeting lipid metabolism,particularly through cholesterol modulation,show promise for treating these conditions.In neurodegenerative diseases such as Alzheimer’s disease,Parkinson disease,and amyotrophic lateral sclerosis,dysregulation of lipid metabolism is closely linked to synaptic dysfunction.Therefore,lipids are not only key molecules in neural regeneration and synaptic repair but may also contribute to neurodegenerative pathology when metabolic dysregulation occurs.Further research is needed to elucidate the specific mechanisms linking lipid metabolism to synaptic dysfunction and to develop targeted lipid therapies for neurological diseases.展开更多
Background Hepatic ischemia-reperfusion （I/R） injury occurs in many clinical procedures. The molecular mechanisms responsible for hepatic I/R injury however remain unknown. Sphingolipids, in particular ceramide, pla...Background Hepatic ischemia-reperfusion （I/R） injury occurs in many clinical procedures. The molecular mechanisms responsible for hepatic I/R injury however remain unknown. Sphingolipids, in particular ceramide, play a role in stress and death receptor-induced hepatocellular death, contributing to the progression of several liver diseases including liver I/R injury. In order to further define the role of sphingolipids in hepatic I/R, systemic analysis of sphingolipids after reperfusion is necessary. Methods We investigated the lipidomic changes of sphingolipids in a rat model of warm hepatic I/R injury, by delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry （DE MALDI-TOF-MS）. Results The total amounts of ceramide and sphingomyelin and the intensity of most kinds of sphingolipids, mainly sphingomyelin, significantly increased at 1 hour after reperfusion （P 〈0.05） and reached peaks at 6 hours after reperfusion （P 〈0.01） compared to controls. Six new forms of ceramide and sphingomyelins appeared 6 hours after reperfusion, they were （m/z） 537.8, 555.7, 567.7, 583.8, 683.5 and 731.4 respectively. A ceramide-monohexoside （m/z） 804.4 （CMH（d18：1C22：1＋Na）＋） also increased after reperfusion and correlated with extent of liver injury after reperfursion. Conclusions Three main forms of sphingolipids, ceramide, sphingomyelin and ceramide-monohexoside, are related to hepatic I/R injury and provide a new perspective in understanding the mechanisms responsible for hepatic I/R injury.展开更多
Non-alcoholic fatty liver disease(NAFLD)is one of the fastest-growing diseases,and its global prevalence is estimated to increase>50%by 2030.NAFLD is comorbid with metabolic syndrome,obesity,type 2 diabetes,and ins...Non-alcoholic fatty liver disease(NAFLD)is one of the fastest-growing diseases,and its global prevalence is estimated to increase>50%by 2030.NAFLD is comorbid with metabolic syndrome,obesity,type 2 diabetes,and insulin resistance.Despite extensive research efforts,there are no pharmacologic or biological therapeutics for the treatment of NAFLD.Bile acids and sphingolipids are well-characterized signaling molecules.Over the last few decades,researchers have uncovered potential mechanisms by which bile acids and sphingolipids regulate hepatic lipid metabolism.Dysregulation of bile acid and sphingolipid metabolism has been linked to steatosis,inflammation,and fibrosis in patients with NAFLD.This clinical observation has been recapitulated in animal models,which are well-accepted by experts in the hepatology field.Recent transcriptomic and lipidomic studies also show that sphingolipids are important players in the pathogenesis of NAFLD.Moreover,the identification of bile acids as activators of sphingolipid-mediated signaling pathways established a novel theory for bile acid and sphingolipid biology.In this review,we summarize the recent advances in the understanding of bile acid and sphingolipid-mediated signaling pathways as potential contributors to NAFLD.A better understanding of the pathologic effects mediated by bile acids and sphingolipids will facilitate the development of new diagnostic and therapeutic strategies for NAFLD.展开更多
目的:探究正常肺组织、肺腺癌癌旁和肺腺癌中所有基因的表达水平趋势,寻找特征性基因并进行实验验证。方法:下载加州大学圣克鲁斯分校(University of California,Santa Cruz,UCSC)数据中心中癌症基因组图谱(the cancer genome atlas,TC...目的:探究正常肺组织、肺腺癌癌旁和肺腺癌中所有基因的表达水平趋势,寻找特征性基因并进行实验验证。方法:下载加州大学圣克鲁斯分校(University of California,Santa Cruz,UCSC)数据中心中癌症基因组图谱(the cancer genome atlas,TCGA)和基因型-组织表达项目(genotype-tissue expression,GTEX)的整合数据,采用R语言分析所有基因的表达趋势,寻找特征性基因,提取癌旁和肿瘤组织共同高表达的基因集,进行GO和KEGG分析富集情况,鉴定最显著的通路中在肺组织和癌旁及肺腺癌中变化最大的基因。通过细胞生物学实验验证候选基因在肿瘤中的作用。结果:整合数据显示存在一群正常组织中低表达但在肺腺癌癌旁和肺腺癌中高表达的基因(DEGS2、PIGY、FUCA、GM2A),GO分析显示该基因群富集最显著的通路是膜脂质代谢过程,对该通路基因和符合趋势的基因取交集,发现DEGS2在癌旁和癌组织中升高最明显,升高倍数达3.27倍。实验证实,敲除DEGS224 h后细胞迁移能力下降,72 h后细胞活性下降55.0%。结论:DEGS2在癌旁和肺腺癌中呈高表达,其表达能促进肺腺癌的增殖和迁移,从而进一步驱动从癌旁组织到癌的发展。展开更多
基金supported by National Research Foundation(NRF)of Korea grants funded by the Korean government,the Ministry of Science and ICT[NRF-2022R1A2C1006737 to Joo-Won Park,NRF-2022R1I1A1A0106408112 to Min Hee Kim].
文摘Breast cancer is one of the most prevalent malignancies among women and comprises a heterogeneous spectrum of molecular subtypes with distinct biological behaviors.Among various regulatory molecules,sphingolipids play pivotal roles in dynamically modulating fundamental cellular processes such as proliferation,apoptosis,and metastasis through metabolic interconversions,including phosphorylation,glycosylation,and the generation of sphingosine-1-phosphate.This review aims to elucidate the mechanisms through which sphingolipid metabolism orchestrates cancer cell fate and drives breast cancer progression.Particular emphasis is placed on the balance between proapoptotic ceramides and pro-survival metabolites,such as sphingosine-1-phosphate,which collectively influence tumor growth and the therapeutic response.Additional sphingolipid species,including glucosylceramide and gangliosides(GD2,GD3,GM1,and GM3),have also been implicated in promoting breast cancer development.Furthermore,sphingolipid-based therapeutic strategies,including immunotherapy and antibody therapy,are discussed.By providing a comprehensive overview of sphingolipid metabolism,this review aims to identify novel therapeutic targets that may help overcome treatment resistance and improve clinical outcomes in breast cancer.
基金supported by the Judith Jane Mason and Harold Stannett Williams Memorial Foundation National Medical Program(#Mason2210)to JX。
文摘Myalgic encephalomyelitis/chronic fatigue syndrome-an insidious disease:The recent COVID-19 pandemic has brought substantial attention to the overlapping symptoms between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS),a chronic and poorly understood neurological disorder(Shankar et al.,2024).
基金the National ＂863＂ Program of China （No. 2001AA624010）the Guangdong Provincial Natural Science Foundation of China （No. 04300674）+1 种基金 the Guangdong Provincial Science and Technology Program Foundation of China （No.2004B30101017） the Foshan City Foundation for the Development of Science and Technology （No. 2005081871）.
文摘A set of three sphingolipids, N-2′-hydroxyplmitoyl-1-O-β-D-glucopyranosyl-9-methyl-4E, 8E-sphingadiene （A）, N-2′-hydroxyl-3′E-octadecenoyl-1-O-β-D-glucopyranosyl-9-methyl-4E, 8E-sphingediene （B） and N-palmitoyldihydrosphingosine （C）, were isolated from two marine-derived mangrove endophytic fungal strains （strains No. 1924 and 3893） from the South China Sea. Their structures were elucidated by 2D NMR and FABMS methods. It is the first time that these sphingolipids were separated and obtained from marine-derived mangrove endophytic fungus from the South China Sea.
基金supported by grants from National Key R&D Program of China(2018YFA0506900,2018YFA0800901)the National Natural Science Foundation of China(NSFC92057202)the Chinese Academy of Sciences(XDB39050900).
文摘Sphingolipids not only exert structural roles in cellular membranes,but also act as signaling molecules in various physiological and pathological processes.A myriad of studies have shown that abnormal levels of sphingolipids and their metabolic enzymes are associated with a variety of human diseases.Moreover,blood sphingolipids can also be used as biomarkers for disease diagnosis.This review summarizes the biosynthesis,metabolism,and pathological roles of sphingolipids,with emphasis on the biosynthesis of ceramide,the precursor for the biosynthesis of complex sphingolipids with different fatty acyl chains.The possibility of using sphingolipids for disease prediction,diagnosis,and treatment is also discussed.Targeting endogenous ceramides and complex sphingolipids along with their specific fatty acyl chain to promote future drug development will also be discussed.
基金supported by the National High-tech R&D Program(863 Program,No.2006AA10A113) of the Ministry of Science and Technology of Chinathe projects of Ministry of Agriculture of China for Transgenic Research (Nos.2009ZX08009-098B and 2008ZX08009-003)
文摘8-Sphingolipid desaturase is the key enzyme that catalyses desaturation at the C8 position of the long-chain base of sphingolipids in higher plants. There have been no previous studies on the genes encoding AS-sphingolipid desaturases in Brassica rapa. In this study, four genes encoding AS-sphingolipid desaturases from B. rapa were isolated and characterised. Phylogenetic analyses indicated that these genes could be divided into two groups： BrD8A, BrD8C and BrD8D in group I, and BrD8B in group II. The two groups of genes diverged before the separation of Arabidopsis and Brassica. Though the four genes shared a high sequence similarity, and their coding desaturases all located in endoplasmic reticulum, they exhibited distinct expression patterns. Heterologous expression in Saccharomyces cerevisiae revealed that BrD8A/B/C/D were functionally diverse AS-sphingolipid desaturases that catalyse different ratios of the two products 8（Z）- and 8（E）-C18-phytosphingenine. The aluminium tolerance of transgenic yeasts expressing BrD8A/B/C/D was enhanced compared with that of control cells. Expression of BrD8A in Arabidopsis changed the ratio of 8（Z）：8（E）-C 18-phytosphingenine in transgenic plants. The information reported here provides new insights into the biochemical functional diversity and evolutionary relationship of AS-sphingolipid desaturase in plants and lays a foundation for further investigation of the mechanism of 8（Z）- and 8（E）-C18- phytosphingenine biosynthesis.
文摘The sphingolipid (SL) signaling pathways are induced by reactive oxygen species and proin-flammatory molecules, which are shown to be upregulated in the obese state. The present work was conducted to determine if an altered SL pathway exists, and contributes to the pathogenesis of hepatic steatosis associated with obesity. Steatotic and non-steatotic livers were procured from Zucker Obese female rats and their lean counterparts in this pre-clinical study, and assessed for enzymes involved in degradation as well as in phos-phorylation of proapoptotic SLs. The expression of enzymes [sphingo-myelinase (SMase), ceramidase, and sphingosine kinase-1 (SK1)] and apoptotic proteins (Bax and Bcl-2) was quantified by ELISA and by Western Blot. Sphingomyelin (SM), ceramide, ceramide-1 phosphate (C1P), sphingosine (SPH), and sphingosine-1-phosphate (S1P) levels were quantified by high-performance liquid chroma-tography (HPLC)-tandem mass spectroscopy (MS). Obese steatotic livers exhibited significantly upregulated ceramidase and down-regulated SK1 and C1P levels (P < 0.05), as well as significantly lower levels of SM and higher levels of ceramide species containing long chain fatty acids, compared to their lean counterparts. These findings demonstrate that obese liver harbours SLs that favour a proapoptotic environment. Moreover, accumulation of ceramides containing long chain fatty acids could be involved in the pathogenesis of hepatic steatosis.
基金Supported by Grants from the National Institutes of Health (NS40516,to Yenari MA)the Veteran's Merit Award(Yenari MA)+3 种基金the Uehara Foundation(2013 Research Fellowship,to Kawabori M)the National Heart,Lung,and Blood Institute/NHLBI(1P01 HL 68738 and R01 HL 090606 to Karliner JS)Grants to Yenari MA and Karliner JS were administered by the Northern California Institute for Research and Educationsupported by resources of the Veterans Affairs Medical Center, San Francisco,California
文摘The sphingolipid metabolites ceramide,sphingosine,and sphingosine-1-phosphate(S1P) and its enzyme sphingosine kinase(SphK) play an important role in the regulation of cell proliferation,survival,inflammation,and cell death.Ceramide and sphingosine usually inhibit proliferation and promote apoptosis,while its metabolite S1P phosphorylated by SphK stimulates growth and suppresses apoptosis.Because these metabolites are interconvertible,it has been proposed that it is not the absolute amounts of these metabolites but rather their relative levels that determine cell fate.The relevance of this "sphingolipid rheostat" and its role in regulating cell fate has been borne out by work in many labs using many different cell types and experimental manipulations.A central finding of these studies is that SphK is a critical regulator of the sphingolipid rheostat,as it not only produces the pro-growth,anti-apoptotic messenger S1P,but also decreases levels of pro-apoptotic ceramide and sphingosine.Activation of bioactive sphingolipid S1P signaling has emerged as a critical protective pathway in response to acute ischemic injury in both cardiac and cerebrovascular disease,and these observations have considerable relevance for future potential therapeutic targets.
基金Supported by the National Natural Science Foundation of China(Nos.42076086,41576166)the Natural Science Foundation of Fujian Province(No.2020J05138)+1 种基金the Education and Research Project for Young and Middle-aged Teachers of Fujian Province(No.JAT190343)the Cultivation Plan for Distinguished Young Scholars in Fujian Universities。
文摘Lipidomics approach by UPLC-Q-Exactive-MS was used for the identification,quantification,comparison,and characterization of sphingolipids in virus infected marine Emiliania huxleyi BOF92 cells.The results show that 16 significantly changed sphingolipids(including Cer,CerG1,and SPHm)were identified during viral infection.Our data confirmed previously recognized facts that viral infection led to a shift toward virus-specific sphingolipids,which is consistent with the down-regulation of genes involved in the host de novo sphingolipid biosynthesis.Moreover,we revealed the upregulation of virusencoded homologous genes participating in de novo sphingolipids biosynthesis and virus-specific hydroxylated long chain bases(LCBs)as phytoCer,suggesting the competitive inhibition of host sphingolipid synthesis to produce the required building blocks for viral production,replication,and assembly.Additionally,Cer 40꞉1;2,Cer 40꞉2;2 isomer,and CerG139꞉0;2,Cer 39꞉0;2 as novel metabolite markers might indicate the general dysfunctions in E.huxleyi in response to viral infection.Our results show that viral infection led to a profound remodeling of host sphingolipidome,by which viruses depend on the hijacking of host sphingolipid metabolism to support the viral life cycle.
基金Supported by The James Graham Brown Cancer Center and NIH, No. CA111987
文摘The sphingosine kinases, SK1 and SK2, produce the potent signaling lipid sphingosine-1-phosphate (S1P). These enzymes have garnered increasing interest for their roles in tumorigenesis, inflammation, vascular diseases, and immunity, as well as other functions. The sphingosine kinases are considered signaling enzymes by producing S1P, and their activity is acutely regulated by a variety of agonists. However, these enzymes are also key players in the control of sphingolipid metabolism. A variety of sphingolipids, such as sphingosine and the ceramides, are potent signaling molecules in their own right. The role of sphingosine kinases in regulating sphingolipid metabolism is potentially a critical aspect of their signaling function. A central aspect of signaling lipids is that their hydrophobic nature constrains them to membranes. Most enzymes of sphingolipid metabolism, including the enzymes that degrade S1P, are membrane enzymes. Therefore the localization of the sphingosine kinases and S1P is likely to be important in S1P signaling. Sphingosine kinase localization affects sphingolipid signaling in several ways. Translocation of SK1 to theplasma membrane promotes extracellular secretion of S1P. SK1 and SK2 localization to specific sites appears to direct S1P to intracellular protein effectors. SK localization also determines the access of these enzymes to their substrates. This may be an important mechanism for the regulation of ceramide biosynthesis by diverting dihydrosphingosine, a precursor in the ceramide biosynthetic pathway, from the de novo production of ceramide.
文摘Objective:Cholangiocarcinoma(CCA)is a rare but highly malignant hepatobiliary cancer with a very poor prognosis and limited treatment options.CCA is commonly associated with chronic cholestasis and significantly elevated levels of primary and conjugated bile acids(CBAs),which are correlated with bile duct obstruction.
基金The work was supported by funds from The Science and Technology Project of Hangzhou City(Agriculture and Social Development,No.2016007)&(Agriculture and Social Development,No.20201231Y131)&(Social Development,No.20140633B57)The Science and Technology Project of Yuhang District,Hangzhou City(Nos.2017002&2014003)+2 种基金The Health Science and Technology Project of Hangzhou City(No.2015B32)Zhejiang Provincial Natural Science Foundation of China under Grant(No.LTGY23H160006)The Health Science and Technology Project of Zhejiang Province(No.2023XY009).
文摘Background:The specific impact of sphingolipid metabolism on developing hepatocellular Carcinoma(HCC)remains unclear.This study aims to explore the relationship between sphingolipid metabolism and HCC prognosis,immune response,and drug sensitivity.Methods:Data were obtained from The Cancer Genome Atlas(TCGA)-Hepatocellular Carcinoma(LIHC)and Gene Expression Omnibus(GEO,GSE14520 datasets).47 sphingolipid metabolism genes were obtained from the Kyoto Encyclopedia of Genes and Genomes(KEGG)database.After classifying HCC samples using the Non-negative Matrix Factorization(NMF)clustering method,differentially expressed genes were screened.Then,8 risk genes were obtained by univariate analysis,survival random forest reduction and lasso analysis.The expression of 8 risk genes was verified in vitro.Results:8 risk genes were used to construct the Sphingolipid score model.High-Sphingolipid score predicted poor prognosis of HCC patients.Sphingolipid score was associated with immune checkpoints(IL-1B,TLR4,TGFB1,and IL-10),immune cells(Th2,Treg,MDSC,Neutrophil,Fibroblasts and macrophage),and MAPK Cascade.In the High-Sphingolipid score group,a significantly higher proportion of patients with TP53(p53)mutations was significantly higher(56%).Furthermore,patients with a high-Sphingolipid score were predicted to have a higher sensitivity to chemotherapy drugs.In vitro validation showed that compared with normal liver cells LX-2,TRIM47,and S100A9 significantly increased in liver cancer cells Hep G2,MHCC-97H,and Hep3B2.1-7,while SLC1A7,LPCAT1,and CFHR4 significantly decreased.Silencing TRIM47 reduced the proliferation and promoted apoptosis.The levels of ceramide synthesis-related indexes(CERS1,CERS6,CERS5,and SPTLC2)increased,and the ACER3 related to catalytic hydrolysis decreased.Conclusion:We constructed a sphingolipid metabolism-related prognostic signature(Sphingolipid score)based on 8 risk genes.TRIM47 may affect the development of liver cancer by regulating the relevant indicators of ceramide synthesis and catalytic hydrolysis.
文摘Cisplatin,a DNA crosslinking agent,is widely used for the treatment of a variety of solid tumors.Numerous studies have demonstrated that sphingolipid metabolism,which acts as a target for cisplatin treatment,is a highly complex network that consists of sphingolipid signaling molecules and related catalytic enzymes.Ceramide(Cer),which is the central molecule of this network,has been established to induce apoptosis.However,another molecule,sphingosine-1-phosphate(S1P),exerts the opposite function,i.e.,serves as a regulator of pro-survival.Other sphingolipid molecules,including dihydroceramide,ceramide-1-phosphate,glucosylceramide(Glu Cer),and sphingosine(Sph),or sphingolipid catalytic enzymes such as Sph kinase(Sph K),Cer synthase(Cer S),and S1 P lyase,have also attracted considerable attention,particularly Cer,Glu Cer,Sph K,Cer S,and S1 P lyase,which have been implicated in cisplatin resistance.This review summarizes specific molecules involved in sphingolipid metabolism and related catalytic enzymes affecting the anticancer effect of cisplatin,particularly in relation to induction of apoptosis and drug resistance.
基金funded by the National Natural Science Foundation of China(No.82370742)the Key Program of Jiangsu Health and Health Committee(No.ZD2022045).
文摘Background:Renal osteodystrophy(ROD)is a skeletal pathology associated with chronic kidney disease-mineral and bone disorder(CKD-MBD)that is characterized by aberrant bone mineralization and remodeling.ROD increases the risk of fracture and mortality in CKD patients.The underlying mechanisms of ROD remain elusive,partially due to the absence of an appropriate animal model.To address this gap,we established a stable mouse model of ROD using an optimized adenine-enriched diet and conducted exploratory analyses through ribonucleic acid sequencing(RNA-seq).Methods:Eight-week-old male C57BL/6J mice were randomly allocated into three groups:control group(n=5),adenine and high-phosphate(HP)diet group(n=20),and the optimized adenine-containing diet group(n=20)for 12 weeks.We assessed the skeletal characteristics of model mice through blood biochemistry,microcomputed tomography(micro-CT),and bone histomorphometry.RNA-seq was utilized to profile gene expression changes of ROD.We elucidated the functions of differentially expressed genes(DEGs)using gene ontology(GO)analysis,Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis,and gene set enrichment analysis(GSEA).DEGs were validated via quantitative real-time polymerase chain reaction(qRT-PCR).Results:By the fifth week,adenine followed by an HP diet induced rapid weight loss and high mortality rates in the mouse group,precluding further model development.Mice with optimized adenine diet-induced ROD displayed significant abnormalities in serum creatinine and blood urea nitrogen levels,accompanied by pronounced hyperparathyroidism and hyperphosphatemia.The femur bone mineral density(BMD)of the model mice was lower than that of control mice,with substantial bone loss and cortical porosity.ROD mice exhibited substantial bone turnover with an increase in osteoblast and osteoclast markers.Transcriptomic profiling revealed 1907 genes with upregulated expression and 723 genes with downregulated expression in the femurs of ROD mice relative to those of control mice.Pathway analyses indicated significant enrichment of upregulated genes in the sphingolipid metabolism pathway.The significant upregulation of alkaline ceramidase 1(Acer1),alkaline ceramidase 2(Acer2),prosaposin-like 1(Psapl1),adenosine A1 receptor(Adora1),and sphingosine-1-phosphate receptor 5(S1pr5)were successfully validated in mouse femurs by qRT-PCR.Conclusions:Optimized adenine diet mouse model may be a valuable proxy for studying ROD.RNA-seq analysis revealed that the sphingolipid metabolism pathway is likely a key player in ROD pathogenesis,thereby providing new avenues for therapeutic intervention.
基金the National Natural Science Foundation of China (31570808)the Fundamental Research Funds for the Central Universities (2662015PY090).
文摘Plant sphingolipids are not only structural components of the plasma membrane and other endomembrane systems but also act as signaling molecules during biotic and abiotic stresses.However,the roles of sphingolipids in plant signal transduction in response to environmental cues are yet to be investigated in detail. In this review,we discuss the signaling roles of sphingolipid metabolites with a focus on plant sphingolipids.We also mention some microbial sphingolipids that initiate signals during their interaction with plants, because of the limited literatures on their plant analogs.The equilibrium of nonphosphorylated and phosphorylated sphingolipid species determine the destiny of plant cells,whereas molecular connections among the enzymes responsible for this equilibrium in a coordinated signaling network are poorly understood.A mechanistic link between the phytohormone-sphingolipid interplay has also not yet been fully understood and many key participants involved in this complex interaction operating under stress conditions await to be identified.Future research is needed to fill these gaps and to better understand the signal pathways of plant sphingolipids and their interplay with other signals in response to environmental stresses.
基金supported by the National Natural Science Foundation of China,No.82201568(to QQ)Capital’s Funds for Health Improvement and Research,No.2024-2-1031(to QQ)Beijing Nova Program,No.20240484566(to QQ).
文摘Synapses are key structures involved in transmitting information in the nervous system,and their functions rely on the regulation of various lipids.Lipids play important roles in synapse formation,neurotransmitter release,and signal transmission,and dysregulation of lipid metabolism is closely associated with various neurodegenerative diseases.The complex roles of lipids in synaptic function and neurological diseases have recently garnered increasing attention,but their specific mechanisms remain to be fully understood.This review aims to explore how lipids regulate synaptic activity in the central nervous system,focusing on their roles in synapse formation,neurotransmitter release,and signal transmission.Additionally,it discusses the mechanisms by which glial cells modulate synaptic function through lipid regulation.This review shows that within the central nervous system,lipids are essential components of the cell membrane bilayer,playing critical roles in synaptic structure and function.They regulate presynaptic vesicular trafficking,postsynaptic signaling pathways,and glial-neuronal interactions.Cholesterol maintains membrane fluidity and promotes the formation of lipid rafts.Glycerophospholipids contribute to the structural integrity of synaptic membranes and are involved in the release of synaptic vesicles.Sphingolipids interact with synaptic receptors through various mechanisms to regulate their activity and are also involved in cellular processes such as inflammation and apoptosis.Fatty acids are vital for energy metabolism and the synthesis of signaling molecules.Abnormalities in lipid metabolism may lead to impairments in synaptic function,affecting information transmission between neurons and the overall health of the nervous system.Therapeutic strategies targeting lipid metabolism,particularly through cholesterol modulation,show promise for treating these conditions.In neurodegenerative diseases such as Alzheimer’s disease,Parkinson disease,and amyotrophic lateral sclerosis,dysregulation of lipid metabolism is closely linked to synaptic dysfunction.Therefore,lipids are not only key molecules in neural regeneration and synaptic repair but may also contribute to neurodegenerative pathology when metabolic dysregulation occurs.Further research is needed to elucidate the specific mechanisms linking lipid metabolism to synaptic dysfunction and to develop targeted lipid therapies for neurological diseases.
基金This work was supported partly by grants from the National Natural Science Foundation of China （No. 30772054 and No. 30672071）.
文摘Background Hepatic ischemia-reperfusion （I/R） injury occurs in many clinical procedures. The molecular mechanisms responsible for hepatic I/R injury however remain unknown. Sphingolipids, in particular ceramide, play a role in stress and death receptor-induced hepatocellular death, contributing to the progression of several liver diseases including liver I/R injury. In order to further define the role of sphingolipids in hepatic I/R, systemic analysis of sphingolipids after reperfusion is necessary. Methods We investigated the lipidomic changes of sphingolipids in a rat model of warm hepatic I/R injury, by delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry （DE MALDI-TOF-MS）. Results The total amounts of ceramide and sphingomyelin and the intensity of most kinds of sphingolipids, mainly sphingomyelin, significantly increased at 1 hour after reperfusion （P 〈0.05） and reached peaks at 6 hours after reperfusion （P 〈0.01） compared to controls. Six new forms of ceramide and sphingomyelins appeared 6 hours after reperfusion, they were （m/z） 537.8, 555.7, 567.7, 583.8, 683.5 and 731.4 respectively. A ceramide-monohexoside （m/z） 804.4 （CMH（d18：1C22：1＋Na）＋） also increased after reperfusion and correlated with extent of liver injury after reperfursion. Conclusions Three main forms of sphingolipids, ceramide, sphingomyelin and ceramide-monohexoside, are related to hepatic I/R injury and provide a new perspective in understanding the mechanisms responsible for hepatic I/R injury.
基金supported by Department of Veteran Affairs Merit Award(No.I01BX004033)Research Career Scientist Award(No.IK6BX0094477)National Institutes of Health Grant(Nos.R01 DK104893,R01DK-057543,and R21 AA026629-01)。
文摘Non-alcoholic fatty liver disease(NAFLD)is one of the fastest-growing diseases,and its global prevalence is estimated to increase>50%by 2030.NAFLD is comorbid with metabolic syndrome,obesity,type 2 diabetes,and insulin resistance.Despite extensive research efforts,there are no pharmacologic or biological therapeutics for the treatment of NAFLD.Bile acids and sphingolipids are well-characterized signaling molecules.Over the last few decades,researchers have uncovered potential mechanisms by which bile acids and sphingolipids regulate hepatic lipid metabolism.Dysregulation of bile acid and sphingolipid metabolism has been linked to steatosis,inflammation,and fibrosis in patients with NAFLD.This clinical observation has been recapitulated in animal models,which are well-accepted by experts in the hepatology field.Recent transcriptomic and lipidomic studies also show that sphingolipids are important players in the pathogenesis of NAFLD.Moreover,the identification of bile acids as activators of sphingolipid-mediated signaling pathways established a novel theory for bile acid and sphingolipid biology.In this review,we summarize the recent advances in the understanding of bile acid and sphingolipid-mediated signaling pathways as potential contributors to NAFLD.A better understanding of the pathologic effects mediated by bile acids and sphingolipids will facilitate the development of new diagnostic and therapeutic strategies for NAFLD.
文摘目的:探究正常肺组织、肺腺癌癌旁和肺腺癌中所有基因的表达水平趋势,寻找特征性基因并进行实验验证。方法:下载加州大学圣克鲁斯分校(University of California,Santa Cruz,UCSC)数据中心中癌症基因组图谱(the cancer genome atlas,TCGA)和基因型-组织表达项目(genotype-tissue expression,GTEX)的整合数据,采用R语言分析所有基因的表达趋势,寻找特征性基因,提取癌旁和肿瘤组织共同高表达的基因集,进行GO和KEGG分析富集情况,鉴定最显著的通路中在肺组织和癌旁及肺腺癌中变化最大的基因。通过细胞生物学实验验证候选基因在肿瘤中的作用。结果:整合数据显示存在一群正常组织中低表达但在肺腺癌癌旁和肺腺癌中高表达的基因(DEGS2、PIGY、FUCA、GM2A),GO分析显示该基因群富集最显著的通路是膜脂质代谢过程,对该通路基因和符合趋势的基因取交集,发现DEGS2在癌旁和癌组织中升高最明显,升高倍数达3.27倍。实验证实,敲除DEGS224 h后细胞迁移能力下降,72 h后细胞活性下降55.0%。结论:DEGS2在癌旁和肺腺癌中呈高表达,其表达能促进肺腺癌的增殖和迁移,从而进一步驱动从癌旁组织到癌的发展。
