PTEN和mTOR蛋白在IDH1基因分型胶质母细胞瘤及P13K/Akt/mTOR信号通路中的表达及其相关性
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摘要
目的研究P13K/Akt/mTOR信号通路中PTEN和mTOR蛋白在IDH1基因分型-突变型与野生型胶质母细胞瘤中的表达及意义。方法采用免疫组化方法检测胶质母细胞瘤手术后组织标本共52例(其中IDH1突变型胶质母细胞瘤10例,IDH1野生型胶质母细胞瘤42例),检测PTEN和mTOR蛋白在这两种不同基因分型胶质母细胞瘤中的表达情况及相关性。结果PTEN蛋白在IDH1突变型与野生型胶质母细胞瘤的表达率分别为20.00%(2/10)和73.81%(31/42),mTOR蛋白的表达率分别为70.00%(7/10)及35.71%(15/42),PTEN和mTOR蛋白在IDH1两种基因分型的胶质母细胞瘤的表达差异均有统计学意义(P<0.01或P<0.05)。PTEN和mTOR的表达呈负相关关系(r=-0.724,P<0.01)。结论 PI3K/AKT/mTOR信号转导通路中两个位点调节因子PTEN及mTOR在IDH1突变型与野生型GBM中分别表达降低及增高,且两种蛋白表达呈负相关的关系,提示PTEN和mTOR在IDH1突变型与野生型胶质母细胞瘤的分子通路中扮演着重要的调控作用。
Objective To investigate the expression and significance of PTEN and mTOR proteins in IDH1 genotype-mutant and wild-type glioblastoma in P13 K/Akt/mTOR signaling pathway. Methods Fiftytwo post-operative tissue specimens(including 10 cases of IDH1 mutant type glioblastoma and 42 cases of IDH1 wild type glioblastoma)from patients with glioblastoma were determined by immunohistochemical method so as to detect the expression and correlation of PTEN and mTOR proteins in these two different genotyping glioblastomas. Results The expression rates of PTEN protein in IDH1 mutant and wild-type glioblastoma were 20.00%(2/10)and 73.81%(31/42)respectively.The expression rates of mTOR protein were 70.00%(7/10)and 35.71%(15/42)respectively.The expression of PTEN and mTOR protein in glioblastoma with two genotypes of IDH1 were significantly different(P <0.01 or P <0.05).There was a negative correlation between the expression of PTEN and mTOR(r =-0.724,P <0.01). Conclusion The expressions of PTEN and mTOR in the PI3 K/AKT/mTOR signal transduction pathway are respectively decreased and increased in IDH1 mutant and wild-type glioblastoma,and the PTEN expression has negative correlation with mTOR expression,suggesting that PTEN and mTOR play an important role in the regulation of molecular pathways of IDH1 mutant and wild type glioblastoma.
Objective To investigate the expression and significance of PTEN and mTOR proteins in IDH1 genotype-mutant and wild-type glioblastoma in P13 K/Akt/mTOR signaling pathway. Methods Fiftytwo post-operative tissue specimens(including 10 cases of IDH1 mutant type glioblastoma and 42 cases of IDH1 wild type glioblastoma)from patients with glioblastoma were determined by immunohistochemical method so as to detect the expression and correlation of PTEN and mTOR proteins in these two different genotyping glioblastomas. Results The expression rates of PTEN protein in IDH1 mutant and wild-type glioblastoma were 20.00%(2/10)and 73.81%(31/42)respectively.The expression rates of mTOR protein were 70.00%(7/10)and 35.71%(15/42)respectively.The expression of PTEN and mTOR protein in glioblastoma with two genotypes of IDH1 were significantly different(P <0.01 or P <0.05).There was a negative correlation between the expression of PTEN and mTOR(r =-0.724,P <0.01). Conclusion The expressions of PTEN and mTOR in the PI3 K/AKT/mTOR signal transduction pathway are respectively decreased and increased in IDH1 mutant and wild-type glioblastoma,and the PTEN expression has negative correlation with mTOR expression,suggesting that PTEN and mTOR play an important role in the regulation of molecular pathways of IDH1 mutant and wild type glioblastoma.
引文
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[2]《中国中枢神经系统胶质瘤诊断和治疗指南》编写组.中国中枢神经系统胶质瘤诊断与治疗指南(2015)[J].中华医学杂志,2016,96(7):485-509.
[3]Stupp R,Hegi ME,Mason WP,et al.Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phaseⅢstudy:5-year analysis of the EORTCNCIC trial[J].Lancet Oncol,2009,10(5):459-466.
[4]Toedt G,Barbus S,Wolter M,et al.Molecular signatures classify astrocytic gliomas by IDH1 mutation status[J].Int J Cancer,2011,128(5):1095-1103.
[5]李智.2016版世界卫生组织中枢神经系统肿瘤分类实践解读Ⅰ(胶质源性肿瘤部分)[J].广东医学,2017:38(1):3-8.
[6]Alexander BM,Mehta MP.Role of isocitrate dehydrogenase in glioma[J].Expert Rev Neurother,2011,11(10):1399-1409.
[7]Hartmann C,Meyer J,Balss J,et al.Type and frequency of IDH1and IDH2mutations are related to astrocytic and oligodendroglial differentiation and age:a study of 1,010diffuse gliomas[J].Acta Neuropathol,2009,118(4):469-474.
[8]Yan H,Parsons DW,Jin G,et al.IDH1and IDH2mutations in gliomas[J].N Engl J Med,2009,360(8):765-773.
[8]Gorovets D,Kannan K,Shen R,et al.IDH mutation and neuroglial developmental features define clinically distinct subclasses of lower grade diffuse astrocytic glioma[J].Clin Cancer Res,2012,18(9):2490-2501.
[9]Parsons DW,Jones S,Zhang X,et al.An integrated genomic analysis of human glioblastoma multiforme[J].Science,2008,321(5897):1807-1812.
[11]Louis DN,Perry A,Reifenberger G,et al.The 2016World Health Organization classification of tumors of the central nervous system:a summary[J].Acta Neuropathol,2016,131(6):803-820.
[12]Chan SM,Weng AP,Tibshirani R,et al.Notch signals positively regulate activity of the mTOR pathway in Tcell acute lymphoblastic leukemia[J].Blood,2007,110(1):278-286.
[13]Chakravarti A,Zhai G,Suzuki Y,et al.The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas[J].J Clin 0ncol,2004,22(10):1926-1933.
[14]Davidson L,Maccario H,Perera NM,et al.Suppression of cellular proliferation and invasion by the concerted lipid and protein phosphatase activities of PTEN[J].Oncogene,2010,29(5):687-697.
[15]Wiencke JK,Zheng S,Jelluma N,et al.Methylation of the PTEN promoter defines low-grade gliomas and secondry glioblastoma[J].Neuro Oncol,2007,9(3):271-279.
[16]Yang Y,Shao N,Luo G,et al.Mutallons of PTEN gene in gliomas correlate to tumor differentiation and shortterm survival rate[J].Anticancer Res,2010,30(3):981-985.
[17]Bjornsti MA,Houghton PJ.The TOR pathway:a target for cancer therapy[J].Nat Rey Cancer,2004,4(5):335-348.
[18]Panagiotou I,Tsiambas E,Lazaris AC,et al.PTEN expression in non small cell lung carcinoma based on digitized image analysis[J].J BUON,2012,17(4):719-723.
[19]Moon SH,Kim DK,Cha Y,et al.PI3K/Akt and Stat3signaling regulated by PTEN control of the cancer stem cell population,proliferation and senescence in a glioblastoma cell line[J].Int J Oncol,2013,42(3):921-928.
[20]Zhao S,Lin Y,Xu W,et al.Glioma-derived mutations in IDH1dominantly inhibit IDH1catalytic activity and induce HIF-1alpha[J].Science,2009,324(5924):261-265.