CTNNBIP1和ICMT基因共表达在膀胱尿路上皮癌中作用和功能分析
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摘要
为了研究CTNNBIP1和ICMT基因共表达在膀胱尿路上皮癌中的作用及对患者预后的诊断价值,本研究选取癌症基因组图谱(TCGA)数据库中412例膀胱尿路上皮癌数据资料,利用cBioPortal数据库对膀胱尿路上皮癌CTNNBIP1基因、ICMT基因及其共表达基因作生存分析,将Pearson和Spearman相关系数均大于0.3的基因定义为中等程度以上共表达相关的基因。通过String数据库获取这些基因共表达的互作关系组。采用DAVID数据库、GO数据库、KEGG数据库分别对其进行信号通路和功能分析,生物学过程聚类分析,信号通路聚类分析。结果显示:TCGA数据库中的膀胱尿路上皮癌患者CTNNBIP1和ICMT存在共表达(Pearson相关系数=0.46和Spearman相关系数=0.47)。String数据库显示基因共表达有38组具有互作关系。KEGG数据库显示CTNNBIP1-ICMT基因共表达所富集的信号通路集中在细胞周期(p<0.05)。DAVID数据库分析其功能主要为调节细胞生长和有丝分裂、负性调控Wnt信号通路、蛋白激酶结合等。生存分析证实CTNNBIPI1和ICMT基因共表达与患者总生存率显著相关(p=0.002 72),CTNNBIPI1和ICMT共表达阳性患者的预后最差。由此得出结论:CTNNBIP1和ICMT在膀胱尿路上皮癌中存在共表达,对CTNNBIP1-ICMT基因共表达网络和生物信息学分析,可找到其在膀胱尿路上皮癌中的作用及信号通路,为深入研究膀胱尿路上皮癌的发病机制提供了理论基础,可提高膀胱尿路上皮癌患者的预后。
To find out the function of co-expressed genes about CTNNBIP1 and ICMT as well as to explore their diagnostic value of prognosis in the Bladder urothelial carcinoma, we downloaded the clinical data from 412 samples in the TCGA database to analyze the co-expression relation between CTNNBIP1 and ICMT and their co-expressed genes and survival by using c BioPortal. Genes that Pearson and Spearman score >0.3 regard as moderately co-expressed genes. The co-expression network of CTNNBIP1 and ICMT were constructed with String database and their pathway, function, biological process cluster and the pathway cluster through DAVID, GO, KEGG database were analyzed as well, respectively. Results showed among the Bladder urothelial carcinoma extracted from TCGA database that CTNNBIP1 and ICMT are co-expressed(Pearson score=0.46, Spearman score=0.47), and there are 38 interaction pairs of CTNNBIP1 and ICMT related co-expressed genes according to the String database, which are enriched in the pathway of cell cycle. The functions of these genes were also enriched cell division, regulation of cell growth, mitotic nuclear division, negative regulation of canonical Wnt signaling pathway, protein kinase binding and so on. According to survival analysis, CTNNBIP11 and ICMT mRNA upregulated was significant for OS(p=0.002 72), by contrast, the patient with CTNNBIP1 and ICMT m RNA upregulation, the prognosis are significantly worse. It is concluded that CTNNBIP1 and ICMT are co-expressed and heir functions and pathway could be found though establishing co-expressed network of CTNNBIP1 and ICMT,bioinformatics analysis. This finding would provide the insights for further study on pathogenesis and prognosis of the Bladder urothelial carcinoma.
To find out the function of co-expressed genes about CTNNBIP1 and ICMT as well as to explore their diagnostic value of prognosis in the Bladder urothelial carcinoma, we downloaded the clinical data from 412 samples in the TCGA database to analyze the co-expression relation between CTNNBIP1 and ICMT and their co-expressed genes and survival by using c BioPortal. Genes that Pearson and Spearman score >0.3 regard as moderately co-expressed genes. The co-expression network of CTNNBIP1 and ICMT were constructed with String database and their pathway, function, biological process cluster and the pathway cluster through DAVID, GO, KEGG database were analyzed as well, respectively. Results showed among the Bladder urothelial carcinoma extracted from TCGA database that CTNNBIP1 and ICMT are co-expressed(Pearson score=0.46, Spearman score=0.47), and there are 38 interaction pairs of CTNNBIP1 and ICMT related co-expressed genes according to the String database, which are enriched in the pathway of cell cycle. The functions of these genes were also enriched cell division, regulation of cell growth, mitotic nuclear division, negative regulation of canonical Wnt signaling pathway, protein kinase binding and so on. According to survival analysis, CTNNBIP11 and ICMT mRNA upregulated was significant for OS(p=0.002 72), by contrast, the patient with CTNNBIP1 and ICMT m RNA upregulation, the prognosis are significantly worse. It is concluded that CTNNBIP1 and ICMT are co-expressed and heir functions and pathway could be found though establishing co-expressed network of CTNNBIP1 and ICMT,bioinformatics analysis. This finding would provide the insights for further study on pathogenesis and prognosis of the Bladder urothelial carcinoma.
引文
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Do M.T.,Chai T.F.,Case P.J.,and Wang M.,2017,Isoprenylcysteine carboxylmethyltransferase function is essential for RA-B4A-mediated integrin beta3 recycling,cell migration and cancer metastasis,Oncogene,36(41):5757-5767
Feng Y.,Yu B.,Wang X.,Wu N.,Lu Z.F.,and Wu B.,2016,Expression and significance of DSG3,MAC387 and p40 in urothelial carcinoma with squamous differentiation,Linchuang Yu Shiyan Binglixue Zazhi(Chinese Journal of Clinical and Experimental Pathology),32(9):989-993(封扬,余波,王璇,吴楠,陆珍凤,吴波,2016,膀胱尿路上皮癌伴鳞状分化中DSG3、MAC387及p40的表达及其临床意义,临床与实验病理学杂志,32(9):989-993)
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Jang G.B.,Kim J.Y.,Cho S.D.,Park K.S.,Jung J.Y.,Lee H.Y.,Hong I.S.,and Nam J.S.,2015,Blockade of Wnt/beta-catenin signaling suppresses breast cancer metastasis by inhibiting CSC-like phenotype,Sci.Rep.,5:12465
Jemal A.,Siegel R.,Xu J.,and Ward E.,2010,Cancer statistics,2010,CA Cancer J.Clin.,60:277-300
Kramer K.,Harrington E.O.,Lu Q.,Bellas R.,Newton J.,Sheahan K.L.,and Rounds S.,2003,Isoprenylcysteine carboxyl methyltransferase activity modulates endothelial cell apoptosis,Mol.Biol.Cell,14(3):848-857
Kruck S.,Eyrich C.,Scharpf M.,Sievert K.D.,Fend F.,Stenzl A.,and Bedke J.,2013,Impact of an altered Wnt1/beta-catenin expression on clinicopathology and prognosis in clear cell renal cell carcinoma,Int.J.Mol.Sci.,14(6):10944-10957
Lau H.Y.,Tang J.,Casey P.J.,and Wang M.,2017,Isoprenylcysteine carboxylmethyltransferase is critical for malignant transformation and tumor maintenance by all RAS isoforms,Oncogene,36(27):3934-3942
Ono M.,Yin P.,Navarro A.,Moravek M.B.,Coon V.J.S.,Druschitz S.A.,Gottardi C.J.,and Bulun S.E.,2014,Inhibition of canonical WNT signaling attenuates human leiomyoma cell growth,Fertil.Steril.,101(5):1441-1449
Pai S.G.,Carneiro B.A.,Mota J.M.,Costa R.,Leite C.A.,BarrosoSousa R.,Kaplan J.B.,Chae Y.K.,and Giles F.J.,2017,Wnt beta-catenin pathway:modulating anticancer immune response,J.Hematol.Oncol.,10(1):101
Sfakianos J.P.,Cha E.K.,Iyer G.,Scott S.N.,Zabor E.C.,Shah R.H.Ren Q.,Bagrodia A.,Kim P.H.,Hakimi A.A.,Ostrovnaya I.Ramirez R.,Hanrahan A.J.,Desai N.B.,Sun A.,Pinciroli P.Rosenberg J.E.,Dalbagni G.,Schultz N.,Bajorin D.F.,Reuter V.E.,Berger M.F.,Bochner B.H.,Al-Ahmadie H.A.,Solit DB.,and Coleman J.A.,2015,Genomic characteriza-tion of upper tract urothelial carcinoma,Eur.Urol.,68(6):970-977
Teh J.T.,Zhu W.L.,Ilkayeva O.R.,Li Y.,Gooding J.,Casey P.JSummers S.A.,Newgard C.B.,and Wang M.,2015,Isoprenylcysteine carboxylmethyltransferase regulates mitochondria respiration and cancer cell metabolism,Oncogene,34(25):3296-3304
Torre L.A.,Bray F.,Siegel R.L.,Ferlay J.,Lortet-Tieulent J.,and Jemal A.,2015,Global cancer statistics,2012,CA Cancer JClin.,65(2):87-108
Wang J.S.,Wang W.J.,Wang T.,and Zhang Y.,2016,Expression of ICAT and Wnt signaling-related proteins in the monocy ic differentiation of HL-60 cells induced by a new steroidal drug NSC67657,Zhonghua Zhongliu Zazhi(Chinese Journal of Oncology),38(4):246-251(王晋蜀,王伟佳,王婷,张彦,2016,甾醇类药NSC67657诱导急性早幼粒细胞白血病HL-60细胞单核系分化中Wnt信号通路相关蛋白的表达,中华肿瘤杂志,38(4):246-251)
Yi G.Z.,Liu Y.W.,Xiang W.,Wang H.,Chen Z.Y.,Xie S.D.,and Qi S.T.,2016,Akt and beta-catenin contribute to TMZresistance and EMT of MGMT negative malignant glioma cell line,J.Neurol.Sci.,367:101-106
Zhang C.,and Yao X.,2017,Research progress on long noncoding RNA in urothelial bladder carcinoma,Zhongguo Zhongliu Linchuang(Chinese Journal of Clinical Oncology),44(17):890-893(张超,姚欣,2017,长链非编码RNA在膀胱尿路上皮癌中的研究进展,中国肿瘤临床,44(17):890-893)
Zhang M.,Wu J.,Xia Z.Y.,Li Y.X.,and Fan J.,2017,Expression of inhibitor of growth family member 4in bladder urothelial carcinoma and its clinical significance,Xibu Yixue(Medical Journal of West China),29(2):199-202(张萌,伍季,夏中友,李云祥,范俊,2017,生长抑制因子4在膀胱尿路上皮癌中的表达及临床意义,西部医学,29(2):199-202)
Do M.T.,Chai T.F.,Case P.J.,and Wang M.,2017,Isoprenylcysteine carboxylmethyltransferase function is essential for RA-B4A-mediated integrin beta3 recycling,cell migration and cancer metastasis,Oncogene,36(41):5757-5767
Feng Y.,Yu B.,Wang X.,Wu N.,Lu Z.F.,and Wu B.,2016,Expression and significance of DSG3,MAC387 and p40 in urothelial carcinoma with squamous differentiation,Linchuang Yu Shiyan Binglixue Zazhi(Chinese Journal of Clinical and Experimental Pathology),32(9):989-993(封扬,余波,王璇,吴楠,陆珍凤,吴波,2016,膀胱尿路上皮癌伴鳞状分化中DSG3、MAC387及p40的表达及其临床意义,临床与实验病理学杂志,32(9):989-993)
Graham T.A.,Clements W.K.,Kimelman D.,and Xu W.,2002,The crystal structure of the beta-catenin/CTNNBIP1 complex reveals the inhibitory mechanism of CTNNBIP1,Mol.Cell,10(3):563-571
Jang G.B.,Kim J.Y.,Cho S.D.,Park K.S.,Jung J.Y.,Lee H.Y.,Hong I.S.,and Nam J.S.,2015,Blockade of Wnt/beta-catenin signaling suppresses breast cancer metastasis by inhibiting CSC-like phenotype,Sci.Rep.,5:12465
Jemal A.,Siegel R.,Xu J.,and Ward E.,2010,Cancer statistics,2010,CA Cancer J.Clin.,60:277-300
Kramer K.,Harrington E.O.,Lu Q.,Bellas R.,Newton J.,Sheahan K.L.,and Rounds S.,2003,Isoprenylcysteine carboxyl methyltransferase activity modulates endothelial cell apoptosis,Mol.Biol.Cell,14(3):848-857
Kruck S.,Eyrich C.,Scharpf M.,Sievert K.D.,Fend F.,Stenzl A.,and Bedke J.,2013,Impact of an altered Wnt1/beta-catenin expression on clinicopathology and prognosis in clear cell renal cell carcinoma,Int.J.Mol.Sci.,14(6):10944-10957
Lau H.Y.,Tang J.,Casey P.J.,and Wang M.,2017,Isoprenylcysteine carboxylmethyltransferase is critical for malignant transformation and tumor maintenance by all RAS isoforms,Oncogene,36(27):3934-3942
Ono M.,Yin P.,Navarro A.,Moravek M.B.,Coon V.J.S.,Druschitz S.A.,Gottardi C.J.,and Bulun S.E.,2014,Inhibition of canonical WNT signaling attenuates human leiomyoma cell growth,Fertil.Steril.,101(5):1441-1449
Pai S.G.,Carneiro B.A.,Mota J.M.,Costa R.,Leite C.A.,BarrosoSousa R.,Kaplan J.B.,Chae Y.K.,and Giles F.J.,2017,Wnt beta-catenin pathway:modulating anticancer immune response,J.Hematol.Oncol.,10(1):101
Sfakianos J.P.,Cha E.K.,Iyer G.,Scott S.N.,Zabor E.C.,Shah R.H.Ren Q.,Bagrodia A.,Kim P.H.,Hakimi A.A.,Ostrovnaya I.Ramirez R.,Hanrahan A.J.,Desai N.B.,Sun A.,Pinciroli P.Rosenberg J.E.,Dalbagni G.,Schultz N.,Bajorin D.F.,Reuter V.E.,Berger M.F.,Bochner B.H.,Al-Ahmadie H.A.,Solit DB.,and Coleman J.A.,2015,Genomic characteriza-tion of upper tract urothelial carcinoma,Eur.Urol.,68(6):970-977
Teh J.T.,Zhu W.L.,Ilkayeva O.R.,Li Y.,Gooding J.,Casey P.JSummers S.A.,Newgard C.B.,and Wang M.,2015,Isoprenylcysteine carboxylmethyltransferase regulates mitochondria respiration and cancer cell metabolism,Oncogene,34(25):3296-3304
Torre L.A.,Bray F.,Siegel R.L.,Ferlay J.,Lortet-Tieulent J.,and Jemal A.,2015,Global cancer statistics,2012,CA Cancer JClin.,65(2):87-108
Wang J.S.,Wang W.J.,Wang T.,and Zhang Y.,2016,Expression of ICAT and Wnt signaling-related proteins in the monocy ic differentiation of HL-60 cells induced by a new steroidal drug NSC67657,Zhonghua Zhongliu Zazhi(Chinese Journal of Oncology),38(4):246-251(王晋蜀,王伟佳,王婷,张彦,2016,甾醇类药NSC67657诱导急性早幼粒细胞白血病HL-60细胞单核系分化中Wnt信号通路相关蛋白的表达,中华肿瘤杂志,38(4):246-251)
Yi G.Z.,Liu Y.W.,Xiang W.,Wang H.,Chen Z.Y.,Xie S.D.,and Qi S.T.,2016,Akt and beta-catenin contribute to TMZresistance and EMT of MGMT negative malignant glioma cell line,J.Neurol.Sci.,367:101-106
Zhang C.,and Yao X.,2017,Research progress on long noncoding RNA in urothelial bladder carcinoma,Zhongguo Zhongliu Linchuang(Chinese Journal of Clinical Oncology),44(17):890-893(张超,姚欣,2017,长链非编码RNA在膀胱尿路上皮癌中的研究进展,中国肿瘤临床,44(17):890-893)
Zhang M.,Wu J.,Xia Z.Y.,Li Y.X.,and Fan J.,2017,Expression of inhibitor of growth family member 4in bladder urothelial carcinoma and its clinical significance,Xibu Yixue(Medical Journal of West China),29(2):199-202(张萌,伍季,夏中友,李云祥,范俊,2017,生长抑制因子4在膀胱尿路上皮癌中的表达及临床意义,西部医学,29(2):199-202)