蛋白质精氨酸甲基转移酶5参与膀胱癌发生、发展的相关性研究
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摘要
目的探讨蛋白质精氨酸甲基转移酶5(PRMT5)在膀胱癌中的表达情况及其与膀胱癌发生、发展的相关性。方法收集癌症和肿瘤基因图谱(TCGA)数据库中膀胱癌患者相关信息,下载PRMT5基因表达谱资料及临床信息资料。分析PRMT5 mRNA表达水平在膀胱癌与癌旁组织中的差异,分析PRMT5与临床病理特征的相关性。通过组织芯片做免疫组化实验,在蛋白水平验证基因水平的结论。结果 PRMT5在癌组织中显著高表达(P=0. 0001)。PRMT5高表达组较低表达组患者预后显著更差(Log-rank P=2. 6×10-4)。PRMT5高表达更倾向于分布在T3、T4期(以TNM分期)。PRMT5在癌和癌旁组织中蛋白质水平表达无显著差异。结论在膀胱癌中,基因水平下PRMT5高表达是一种预后不良因素,蛋白水平未发现明显差异。
Objective To investigate the expression of protein arginine methyltransferase 5( PRMT5) in bladder cancer,and its correlation with occurrence and development of bladder cancer.Methods The PRMT5 gene expression profiles in Cancer Genome Atlas( TCGA) were collected and clinical information were downloaded. The differences in PRMT5 mRNA expression levels in bladder cancer and paracancerous tissue were analyzed,and the correlation between PRMT5 and clinicopathologic feature was analyzed. The protein level was determined by immunohistochemistry. Results PRMT5 had higher expression in cancer tissues( P = 0. 0001). The prognosis in high expression group was poorer compared with PRMT5 lower expression group( Log-rank P = 2. 6 × 10-4). High expression of PRMT5 was more likely to be distributed in T3 and T4 stage in TNM stage,and there was no significant difference in PRMT5 expression between cancer and para-carcinoma tissue. Conclusion High expression of PRMT5 at the gene level in bladder cancer is a poor prognostic factor,and no significant differences in protein levels are found.
Objective To investigate the expression of protein arginine methyltransferase 5( PRMT5) in bladder cancer,and its correlation with occurrence and development of bladder cancer.Methods The PRMT5 gene expression profiles in Cancer Genome Atlas( TCGA) were collected and clinical information were downloaded. The differences in PRMT5 mRNA expression levels in bladder cancer and paracancerous tissue were analyzed,and the correlation between PRMT5 and clinicopathologic feature was analyzed. The protein level was determined by immunohistochemistry. Results PRMT5 had higher expression in cancer tissues( P = 0. 0001). The prognosis in high expression group was poorer compared with PRMT5 lower expression group( Log-rank P = 2. 6 × 10-4). High expression of PRMT5 was more likely to be distributed in T3 and T4 stage in TNM stage,and there was no significant difference in PRMT5 expression between cancer and para-carcinoma tissue. Conclusion High expression of PRMT5 at the gene level in bladder cancer is a poor prognostic factor,and no significant differences in protein levels are found.
引文
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[29]Hsu J M,Chen C T,Chou C K,et al.Crosstalk between Arg1175 methylation and Tyr 1173 phosphorylation negatively modulates EGFR-mediated ERK activation[J].Nature cell biology,2011,13(2):174-181.
[30]Yan F,Alinari L,Lustberg M E,et al.Genetic validation of the protein arginine methyltransferase PRMT5 as a candidate therapeutic target in glioblastoma[J].Cancer research,2014,74(6):1752-1765.
[31]Jeon J Y,Lee J S,Park E R,et al.Protein arginine methyltransferase 5 is implicated in the aggressiveness of human hepatocellular carcinoma and controls the invasive activity of cancer cells[J].Oncology reports,2018,40(1):536-544.
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[2]Torre L A,Bray F,Siegel R L,et al.Global cancer statistics,2012[J].CA Cancer J Clin,2015,65(2):87-108.
[3]Chen W,Zheng R,Baade P D,et al.Cancer statistics in China,2015[J].CA Cancer J Clin,2016,66(2):115-132.
[4]Chen W,Zheng R,Zeng H,et al.Annual report on status of cancer in China,2011[J].Chin J Cancer Res,2015,27(1):2-12.
[5]Chen W,Zheng R,Zeng H,et al.Trend analysis of the changes of male/female,urban/rural incidences and average age of cancer patients in China 1989-2008[J].Zhonghua Zhong Liu Za Zhi,2014,36(10):796-800.
[6]Jacobs B L,Lee C T,Montie J E.Bladder cancer in 2010:how far have we come[J].CA Cancer J Clin,2010,60(4):244-272.
[7]Siegel R,Naishadham D,Jemal A.Cancer statistics,2013[J].CA Cancer J Clin,2013,63(1):11-30.
[8]Khandelwal P,Abraham S N,Apodaca G.Cell biology and physiology of the uroepithelium[J].Am J Physiol Renal Physiol,2009,297(6):F1477-F1501.
[9]Letasiova S,Medve'ova A,Sovcikova A,et al.Bladder cancer,a review of the environmental risk factors[J].Environ Health,2012,11(Suppl 1):S11-S19.
[10]Zeegers M P,Tan F E,Dorant E,et al.The impact of characteristics of cigarette smoking on urinary tract cancer risk:a meta-analysis of epidemiologic studies[J].Cancer,2000,89(3):630-639.
[11]Kuper H,Boffetta P,Adami H O.Tobacco use and cancer causation:association by tumour type[J].J Intern Med,2002,252(3):206-224.
[12]Czerniak B,Dinney C,Mc Conkey D.Origins of Bladder Cancer[J].Annu Rev Pathol,2016,11:149-174.
[13]Yu M C,Skipper P L,Tannenbaum S R,et al.Arylamine exposures and bladder cancer risk[J].Mutat Res,2002,506/507:21-28.
[14]Davie J K,Dent S Y.Transcriptional control:an activating role for arginine methylation[J].Current biology,2002,12(2):R59-R61.
[15]Trievel R C.Structure and function of histone methyltransferases[J].Critical reviews in eukaryotic gene expression,2004,14(3):147-169.
[16]Wysocka J,Allis C D,Coonrod S.Histone arginine methylation and its dynamic regulation[J].Frontiers in bioscience:a journal and virtual library,2006,11:344-355.
[17]Stopa N,Krebs J E,Shechter D.The PRMT5 arginine methyltransferase:many roles in development,cancer and beyond[J].Cellular and molecular life sciences,2015,72(11):2041-2059.
[18]Karkhanis V,Hu Y J,Baiocchi R A,et al.Versatility of PRMT5-induced methylation in growth control and development[J].Trends in biochemical sciences,2011,36(12):633-641.
[19]Huddleston J E.Development:a new move for PRMT5[J].Nature reviews Molecular cell biology,2011,12(2):76-84.
[20]Zhang H T,Zhang D,Zha Z G,et al.Transcriptional activation of PRMT5 by NF-Y is required for cell growth and negatively regulated by the PKC/c-Fos signaling in prostate cancer cells[J].Biochimica et biophysica acta,2014,1839(11):1330-1340.
[21]Hu H,Qian K,Ho M C,et al.Small Molecule Inhibitors of Protein Arginine Methyltransferases[J].Expert opinion on investigational drugs,2016,25(3):335-358.
[22]Bedford M T,Clarke S G.Protein arginine methylation in mammals:who,what,and why[J].Molecular cell,2009,33(1):1-13.
[23]Yang Y,Bedford M T.Protein arginine methyltransferases and cancer[J].Nature reviews Cancer,2013,13(1):37-50.
[24]Wei H,Wang B,Miyagi M,et al.PRMT5 dimethylates R30of the p65 subunit to activate NF-kappaB[J].Proceedings of the National Academy of Sciences of the United States of A-merica,2013,110(33):13516-13521.
[25]Cho E C,Zheng S,Munro S,et al.Arginine methylation controls growth regulation by E2F-1[J].The EMBO journal,2012,31(7):1785-1797.
[26]Wang L,Pal S,Sif S.Protein arginine methyltransferase 5suppresses the transcription of the RB family of tumor suppressors in leukemia and lymphoma cells[J].Molecular and cellular biology,2008,28(20):6262-6277.
[27]Bandyopadhyay S,Harris D P,Adams G N,et al.HOXA9methylation by PRMT5 is essential for endothelial cell expression of leukocyte adhesion molecules[J].Molecular and cellular biology,2012,32(7):1202-1213.
[28]Powers M A,Fay M M,Factor R E,et al.Protein arginine methyltransferase 5 accelerates tumor growth by arginine methylation of the tumor suppressor programmed cell death 4[J].Cancer research,2011,71(16):5579-5587.
[29]Hsu J M,Chen C T,Chou C K,et al.Crosstalk between Arg1175 methylation and Tyr 1173 phosphorylation negatively modulates EGFR-mediated ERK activation[J].Nature cell biology,2011,13(2):174-181.
[30]Yan F,Alinari L,Lustberg M E,et al.Genetic validation of the protein arginine methyltransferase PRMT5 as a candidate therapeutic target in glioblastoma[J].Cancer research,2014,74(6):1752-1765.
[31]Jeon J Y,Lee J S,Park E R,et al.Protein arginine methyltransferase 5 is implicated in the aggressiveness of human hepatocellular carcinoma and controls the invasive activity of cancer cells[J].Oncology reports,2018,40(1):536-544.
[32]Shimizu D,Kanda M,Sugimoto H,et al.The protein arginine methyltransferase 5 promotes malignant phenotype of hepatocellular carcinoma cells and is associated with adverse patient outcomes after curative hepatectomy[J].International journal of oncology,2017,50(2):381-386.