Glycerophospholipids pathways and chromosomal instability in gastric cancer: Global lipidomics analysis
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摘要
BACKGROUND Based on the breakthrough of genomics analysis, The Cancer Genome Atlas Research Group recently proposed an integrative genomic analysis, dividing gastric cancer(GC) into four subtypes, characterized by the chromosomal instability(CIN) status. However, the CIN status of GC is still vaguely characterized and lacking the valuable easy-to-use CIN markers to diagnosis in molecular and histological detection.AIM To explore the associations of CIN with downstream lipidomics profiles.METHODS We collected cancerous and noncancerous tissue samples from 18 patients with GC; the samples were divided into CIN and non-CIN types based on the system of The Cancer Genome Atlas Research Group and 409 sequenced oncogenes and tumor suppressor genes. We identified the lipidomics profiles of the GC samples and samples of their adjacent noncancerous tissues by using liquid chromatography–mass spectrometry. Furthermore, we selected leading metabolites based on variable importance in projection scores of > 1.0 and P <0.05.RESULTS Twelve men and six women participated in this study; the participants had a median age of 67.5 years(range, 52–87 years) and were divided into CIN(n = 9)and non-CIN(n = 9) groups. The GC samples exhibited distinct profiles of lysophosphocholine, phosphocholine, phosphatidylethanolamine,phosphatidylinositol, phosphoserine, sphingomyelin, ceramide, and triglycerides compared with their adjacent noncancerous tissues. The glycerophospholipid levels(phosphocholine, phosphatidylethanolamine, and phosphatidylinositol)were 1.4-to 2.3-times higher in the CIN group compared with the non-CIN group(P < 0.05). Alterations in the glycerolipid and glycerophospholipid pathways indicated progression of GC toward CIN.CONCLUSION The lipidomics profiles of GC samples were distinct from those of their adjacent noncancerous tissues. CIN status of GC is primarily associated with downstream lipidomics in the glycerophospholipid pathway.
BACKGROUND Based on the breakthrough of genomics analysis, The Cancer Genome Atlas Research Group recently proposed an integrative genomic analysis, dividing gastric cancer(GC) into four subtypes, characterized by the chromosomal instability(CIN) status. However, the CIN status of GC is still vaguely characterized and lacking the valuable easy-to-use CIN markers to diagnosis in molecular and histological detection.AIM To explore the associations of CIN with downstream lipidomics profiles.METHODS We collected cancerous and noncancerous tissue samples from 18 patients with GC; the samples were divided into CIN and non-CIN types based on the system of The Cancer Genome Atlas Research Group and 409 sequenced oncogenes and tumor suppressor genes. We identified the lipidomics profiles of the GC samples and samples of their adjacent noncancerous tissues by using liquid chromatography–mass spectrometry. Furthermore, we selected leading metabolites based on variable importance in projection scores of > 1.0 and P <0.05.RESULTS Twelve men and six women participated in this study; the participants had a median age of 67.5 years(range, 52–87 years) and were divided into CIN(n = 9)and non-CIN(n = 9) groups. The GC samples exhibited distinct profiles of lysophosphocholine, phosphocholine, phosphatidylethanolamine,phosphatidylinositol, phosphoserine, sphingomyelin, ceramide, and triglycerides compared with their adjacent noncancerous tissues. The glycerophospholipid levels(phosphocholine, phosphatidylethanolamine, and phosphatidylinositol)were 1.4-to 2.3-times higher in the CIN group compared with the non-CIN group(P < 0.05). Alterations in the glycerolipid and glycerophospholipid pathways indicated progression of GC toward CIN.CONCLUSION The lipidomics profiles of GC samples were distinct from those of their adjacent noncancerous tissues. CIN status of GC is primarily associated with downstream lipidomics in the glycerophospholipid pathway.
BACKGROUND Based on the breakthrough of genomics analysis, The Cancer Genome Atlas Research Group recently proposed an integrative genomic analysis, dividing gastric cancer(GC) into four subtypes, characterized by the chromosomal instability(CIN) status. However, the CIN status of GC is still vaguely characterized and lacking the valuable easy-to-use CIN markers to diagnosis in molecular and histological detection.AIM To explore the associations of CIN with downstream lipidomics profiles.METHODS We collected cancerous and noncancerous tissue samples from 18 patients with GC; the samples were divided into CIN and non-CIN types based on the system of The Cancer Genome Atlas Research Group and 409 sequenced oncogenes and tumor suppressor genes. We identified the lipidomics profiles of the GC samples and samples of their adjacent noncancerous tissues by using liquid chromatography–mass spectrometry. Furthermore, we selected leading metabolites based on variable importance in projection scores of > 1.0 and P <0.05.RESULTS Twelve men and six women participated in this study; the participants had a median age of 67.5 years(range, 52–87 years) and were divided into CIN(n = 9)and non-CIN(n = 9) groups. The GC samples exhibited distinct profiles of lysophosphocholine, phosphocholine, phosphatidylethanolamine,phosphatidylinositol, phosphoserine, sphingomyelin, ceramide, and triglycerides compared with their adjacent noncancerous tissues. The glycerophospholipid levels(phosphocholine, phosphatidylethanolamine, and phosphatidylinositol)were 1.4-to 2.3-times higher in the CIN group compared with the non-CIN group(P < 0.05). Alterations in the glycerolipid and glycerophospholipid pathways indicated progression of GC toward CIN.CONCLUSION The lipidomics profiles of GC samples were distinct from those of their adjacent noncancerous tissues. CIN status of GC is primarily associated with downstream lipidomics in the glycerophospholipid pathway.
引文
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13 Uehara T,Kikuchi H,Miyazaki S,Iino I,Setoguchi T,Hiramatsu Y,Ohta M,Kamiya K,Morita Y,Tanaka H,Baba S,Hayasaka T,Setou M,Konno H.Overexpression of Lysophosphatidylcholine Acyltransferase 1 and Concomitant Lipid Alterations in Gastric Cancer.Ann Surg Oncol 2016;23 Suppl 2:S206-S213[PMID:25752890 DOI:10.1245/s10434-015-4459-6]
14 Lamaziere A,Wolf C,Quinn PJ.Perturbations of lipid metabolism indexed by lipidomic biomarkers.Metabolites 2012;2:1-18[PMID:24957365 DOI:10.3390/metabo2010001]
15 Luo X,Cheng C,Tan Z,Li N,Tang M,Yang L,Cao Y.Emerging roles of lipid metabolism in cancer metastasis.Mol Cancer 2017;16:76[PMID:28399876 DOI:10.1186/s12943-017-0646-3]
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17 Folch J,Lees M,Sloane Stanley GH.A simple method for the isolation and purification of total lipides from animal tissues.J Biol Chem 1957;226:497-509[PMID:13428781]
18 Cajka T,Fiehn O.Increasing lipidomic coverage by selecting optimal mobile-phase modifiers in LC-MSof blood plasma.Metabolomics 2016;12:34-44[DOI:10.1007/s11306-015-0929-x]
19 Want EJ,Wilson ID,Gika H,Theodoridis G,Plumb RS,Shockcor J,Holmes E,Nicholson JK.Global metabolic profiling procedures for urine using UPLC-MS.Nat Protoc 2010;5:1005-1018[PMID:20448546 DOI:10.1038/nprot.2010.50]
20 Chong J,Soufan O,Li C,Caraus I,Li S,Bourque G,Wishart DS,Xia J.MetaboAnalyst 4.0:towards more transparent and integrative metabolomics analysis.Nucleic Acids Res 2018;46:W486-W494[PMID:29762782 DOI:10.1093/nar/gky310]
21 Fahy E,Subramaniam S,Murphy RC,Nishijima M,Raetz CR,Shimizu T,Spener F,van Meer G,Wakelam MJ,Dennis EA.Update of the LIPID MAPS comprehensive classification system for lipids.JLipid Res 2009;50 Suppl:S9-14[PMID:19098281 DOI:10.1194/jlr.R800095-JLR200]
22 Smith CA,O'Maille G,Want EJ,Qin C,Trauger SA,Brandon TR,Custodio DE,Abagyan R,Siuzdak G.METLIN:a metabolite mass spectral database.Ther Drug Monit 2005;27:747-751[PMID:16404815DOI:10.1097/01.ftd.0000179845.53213.39]
23 Chan AW,Gill RS,Schiller D,Sawyer MB.Potential role of metabolomics in diagnosis and surveillance of gastric cancer.World J Gastroenterol 2014;20:12874-12882[PMID:25278684 DOI:10.3748/wjg.v20.i36.12874]
24 Abbassi-Ghadi N,Kumar S,Huang J,Goldin R,Takats Z,Hanna GB.Metabolomic profiling of oesophago-gastric cancer:a systematic review.Eur J Cancer 2013;49:3625-3637[PMID:23896378DOI:10.1016/j.ejca.2013.07.004]
25 Ramachandran GK,Yong WP,Yeow CH.Identification of Gastric Cancer Biomarkers Using 1HNuclear Magnetic Resonance Spectrometry.PLoS One 2016;11:e0162222[PMID:27611679 DOI:10.1371/journal.pone.0162222]
26 Huang C,Freter C.Lipid metabolism,apoptosis and cancer therapy.Int J Mol Sci 2015;16:924-949[PMID:25561239 DOI:10.3390/ijms16010924]
27 Riquelme I,Saavedra K,Espinoza JA,Weber H,García P,Nervi B,Garrido M,Corvalán AH,Roa JC,Bizama C.Molecular classification of gastric cancer:Towards a pathway-driven targeted therapy.Oncotarget 2015;6:24750-24779[PMID:26267324 DOI:10.18632/oncotarget.4990]
28 Perrotti F,Rosa C,Cicalini I,Sacchetta P,Del Boccio P,Genovesi D,Pieragostino D.Advances in Lipidomics for Cancer Biomarkers Discovery.Int J Mol Sci 2016;17:E1992[PMID:27916803 DOI:10.3390/ijms17121992]
29 Shimizu D,Kanda M,Kodera Y.Review of recent molecular landscape knowledge of gastric cancer.Histol Histopathol 2018;33:11-26[PMID:28447336 DOI:10.14670/HH-11-898]
30 Lario S, Ramírez-Lázaro MJ, Sanjuan-Herráez D, Brunet-Vega A, Pericay C, Gombau L, Junquera F,Quintás G, Calvet X. Plasma sample based analysis of gastric cancer progression using targeted metabolomics. Sci Rep 2017; 7:17774[PMID:29259332 DOI:10.1038/s41598-017-17921-x]
2 Grabsch HI,Tan P.Gastric cancer pathology and underlying molecular mechanisms.Dig Surg 2013;30:150-158[PMID:23867592 DOI:10.1159/000350876]
3 Cancer Genome Atlas Research Network.Comprehensive molecular characterization of gastric adenocarcinoma.Nature 2014;513:202-209[PMID:25079317 DOI:10.1038/nature13480]
4 Rochfort S.Metabolomics reviewed:a new"omics"platform technology for systems biology and implications for natural products research.J Nat Prod 2005;68:1813-1820[PMID:16378385 DOI:10.1021/np050255w]
5 Strand MS,Lockhart AC,Fields RC.Genetics of Gastric Cancer.Surg Clin North Am 2017;97:345-370[PMID:28325191 DOI:10.1016/j.suc.2016.11.009]
6 Jayavelu ND,Bar NS.Metabolomic studies of human gastric cancer:review.World J Gastroenterol 2014;20:8092-8101[PMID:25009381 DOI:10.3748/wjg.v20.i25.8092]
7 Chan AW,Mercier P,Schiller D,Bailey R,Robbins S,Eurich DT,Sawyer MB,Broadhurst D.(1)H-NMR urinary metabolomic profiling for diagnosis of gastric cancer.Br J Cancer 2016;114:59-62[PMID:26645240 DOI:10.1038/bjc.2015.414]
8 Liang Q,Wang C,Li B.Metabolomic Analysis Using Liquid Chromatography/Mass Spectrometry for Gastric Cancer.Appl Biochem Biotechnol 2015;176:2170-2184[PMID:26088916 DOI:10.1007/s12010-015-1706-z]
9 Jung J,Jung Y,Bang EJ,Cho SI,Jang YJ,Kwak JM,Ryu DH,Park S,Hwang GS.Noninvasive diagnosis and evaluation of curative surgery for gastric cancer by using NMR-based metabolomic profiling.Ann Surg Oncol 2014;21 Suppl 4:S736-S742[PMID:25092158 DOI:10.1245/s10434-014-3886-0]
10 Yu L,Aa J,Xu J,Sun M,Qian S,Cheng L,Yang S,Shi R.Metabolomic phenotype of gastric cancer and precancerous stages based on gas chromatography time-of-flight mass spectrometry.J Gastroenterol Hepatol 2011;26:1290-1297[PMID:21443661 DOI:10.1111/j.1440-1746.2011.06724.x]
11 Wymann MP,Schneiter R.Lipid signalling in disease.Nat Rev Mol Cell Biol 2008;9:162-176[PMID:18216772 DOI:10.1038/nrm2335]
12 Guo S,Wang Y,Zhou D,Li Z.Significantly increased monounsaturated lipids relative to polyunsaturated lipids in six types of cancer microenvironment are observed by mass spectrometry imaging.Sci Rep 2014;4:5959[PMID:25091112 DOI:10.1038/srep05959]
13 Uehara T,Kikuchi H,Miyazaki S,Iino I,Setoguchi T,Hiramatsu Y,Ohta M,Kamiya K,Morita Y,Tanaka H,Baba S,Hayasaka T,Setou M,Konno H.Overexpression of Lysophosphatidylcholine Acyltransferase 1 and Concomitant Lipid Alterations in Gastric Cancer.Ann Surg Oncol 2016;23 Suppl 2:S206-S213[PMID:25752890 DOI:10.1245/s10434-015-4459-6]
14 Lamaziere A,Wolf C,Quinn PJ.Perturbations of lipid metabolism indexed by lipidomic biomarkers.Metabolites 2012;2:1-18[PMID:24957365 DOI:10.3390/metabo2010001]
15 Luo X,Cheng C,Tan Z,Li N,Tang M,Yang L,Cao Y.Emerging roles of lipid metabolism in cancer metastasis.Mol Cancer 2017;16:76[PMID:28399876 DOI:10.1186/s12943-017-0646-3]
16 Tsai CK,Yeh TS,Wu RC,Lai YC,Chiang MH,Lu KY,Hung CY,Ho HY,Cheng ML,Lin G.Metabolomic alterations and chromosomal instability status in gastric cancer.World J Gastroenterol 2018;24:3760-3769[PMID:30197481 DOI:10.3748/wjg.v24.i33.3760]
17 Folch J,Lees M,Sloane Stanley GH.A simple method for the isolation and purification of total lipides from animal tissues.J Biol Chem 1957;226:497-509[PMID:13428781]
18 Cajka T,Fiehn O.Increasing lipidomic coverage by selecting optimal mobile-phase modifiers in LC-MSof blood plasma.Metabolomics 2016;12:34-44[DOI:10.1007/s11306-015-0929-x]
19 Want EJ,Wilson ID,Gika H,Theodoridis G,Plumb RS,Shockcor J,Holmes E,Nicholson JK.Global metabolic profiling procedures for urine using UPLC-MS.Nat Protoc 2010;5:1005-1018[PMID:20448546 DOI:10.1038/nprot.2010.50]
20 Chong J,Soufan O,Li C,Caraus I,Li S,Bourque G,Wishart DS,Xia J.MetaboAnalyst 4.0:towards more transparent and integrative metabolomics analysis.Nucleic Acids Res 2018;46:W486-W494[PMID:29762782 DOI:10.1093/nar/gky310]
21 Fahy E,Subramaniam S,Murphy RC,Nishijima M,Raetz CR,Shimizu T,Spener F,van Meer G,Wakelam MJ,Dennis EA.Update of the LIPID MAPS comprehensive classification system for lipids.JLipid Res 2009;50 Suppl:S9-14[PMID:19098281 DOI:10.1194/jlr.R800095-JLR200]
22 Smith CA,O'Maille G,Want EJ,Qin C,Trauger SA,Brandon TR,Custodio DE,Abagyan R,Siuzdak G.METLIN:a metabolite mass spectral database.Ther Drug Monit 2005;27:747-751[PMID:16404815DOI:10.1097/01.ftd.0000179845.53213.39]
23 Chan AW,Gill RS,Schiller D,Sawyer MB.Potential role of metabolomics in diagnosis and surveillance of gastric cancer.World J Gastroenterol 2014;20:12874-12882[PMID:25278684 DOI:10.3748/wjg.v20.i36.12874]
24 Abbassi-Ghadi N,Kumar S,Huang J,Goldin R,Takats Z,Hanna GB.Metabolomic profiling of oesophago-gastric cancer:a systematic review.Eur J Cancer 2013;49:3625-3637[PMID:23896378DOI:10.1016/j.ejca.2013.07.004]
25 Ramachandran GK,Yong WP,Yeow CH.Identification of Gastric Cancer Biomarkers Using 1HNuclear Magnetic Resonance Spectrometry.PLoS One 2016;11:e0162222[PMID:27611679 DOI:10.1371/journal.pone.0162222]
26 Huang C,Freter C.Lipid metabolism,apoptosis and cancer therapy.Int J Mol Sci 2015;16:924-949[PMID:25561239 DOI:10.3390/ijms16010924]
27 Riquelme I,Saavedra K,Espinoza JA,Weber H,García P,Nervi B,Garrido M,Corvalán AH,Roa JC,Bizama C.Molecular classification of gastric cancer:Towards a pathway-driven targeted therapy.Oncotarget 2015;6:24750-24779[PMID:26267324 DOI:10.18632/oncotarget.4990]
28 Perrotti F,Rosa C,Cicalini I,Sacchetta P,Del Boccio P,Genovesi D,Pieragostino D.Advances in Lipidomics for Cancer Biomarkers Discovery.Int J Mol Sci 2016;17:E1992[PMID:27916803 DOI:10.3390/ijms17121992]
29 Shimizu D,Kanda M,Kodera Y.Review of recent molecular landscape knowledge of gastric cancer.Histol Histopathol 2018;33:11-26[PMID:28447336 DOI:10.14670/HH-11-898]
30 Lario S, Ramírez-Lázaro MJ, Sanjuan-Herráez D, Brunet-Vega A, Pericay C, Gombau L, Junquera F,Quintás G, Calvet X. Plasma sample based analysis of gastric cancer progression using targeted metabolomics. Sci Rep 2017; 7:17774[PMID:29259332 DOI:10.1038/s41598-017-17921-x]