谷胱甘肽过氧化物酶1在肝癌组织中的表达及其意义的生物信息学分析
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摘要
目的:通过生物信息学的方法分析谷胱甘肽过氧化物酶1(GPX1)在肝癌组织中的表达及意义。方法:从Ualcan数据库获取正常肝组织及原发性肝癌组织GPX1表达数据,在LinkedOmics中检索GPX1的共表达基因,并通过GO富集分析、KEGG通路分析确定这些基因的参与的生物学过程及功能,利用STRING数据库分析相关基因编码蛋白的互作网络。最后利用GEPIA数据库分析GPX1表达与肝癌患者预后的关系。结果:与正常肝组织比较,不同分期(IV期除外)、不同年龄患者肝癌组织中GPX1表达水平均明显升高,且男性肝癌患者肝癌组织中GPX1表达明显高于女性患者(均P<0.05)。GPX1共表达基因主要参与基因转录、翻译、蛋白泛素化、蛋白质磺酰化、mRNA稳定性调节、蛋白酶体复合体、线粒体翻译等分子生物学过程,并参与TGF-β、mTOR、WNT、MAPK、HIF-1α、NF-κB、VEGF、Notch等信号通路及各种癌症疾病通路。10个肝癌相关基因编码的蛋白与GPX1所编码的蛋白存在互作关系。GPX1高表达患者的总生存率、无病生存率均明显低于GPX1低表达患者(P=0.048、P=0.035)。结论:GPX1在肝癌组织中高表达,且与肝癌的发生、发展及预后密切相关,可以作为肝癌筛选、预后预测的标志物之一。
Objective: To analyze the expression of glutathione peroxidase 1(GPX1) in hepatocellular carcinoma(HCC) tissue and its significance by bioinformatics approaches. Methods: The expression data of GPX1 in normal lover tissue and HCC tissue were obtained in Ualcan database, the co-expressed genes of GPX1 were retrieved in LinkedOmics, and the biological processes and functions of these genes were determined by GO enrichment analysis and KEGG pathway analysis. Then, the interaction network of the proteins encoded by the relevant genes was analyzed by using STRING. Finally, the relationship between GPX1 expression and the prognosis of the HCC patients was analyzed based on GEPIA database.Results: Compared with normal liver tissue, the expression levels of GPX1 in HCC tissues from patients with different disease stages(except stage IV) or different ages were significantly increased, further the GPX1 expression levels in HCC tissues from male patients were significantly higher than that from female patients(all P<0.05). The co-expressed genes of GPX1 mainly participated in the biochemical processes such as the transcription and translation of genes, ubiquitination and sulfonylation of proteins, regulation of mRNA stability, and translation of proteasome complex and mitochondria, and were involved in the TGF-β, mTOR, WNT, MAPK, HIF-1α, NF-κB, VEGF and Notch pathways as well as cancer-related pathways. Ten proteins encoded by HCC-related genes were found having interactions with GPX1 encoded protein. The overall survival rates and disease-free survival rates in HCC patients with high GPX1 expression were significantly lower than those in HCC patients with low GPX1 expression(P=0.048, P=0.035).Conclusion: GPX1 expression is increased in HCC tissue, and its expression is closely related to the occurrence and development as well as prognosis of HCC. So, it can be used as a marker for screening and prognosis estimation of HCC.
Objective: To analyze the expression of glutathione peroxidase 1(GPX1) in hepatocellular carcinoma(HCC) tissue and its significance by bioinformatics approaches. Methods: The expression data of GPX1 in normal lover tissue and HCC tissue were obtained in Ualcan database, the co-expressed genes of GPX1 were retrieved in LinkedOmics, and the biological processes and functions of these genes were determined by GO enrichment analysis and KEGG pathway analysis. Then, the interaction network of the proteins encoded by the relevant genes was analyzed by using STRING. Finally, the relationship between GPX1 expression and the prognosis of the HCC patients was analyzed based on GEPIA database.Results: Compared with normal liver tissue, the expression levels of GPX1 in HCC tissues from patients with different disease stages(except stage IV) or different ages were significantly increased, further the GPX1 expression levels in HCC tissues from male patients were significantly higher than that from female patients(all P<0.05). The co-expressed genes of GPX1 mainly participated in the biochemical processes such as the transcription and translation of genes, ubiquitination and sulfonylation of proteins, regulation of mRNA stability, and translation of proteasome complex and mitochondria, and were involved in the TGF-β, mTOR, WNT, MAPK, HIF-1α, NF-κB, VEGF and Notch pathways as well as cancer-related pathways. Ten proteins encoded by HCC-related genes were found having interactions with GPX1 encoded protein. The overall survival rates and disease-free survival rates in HCC patients with high GPX1 expression were significantly lower than those in HCC patients with low GPX1 expression(P=0.048, P=0.035).Conclusion: GPX1 expression is increased in HCC tissue, and its expression is closely related to the occurrence and development as well as prognosis of HCC. So, it can be used as a marker for screening and prognosis estimation of HCC.
引文
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[2]李相成,王宏伟,李长贤,等.肝癌综合治疗的现状与展望[J].中华消化外科杂志,2018,17(5):433-436.doi:10.3760/cma.j.issn.1673-9752.2018.05.004.Li XC,Wang HW,Li CX,et al.Present situation and prospect of comprehensive treatment of hepatocellular carcinoma[J].Chinese Journal of Digestive Surgery,2018,17(5):433-436.doi:10.3760/cma.j.issn.1673-9752.2018.05.004.
[3]陈世发,赵礼金.肝癌发生发展机制的研究进展及其治疗现状[J].中国普通外科杂志,2018,27(7):910-923.doi:10.3978/j.issn.1005-6947.2018.07.016.Chen SF,Zhao LJ.Research progress on mechanisms for occurrence of liver cancer and its treatment status[J].Chinese Journal of General Surgery,2018,27(7):910-923.doi:10.3978/j.issn.1005-6947.2018.07.016.
[4]Riordan SM,Williams R.Medical management of hepatocellular carcinoma[J].Methods Mol Med,2000,45:21-34.doi:10.1385/1-59259-079-9:21.
[5]Król MB,Galicki M,Gre?ner P,et al.The ESR1 and GPX1 gene expression level in human malignant and non-malignant breast tissues[J].Acta Biochim Pol,2018,65(1):51-57.doi:10.18388/abp.2016_1425.Epub 2018 Mar 15.
[6]Miar A,Hevia D,Mu?oz-Cimadevilla H,et al.Manganese superoxide dismutase(SOD2/MnSOD)/catalase and SOD2/GPx1ratios as biomarkers for tumor progression and metastasis in prostate,colon,and lung cancer[J].Free Radic Biol Med,2015,85:45-55.doi:10.1016/j.freeradbiomed.2015.04.001.
[7]Arsova-Sarafinovska Z,Matevska N,Eken A,et al.Glutathione peroxidase 1(GPX1)genetic polymorphism,erythrocyte GPXactivity,and prostate cancer risk[J].Int Urol Nephrol,2009,41(1):63-70.doi:10.1007/s11255-008-9407-y.
[8]Ahwach SM,Thomas M,Onstead-Haas L,et al.The glutathione mimic ebselen inhibits oxidative stress but not endoplasmic reticulum stress in endothelial cells[J].Life Sci,2015,134:9-15.doi:10.1016/j.lfs.2015.05.004.
[9]Brigelius-FlohéR,Maiorino M.Glutathione peroxidases[J].Biochim Biophys Acta,2013,1830(5):3289-3303.doi:10.1016/j.bbagen.2012.11.020.
[10]Tan SM,Stefanovic N,Tan G,et al.Lack of the antioxidant glutathione peroxidase-1(GPx1)exacerbates retinopathy of prematurity in mice[J].Invest Ophthalmol Vis Sci,2013,54(1):555-562.doi:10.1167/iovs.12-10685.
[11]Kang SW,Lee S,Lee EK.ROS and energy metabolism in cancer cells:alliance for fast growth[J].Arch Pharm Res,2015,38(3):338-345.doi:10.1007/s12272-015-0550-6.
[12]Li WJ,Nie SP,Yao YF,et al.Ganoderma atrum Polysaccharide Ameliorates Hyperglycemia-Induced Endothelial Cell Death via a Mitochondria-ROS Pathway[J].J Agric Food Chem,2015,63(37):8182-8191.doi:10.1021/acs.jafc.5b03462.
[13]Vital P,Castro P,Ittmann M.Oxidative stress promotes benign prostatic hyperplasia[J].Prostate,2016,76(1):58-67.doi:10.1002/pros.23100.
[14]Basu S,De D,Dev Khanna H,et al.Lipid peroxidation,DNA damage and total antioxidant status in neonatal hyperbilirubinemia[J].J Perinatol,2014,34(7):519-523.doi:10.1038/jp.2014.45.
[15]Zhao H,Tang J,Xu J,et al.Selenoprotein Genes Exhibit Differential Expression Patterns Between Hepatoma HepG2 and Normal Hepatocytes LO2 Cell Lines[J].Biol Trace Elem Res,2015,167(2):236-241.doi:10.1007/s12011-015-0323-6.
[16]Su S,He K,Li J,et al.Genetic polymorphisms in antioxidant enzyme genes and susceptibility to hepatocellular carcinoma in Chinese population:a case-control study[J].Tumour Biol,2015,36(6):4627-4632.doi:10.1007/s13277-015-3110-2.
[17]汪晋,马金良.肝癌预后相关影响因素[J].中国普通外科杂志,2015,24(2):270-274.doi:10.3978/j.issn.1005-6947.2015.02.022.Wang J,Ma JL.Prognostic factors in liver cancer[J].Chinese Journal of General Surgery,2015,24(2):270-274.doi:10.3978/j.issn.1005-6947.2015.02.022.
[18]Katz LH,Likhter M,Jogunoori W,et al.TGF-βsignaling in liver and gastrointestinal cancers[J].Cancer Lett,2016,379(2):166-172.doi:10.1016/j.canlet.2016.03.033.
[19]刘磊,韩文豪,陈涛,等.晚期肝癌患者血清转化生长因子β1在肝动脉化疗栓塞术前后变化及对预后的意义[J].中国普通外科杂志,2018,27(1):94-100.doi:10.3978/j.issn.1005-6947.2018.01.015.Liu L,Han WH,Chen T,et al.Changes in serum transforming growth factorβ1 level in patients with advanced primary hepatic carcinoma before and after transcatheter arterial chemoembolization and its prognostic significance[J].Chinese Journal of General Surgery,2018,27(1):94-100.doi:10.3978/j.issn.1005-6947.2018.01.015.
[20]Delire B,St?rkel P.The Ras/MAPK pathway and hepatocarcinoma:pathogenesis and therapeutic implications[J].Eur J Clin Invest,2015,45(6):609-623.doi:10.1111/eci.12441.
[21]He G,Karin M.NF-κB and STAT3-key players in liver inflammation and cancer[J].Cell Res,2011,21(1):159-168.doi:10.1038/cr.2010.183.
[22]李艳,黄祥,伊航,等.Smad4和NF-κBp65蛋白在肝癌组织中的表达及意义[J].中国普通外科杂志,2018,27(7):934-938.doi:10.3978/j.issn.1005-6947.2018.07.019.Li Y,Huang X,Yin H,et al.Expressions of Smad4 and NF-κBp65proteins in liver cancer tissue and their significance[J].Chinese Journal of General Surgery,2018,27(7):934-938.doi:10.3978/j.issn.1005-6947.2018.07.019.
[23]Guo LY,Zhu P,Jin XP.Association between the expression of HIF-1αand VEGF and prognostic implications in primary liver cancer[J].Genet Mol Res,2016,15(2).doi:10.4238/gmr.15028107.
[24]Tanimizu N,Miyajima A.Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors[J].J Cell Sci,2004,117(Pt 15):3165-3174.doi:10.1242/jcs.01169.
[25]Zhou L,Zhang N,Li QJ,et al.Associations between high levels of Notch1 expression and high invasion and poor overall survival in hepatocellular carcinoma[J].Tumour Biol,2013,34(1):543-553.doi:10.1007/s13277-012-0580-3.