Identification of pathogenic genes of pterygium based on the Gene Expression Omnibus database
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摘要
AIM: To identify the pathogenic genes in pterygium.METHODS: We obtained m RNA expression profiles from the Gene Expression Omnibus database(GEO) to identify differentially expressed genes(DEGs) between pterygium tissues and normal conjunctiva tissues. The Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway analysis, protein-protein interaction(PPI) network and transcription factors(TFs)-target gene regulatory network was performed to understand the function of DEGs. The expression of selected DEGs were validated by the quantitative real-time polymerase chain reaction(qRT-PCR).RESULTS: A total of 557 DEGs were identified between pterygium and normal individual. In PPI network, several genes were with high degrees such as FN1, KPNB1, DDB1, NF2 and BUB3. SSH1, PRSS23, LRP5L, MEOX1, RBM14, ABCA1, JOSD1, KRT6 A and UPK1B were the most downstream genes regulated by TFs. q RT-PCR results showed that FN1, PRSS23, ABCA1, KRT6A, ECT2 and SPARC were significantly up-regulated in pterygium and MEOX1 and MMP3 were also up-regulated with no significance, which was consistent with the our integrated analysis. CONCLUSION: The deregulated genes might be involved in the pathology of pterygium and could be used as treatment targets for pterygium.
AIM: To identify the pathogenic genes in pterygium.METHODS: We obtained m RNA expression profiles from the Gene Expression Omnibus database(GEO) to identify differentially expressed genes(DEGs) between pterygium tissues and normal conjunctiva tissues. The Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway analysis, protein-protein interaction(PPI) network and transcription factors(TFs)-target gene regulatory network was performed to understand the function of DEGs. The expression of selected DEGs were validated by the quantitative real-time polymerase chain reaction(qRT-PCR).RESULTS: A total of 557 DEGs were identified between pterygium and normal individual. In PPI network, several genes were with high degrees such as FN1, KPNB1, DDB1, NF2 and BUB3. SSH1, PRSS23, LRP5L, MEOX1, RBM14, ABCA1, JOSD1, KRT6 A and UPK1B were the most downstream genes regulated by TFs. q RT-PCR results showed that FN1, PRSS23, ABCA1, KRT6A, ECT2 and SPARC were significantly up-regulated in pterygium and MEOX1 and MMP3 were also up-regulated with no significance, which was consistent with the our integrated analysis. CONCLUSION: The deregulated genes might be involved in the pathology of pterygium and could be used as treatment targets for pterygium.
AIM: To identify the pathogenic genes in pterygium.METHODS: We obtained m RNA expression profiles from the Gene Expression Omnibus database(GEO) to identify differentially expressed genes(DEGs) between pterygium tissues and normal conjunctiva tissues. The Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway analysis, protein-protein interaction(PPI) network and transcription factors(TFs)-target gene regulatory network was performed to understand the function of DEGs. The expression of selected DEGs were validated by the quantitative real-time polymerase chain reaction(qRT-PCR).RESULTS: A total of 557 DEGs were identified between pterygium and normal individual. In PPI network, several genes were with high degrees such as FN1, KPNB1, DDB1, NF2 and BUB3. SSH1, PRSS23, LRP5L, MEOX1, RBM14, ABCA1, JOSD1, KRT6 A and UPK1B were the most downstream genes regulated by TFs. q RT-PCR results showed that FN1, PRSS23, ABCA1, KRT6A, ECT2 and SPARC were significantly up-regulated in pterygium and MEOX1 and MMP3 were also up-regulated with no significance, which was consistent with the our integrated analysis. CONCLUSION: The deregulated genes might be involved in the pathology of pterygium and could be used as treatment targets for pterygium.
引文
1 Seet LF,Tong L,Su R,Wong TT.Involvement of SPARC and MMP-3 in the pathogenesis of human pterygium.Invest Ophthalmol Vis Sci 2012;53(2):587-595.
2 Chui J,Di Girolamo N,Wakefield D,Coroneo MT.The pathogenesis of pterygium:current concepts and their therapeutic implications.Ocul Surf2008;6(1):24-43.
3 Luthra R,Nemesure BB,Wu SY,Xie SH,Leske MC,Barbados Eye Studies Group.Frequency and risk factors for pterygium in the Barbados Eye Study.Arch Ophthalmol 2001;119(12):1827-1832.
4 Di Girolamo N,Chui J,Coroneo MT,Wakefield D.Pathogenesis of pterygia:role of cytokines,growth factors,and matrix metalloproteinases.Prog Retin Eye Res 2004;23(2):195-228.
5 Sánchez-Thorin JC,Rocha G,Yelin JB.Meta-analysis on the recurrence rates after bare sclera resection with and without mitomycin C use and conjunctival autograft placement in surgery for primary pterygium.Br JOphthalmol 1998;82(6):661-665.
6 Hirst LW.The treatment of pterygium.Surv Ophthalmol 2003;48(2):145-180.
7 Wong YW,Chew J,Yang H,Tan DT,Beuerman R.Expression of insulin-like growth factor binding protein-3 in pterygium tissue.Br JOphthalmol 2006;90(6):769-772.
8 Guo Y,Cepurna WO,Dyck JA,Doser TA,Johnson EC,Morrison JC.Retinal cell responses to elevated intraocular pressure:a gene array comparison between the whole retina and retinal ganglion cell layer.Invest Ophthalmol Vis Sci 2010;51(6):3003-3018.
9 Engelsvold DH,Utheim TP,Olstad OK,Gonzalez P,Eidet JR,Lyberg T,Tr?seid AM,Dartt DA,Raeder S.mi RNA and m RNA expression profiling identifies members of the mi R-200 family as potential regulators of epithelial-mesenchymal transition in pterygium.Exp Eye Res2013;115:189-198.
10 Oliver VF,Jaffe AE,Song J,Wang G,Zhang P,Branham KE,Swaroop A,Eberhart CG,Zack DJ,Qian J,Merbs SL.Differential DNA methylation identified in the blood and retina of AMD patients.Epigenetics 2015;10(8):698-707.
11 Johnson EC,Jia L,Cepurna WO,Doser TA,Morrison JC.Global changes in optic nerve head gene expression after exposure to elevated intraocular pressure in a rat glaucoma model.Invest Ophthalmol Vis Sci2007;48(7):3161-3177.
12 Suarez MJ,Rivera-Michlig R,Dubovy S,Rodriguez FJ.Clinicopathological features of ophthalmic neoplasms arising in the setting of xeroderma pigmentosum.Ocul Oncol Pathol 2015;2(2):112-121.
13 Chan CC,Koch CA,Kaiser-Kupfer MI,Parry DM,Gutmann DH,Zhuang ZP,Vortmeyer AO.Loss of heterozygosity for the NF2 gene in retinal and optic nerve lesions of patients with neurofibromatosis 2.JPathol 2002;198(1):14-20.
14 Ren G,Li H,Qiao W,Shen H,Zhuang Y,Shao T,Hu H,Zhang X.Possible association of killer cell immunoglobulin-like receptor genotypes and haplotypes with dry eye disease in a Han Chinese population.Mol Vis2015;21:948-954.
15 Bharadwaj AS,Appukuttan B,Wilmarth PA,Pan Y,Stempel AJ,Chipps TJ,Benedetti EE,Zamora DO,Choi D,David LL,Smith JR.Role of the retinal vascular endothelial cell in ocular disease.Prog Retin Eye Res 2013;32:102-180.
16 Wang Q,Marcucci F,Cerullo I,Mason C.Ipsilateral and contralateral retinal ganglion cells express distinct genes during decussation at the optic chiasm.e Neuro 2016;3(6):ENEURO.0169-ENEURO.0116.2016.
17 Jiang B,Harper MM,Kecova H,Adamus G,Kardon RH,Grozdanic SD,Kuehn MH.Neuroinflammation in advanced canine glaucoma.Mol Vis 2010;16:2092-2108.
18 Yazar S,Mishra A,Ang W,Kearns LS,Mountain JA,Pennell C,Montgomery GW,Young TL,Hammond CJ,Macgregor S,Mackey DA,Hewitt AW.Interrogation of the platelet-derived growth factor receptor alpha locus and corneal astigmatism in Australians of Northern European ancestry:results of a genome-wide association study.Mol Vis2013;19:1238-1246.
19 Skuntz S,Mankoo B,Nguyen MT,Hustert E,Nakayama A,TournierLasserve E,Wright CV,Pachnis V,Bharti K,Arnheiter H.Lack of the mesodermal homeodomain protein MEOX1 disrupts sclerotome polarity and leads to a remodeling of the cranio-cervical joints of the axial skeleton.Dev Biol 2009;332(2):383-395.
20 Brooks-Wilson A,Marcil M,Clee SM,Zhang LH,Roomp K,van Dam M,Yu L,Brewer C,Collins JA,Molhuizen HO,Loubser O,Ouelette BF,Fichter K,Ashbourne-Excoffon KJ,Sensen CW,Scherer S,Mott S,Denis M,Martindale D,Frohlich J,Morgan K,Koop B,Pimstone S,Kastelein JJ,Genest J Jr,Hayden MR.Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.Nat Genet 1999;22(4):336-345.
21 Cvekl A,Wang WL.Retinoic acid signaling in mammalian eye development.Exp Eye Res 2009;89(3):280-291.
22 Chen W,Stambolian D,Edwards AO,et al.Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration.Proc Natl Acad Sci US A 2010;107(16):7401-7406.
23 Tong L,Chew J,Yang H,Ang LP,Tan DT,Beuerman RW.Distinct gene subsets in pterygia formation and recurrence:dissecting complex biological phenomenon using genome wide expression data.BMC Med Genomics 2009;2:14.
24 Lee JG,Heur M.Interleukin-1β-induced Wnt5a enhances human corneal endothelial cell migration through regulation of Cdc42 and Rho A.Molecular Cell Biol 2014;34(18):3535-3545.
25 Khundakar AA,Hanson PS,Erskine D,et al.Analysis of primary visual cortex in dementia with Lewy bodies indicates GABAergic involvement associated with recurrent complex visual hallucinations.Acta Neuropathol Commun 2016;4:66.
26 Adachi W,Okubo K,Kinoshita S.Human uroplakin Ib in ocular surface epithelium.Invest Ophthalmol Vis Sci 2000;41(10):2900-2905.
27 Houston SK,Pina Y,Clarke J,Koru-Sengul T,Scott WK,Nathanson L,Schefler AC,Murray TG.Regional and temporal differences in gene expression of LH(BETA)T(AG)retinoblastoma tumors.Invest Ophthalmol Vis Sci 2011;52(8):5359-5368.
28 Sano M,Genkai N,Yajima N,Tsuchiya N,Homma J,Tanaka R,Miki T,Yamanaka R.Expression level of ECT2 proto-oncogene correlates with prognosis in glioma patients.Oncol Rep 2006;16(5):1093-1098.
29 Nalini V,Segu R,Deepa PR,Khetan V,Vasudevan M,Krishnakumar S.Molecular insights on post-chemotherapy retinoblastoma by microarray gene expression analysis.Bioinform Biol Insights 2013;7:289-306.
30 Greco D,Vellonen KS,Turner HC,H?kli M,Tervo T,Auvinen P,Wolosin JM,Urtti A.Gene expression analysis in SV-40 immortalized human corneal epithelial cells cultured with an air-liquid interface.Mol Vis 2010;16:2109-2120.
31 Di Girolamo N,Mc Cluskey P,Lloyd A,Coroneo MT,Wakefield D.Expression of MMPs and TIMPs in human pterygia and cultured pterygium epithelial cells.Invest Ophthalmol Vis Sci 2000;41(3):671-679.
32 Bradshaw AD.The role of SPARC in extracellular matrix assembly.JCell Commun Signal 2009;3(3-4):239-246.
2 Chui J,Di Girolamo N,Wakefield D,Coroneo MT.The pathogenesis of pterygium:current concepts and their therapeutic implications.Ocul Surf2008;6(1):24-43.
3 Luthra R,Nemesure BB,Wu SY,Xie SH,Leske MC,Barbados Eye Studies Group.Frequency and risk factors for pterygium in the Barbados Eye Study.Arch Ophthalmol 2001;119(12):1827-1832.
4 Di Girolamo N,Chui J,Coroneo MT,Wakefield D.Pathogenesis of pterygia:role of cytokines,growth factors,and matrix metalloproteinases.Prog Retin Eye Res 2004;23(2):195-228.
5 Sánchez-Thorin JC,Rocha G,Yelin JB.Meta-analysis on the recurrence rates after bare sclera resection with and without mitomycin C use and conjunctival autograft placement in surgery for primary pterygium.Br JOphthalmol 1998;82(6):661-665.
6 Hirst LW.The treatment of pterygium.Surv Ophthalmol 2003;48(2):145-180.
7 Wong YW,Chew J,Yang H,Tan DT,Beuerman R.Expression of insulin-like growth factor binding protein-3 in pterygium tissue.Br JOphthalmol 2006;90(6):769-772.
8 Guo Y,Cepurna WO,Dyck JA,Doser TA,Johnson EC,Morrison JC.Retinal cell responses to elevated intraocular pressure:a gene array comparison between the whole retina and retinal ganglion cell layer.Invest Ophthalmol Vis Sci 2010;51(6):3003-3018.
9 Engelsvold DH,Utheim TP,Olstad OK,Gonzalez P,Eidet JR,Lyberg T,Tr?seid AM,Dartt DA,Raeder S.mi RNA and m RNA expression profiling identifies members of the mi R-200 family as potential regulators of epithelial-mesenchymal transition in pterygium.Exp Eye Res2013;115:189-198.
10 Oliver VF,Jaffe AE,Song J,Wang G,Zhang P,Branham KE,Swaroop A,Eberhart CG,Zack DJ,Qian J,Merbs SL.Differential DNA methylation identified in the blood and retina of AMD patients.Epigenetics 2015;10(8):698-707.
11 Johnson EC,Jia L,Cepurna WO,Doser TA,Morrison JC.Global changes in optic nerve head gene expression after exposure to elevated intraocular pressure in a rat glaucoma model.Invest Ophthalmol Vis Sci2007;48(7):3161-3177.
12 Suarez MJ,Rivera-Michlig R,Dubovy S,Rodriguez FJ.Clinicopathological features of ophthalmic neoplasms arising in the setting of xeroderma pigmentosum.Ocul Oncol Pathol 2015;2(2):112-121.
13 Chan CC,Koch CA,Kaiser-Kupfer MI,Parry DM,Gutmann DH,Zhuang ZP,Vortmeyer AO.Loss of heterozygosity for the NF2 gene in retinal and optic nerve lesions of patients with neurofibromatosis 2.JPathol 2002;198(1):14-20.
14 Ren G,Li H,Qiao W,Shen H,Zhuang Y,Shao T,Hu H,Zhang X.Possible association of killer cell immunoglobulin-like receptor genotypes and haplotypes with dry eye disease in a Han Chinese population.Mol Vis2015;21:948-954.
15 Bharadwaj AS,Appukuttan B,Wilmarth PA,Pan Y,Stempel AJ,Chipps TJ,Benedetti EE,Zamora DO,Choi D,David LL,Smith JR.Role of the retinal vascular endothelial cell in ocular disease.Prog Retin Eye Res 2013;32:102-180.
16 Wang Q,Marcucci F,Cerullo I,Mason C.Ipsilateral and contralateral retinal ganglion cells express distinct genes during decussation at the optic chiasm.e Neuro 2016;3(6):ENEURO.0169-ENEURO.0116.2016.
17 Jiang B,Harper MM,Kecova H,Adamus G,Kardon RH,Grozdanic SD,Kuehn MH.Neuroinflammation in advanced canine glaucoma.Mol Vis 2010;16:2092-2108.
18 Yazar S,Mishra A,Ang W,Kearns LS,Mountain JA,Pennell C,Montgomery GW,Young TL,Hammond CJ,Macgregor S,Mackey DA,Hewitt AW.Interrogation of the platelet-derived growth factor receptor alpha locus and corneal astigmatism in Australians of Northern European ancestry:results of a genome-wide association study.Mol Vis2013;19:1238-1246.
19 Skuntz S,Mankoo B,Nguyen MT,Hustert E,Nakayama A,TournierLasserve E,Wright CV,Pachnis V,Bharti K,Arnheiter H.Lack of the mesodermal homeodomain protein MEOX1 disrupts sclerotome polarity and leads to a remodeling of the cranio-cervical joints of the axial skeleton.Dev Biol 2009;332(2):383-395.
20 Brooks-Wilson A,Marcil M,Clee SM,Zhang LH,Roomp K,van Dam M,Yu L,Brewer C,Collins JA,Molhuizen HO,Loubser O,Ouelette BF,Fichter K,Ashbourne-Excoffon KJ,Sensen CW,Scherer S,Mott S,Denis M,Martindale D,Frohlich J,Morgan K,Koop B,Pimstone S,Kastelein JJ,Genest J Jr,Hayden MR.Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.Nat Genet 1999;22(4):336-345.
21 Cvekl A,Wang WL.Retinoic acid signaling in mammalian eye development.Exp Eye Res 2009;89(3):280-291.
22 Chen W,Stambolian D,Edwards AO,et al.Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration.Proc Natl Acad Sci US A 2010;107(16):7401-7406.
23 Tong L,Chew J,Yang H,Ang LP,Tan DT,Beuerman RW.Distinct gene subsets in pterygia formation and recurrence:dissecting complex biological phenomenon using genome wide expression data.BMC Med Genomics 2009;2:14.
24 Lee JG,Heur M.Interleukin-1β-induced Wnt5a enhances human corneal endothelial cell migration through regulation of Cdc42 and Rho A.Molecular Cell Biol 2014;34(18):3535-3545.
25 Khundakar AA,Hanson PS,Erskine D,et al.Analysis of primary visual cortex in dementia with Lewy bodies indicates GABAergic involvement associated with recurrent complex visual hallucinations.Acta Neuropathol Commun 2016;4:66.
26 Adachi W,Okubo K,Kinoshita S.Human uroplakin Ib in ocular surface epithelium.Invest Ophthalmol Vis Sci 2000;41(10):2900-2905.
27 Houston SK,Pina Y,Clarke J,Koru-Sengul T,Scott WK,Nathanson L,Schefler AC,Murray TG.Regional and temporal differences in gene expression of LH(BETA)T(AG)retinoblastoma tumors.Invest Ophthalmol Vis Sci 2011;52(8):5359-5368.
28 Sano M,Genkai N,Yajima N,Tsuchiya N,Homma J,Tanaka R,Miki T,Yamanaka R.Expression level of ECT2 proto-oncogene correlates with prognosis in glioma patients.Oncol Rep 2006;16(5):1093-1098.
29 Nalini V,Segu R,Deepa PR,Khetan V,Vasudevan M,Krishnakumar S.Molecular insights on post-chemotherapy retinoblastoma by microarray gene expression analysis.Bioinform Biol Insights 2013;7:289-306.
30 Greco D,Vellonen KS,Turner HC,H?kli M,Tervo T,Auvinen P,Wolosin JM,Urtti A.Gene expression analysis in SV-40 immortalized human corneal epithelial cells cultured with an air-liquid interface.Mol Vis 2010;16:2109-2120.
31 Di Girolamo N,Mc Cluskey P,Lloyd A,Coroneo MT,Wakefield D.Expression of MMPs and TIMPs in human pterygia and cultured pterygium epithelial cells.Invest Ophthalmol Vis Sci 2000;41(3):671-679.
32 Bradshaw AD.The role of SPARC in extracellular matrix assembly.JCell Commun Signal 2009;3(3-4):239-246.