关于食管癌亚型食管基底细胞样鳞癌的基因芯片数据分析
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摘要
分析食管基底细胞样鳞癌(basaloid squamous cell carcinoma of the esophagus,BSCCE)的组织样本基因表达情况,探讨其病理学过程和肿瘤免疫逃逸机制,同时对BSCCE独特的肿瘤微环境及潜在的临床指标在对其远期预后的病理基础进行讨论,以期为临床工作中更好的治疗BSCCE提供一定的理论基础。利用临床术中获取的组织样本及其基因芯片数据,进一步获取BSCCE组织样本与同体正常组织样本的基因差异表达情况(log|FC|≥2,p<0.05),其中BSCCE组织相对于正常组织的上调表达差异表达基因共489个,下调差异表达基因922个,利用DAVID在线分析系统对差异表达基因进行京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes,KEGG)信号通路分析获取对BSCCE组织病理情况相关的分析结果,进一步利用STRING-OL工具对差异表达基因的可信度(可信度≥0.4)进行筛选,获取差异表达基因的蛋白质相互作用分析(protein-protein interaction,PPI)结果,进一步利用Cytoscape软件对筛选后的PPI结果制作相应的基因相互作用网状图,并进一步筛选核心表达的差异基因。在上调差异基因的KEGG分析中获得了88个结果,如p53signaling pathway、Cytokine-cytokine receptor interaction pathway、Toll-like receptor signaling pathway等,在下调的差异基因KEGG分析中获得了125个结果,如Drug metabolism-cytochrome P450 pathway、MAPK signaling pathway、Calcium signaling pathway、Cytokine-cytokine receptor interaction pathway等,这些相关的信号通路对进一步理解BSCCE的肿瘤微环境变化及肿瘤病理相关机制有重要意义,通过PPI分析,我们筛选出了一些与肿瘤远期生存率(overall survival,OS)相关的基因:CDC6、CDC20、TOP2A、NEK2、CDC25A等,这为我们进一步研究BSCCE及其肿瘤病理标志物和远期生存的关系提供了理论基础。
To further understand the basaloid squamous cell carcinoma of the esophagus, BSCCE, with the pathological characteristic of BSCCE and excavate potential therapeutic targets, so as to improve the Overall survival for the clinical treatment. This study using bioinformatics methods and the technology of gene chip, The tissue samples of BSCCE were analyzed. The expression gene(489 up-regulated and 922 down-regulated, log|FC|≥2, p<0.05) which related to the possible process of pathology and tumor immune escape mechanism will be discuss and assay by kyoto encyclopedia of genes and genomes(KEGG) and protein-protein interaction(PPI). In the assay, DAVID and STRING-OL(credibility≥0.4) was be used. Then the Cytoscape software was used to construct protein-protein interaction network, with the up-regulated expression genes, the KEGG study shows 88 results, such as 53 signaling pathway, cytokine-cytokine receptor interaction pathway, toll-like receptor signaling pathway and et al, In the down-regulated expression genes, the KEGG study shows 125 results, such as Drug metabolism-cytochrome P450 pathway, MAPK signaling pathway, calcium signaling pathway, cytokine-cytokine receptor interaction pathway. All of these signaling pathway have the correlation with tumor microenvironment.At the same time, the Overall survival and tumor micro-environment of BSCCE has be discussion by PPI assay,such as CDC6, CDC20, TOP2 A, NEK2, CDC25 and et al.. This research is a base for more BSCCE or SCC clinical study and treatment.
To further understand the basaloid squamous cell carcinoma of the esophagus, BSCCE, with the pathological characteristic of BSCCE and excavate potential therapeutic targets, so as to improve the Overall survival for the clinical treatment. This study using bioinformatics methods and the technology of gene chip, The tissue samples of BSCCE were analyzed. The expression gene(489 up-regulated and 922 down-regulated, log|FC|≥2, p<0.05) which related to the possible process of pathology and tumor immune escape mechanism will be discuss and assay by kyoto encyclopedia of genes and genomes(KEGG) and protein-protein interaction(PPI). In the assay, DAVID and STRING-OL(credibility≥0.4) was be used. Then the Cytoscape software was used to construct protein-protein interaction network, with the up-regulated expression genes, the KEGG study shows 88 results, such as 53 signaling pathway, cytokine-cytokine receptor interaction pathway, toll-like receptor signaling pathway and et al, In the down-regulated expression genes, the KEGG study shows 125 results, such as Drug metabolism-cytochrome P450 pathway, MAPK signaling pathway, calcium signaling pathway, cytokine-cytokine receptor interaction pathway. All of these signaling pathway have the correlation with tumor microenvironment.At the same time, the Overall survival and tumor micro-environment of BSCCE has be discussion by PPI assay,such as CDC6, CDC20, TOP2 A, NEK2, CDC25 and et al.. This research is a base for more BSCCE or SCC clinical study and treatment.
引文
Boelens M.C.,Wu T.J.,Nabet B.Y.,Xu B.,Qiu Y.,Yoon T.,Azzam D.J.,Twyman-Saint V.C.,Wiemann B.Z.,Ishwaran H.,Ter Brugge P.J.,Jonkers J.,Slingerland J.,and Minn A.J.,2014,Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways,Cell,159(3):499-513
Borsuk E.,Jachowicz J.,Kloc M.,Tassan J.P.,and Kubiak J.Z.,2017,Role of Cdc6 during oogenesis and early embryo development in mouse and xenopus laevis,Results Probl.Cell Differ.,59:201-211
Chen D.J.,Li X.S.,Zhao H.,Fu Y.,Kang H.R.,Yao F.F.,Hu J.,Qi N.,Zhang H.H.,Du.N.,and Chen W.R..,2017,Dinitrophenyl hapten with laser immunotherapy for advanced malignant melanoma:A clinical study,Oncol.Lett.,13(3):1425-1431
Chen J.R.,Chien H.P.,Chen K.S.,Hwang C.C.,Chen H.Y.,Yeh K.Y.,Hsieh T.Y.,Chang L.C.,Hsu Y.C.,Lu R.J.,and Hua C.C.,2017,Amplification of HER2 and TOP2A and deletion of TOP2A genes in a series of Taiwanese breast cancer,Medicine(Baltimore),96(2):e5582
Edfeldt K.,Hellman P.,Westin G.,and Stalberg P.,2016,A plausible role for actin gamma smooth muscle 2(ACTG2)in small intestinal neuroendocrine tumorigenesis,BMC Endocr Disord,16(1):19
Han L.,Wang W.,Ding W.,Ding W.,and Zhang L.,2017,Mi R-9is involved in TGF-β1-induced lung cancer cell invasion and adhesion by targeting SOX7,J.Cell Mol.Med.,21(9):2000-2008
Ishida H.,Nakano T.,Fujishima F.,Kamei T.,Taniyama Y.,Sakurai T.,Sato C.,Fukutomi T.,Kamiya K.,Ozawa Y.,Sasano H.,and Ohuchi N.,2015,Surgical resection and chemoradiotherapy for metachronous pulmonary metastasis of basaloid squamous cell carcinoma of the oesophagus,Int.J.Surg.Case Rep.,17:151-154
Jemal A.,Bray F.,Center M.M.,Ferlay J.J.,Ward E.,and Forman D.,2011,Global cancer statistics,CA Cancer,61:69-90
Kim T.H.,Chang J.H.,Lee H.J.,Kim J.A.,Lim Y.S.,Kim C.W.,and Han S.W.,2016,m RNA expression of CDH3,IGF2BP3,and BIRC5 in biliary brush cytology specimens is a useful adjunctive tool of cytology for the diagnosis of malignant biliary stricture.,Medicine(Baltimore),95(27):e4132
Li B.,Xu W.W.,Han L.,Chan K.T.,Tsao S.W.,Lee N.P.,Law S.,Xu L.Y.,Li E.M.,Chan K.W.,Qin Y.R.,Guan X.Y.,He Q.Y.,and Cheung A.L.,2017,Micro RNA-377 suppresses initiation and progression of esophageal cancer by inhibiting CD133 and VEGF,Oncogene,36(28):3986-4000
Li G.,Zhong Y.,Shen Q.,Zhou Y.,Deng X.F.,Li C.,Chen J.,Zhou Y.,and He M.,2017,NEK2 serves as a prognostic biomarker for hepatocellular carcinoma,Int.J.Oncol.,50(2):405-413
Luce L.N.,Abbate M.,Cotignola J.,and Giliberto F.,2017,Non-myogenic tumors display altered expression of dystrophin(DMD)and a high frequency of genetic alterations,Oncotarget,8(1):145-155
Lv L.,Pan K.,Li X.D.,She K.L.,Zhao J.J.,Wang W.,Chen J.G.,Chen Y.B.,Yun J.P.,and Xia J.C.,2011,The accumulation and prognosis value of tumor infiltrating IL-17 producing cells in esophageal squamous cell carcinoma,PLo S One,6(3):e18219
Nakasone E.S.,Askautrud H.A.,Park J.H.,Plaks V.,Ewald A.J.,Fein M.,Rasch M.G.,Tan Y.X.,Qiu J.,Park J.,Sinha P.,Bissell M.J.,Frengen E.,Werb Z.,and Egeblad M.,2012,Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance,Cancer Cell,21(4):488-503
Pakchuen S.,Ishibashi M.,Takakusagi E.,Shirahige K.,and Sutani T.,2016,Physical association of saccharomyces cerevisiae Polo-like Kinase Cdc5 with Chromosomal Cohesin Facilitates DNA Damage Response,J.Biol Chem,291(33):17228-17246
Stanilov N.S.,Miteva L.,Cirovski G.,and Stanilova S.A.,2016,Increased transforming growth factorβand interleukin 10transcripts in peripheral blood mononuclear cells of colorectalcancer patients,Contemp Oncol(Pozn),20(6):458-462
Szedlak A.,Smith N.,Liu L.,Paternostro G.,and Piermarocchi C.,2016,Evolutionary and topological properties of genes and community structures in human gene regulatory networks,PLo S.Comput.Biol.,12(6):e1005009
Toor S.M.,Syed Khaja A.S.,E Salhat H.,Faour I.,Kanbar J.,Quadri A.A.,Albashir M.,and Elkord E.,2017,Myeloid cells in circulation and tumor microenvironment of breast cancer patients,Cancer Immunol Immunother,66(6):753-764
von Mering C.,Huynen M.,Jaeggi D.,Schmidt S.,Bork P.,and Snel B.,2003,STRING:a database of predicted functional associations between proteins,Nucleic Acids Res.,31(1):258-261
Wang J.,Jia Y.,Wang N.,Zhang X.,Tan B.,Zhang G.,and Cheng Y.,2014,The clinical significance of tumor-infiltrating neutrophils and neutrophil-to-CD8+lymphocyte ratio in patients with resectable esophageal squamous cell carcinoma,Transl.Med.,12:7
Wang S.C.,Chou J.F.,Strong V.E.,Brennan M.F.,Capanu M.,and Coit D.G.,2016,Pretreatment neutrophil to lymphocyte ratio independently predicts disease-specific survival in resectable g astroesophageal junction and gastric adenocarcinoma,Ann Surg.,263(2):292-297
Wang T.L.,Ren Y.W.,Wang H.T.,Yu H.,and Zhao Y.X.,2017,Association of topoisomeraseⅡ(TOP2A)and dual-specificity phosphatase 6(DUSP6)single nucleotide polymorphisms with radiation treatment response and prognosis of lung cancer in Han Chinese,Med.Sci.Monit.,23:984-993
Xiao Q.,Zhang B.,Deng X.,Wu J.,Wang H.,Wang Y.,and Wang W.,2016,The Preoperative Neutrophil-To-Lymphocyte Ratio is a novel immune parameter for the prognosis of esophageal basaloid squamous cell carcinoma,PLo SOne,11(12):e0168299
Yu H.L.,Jiang S.H.,Bu X.L.,Wang J.H.,Weng J.Y.,Yang X.M.,He K.Y.,Zhang Z.G.,Ao P.,Xu J.,and Xu M.J.,2017,Structural diversity of anti-pancreatic cancer capsimycins identified in mangrove-derived Strep tomyces xiamenensis318 and post-modification via a novel cytochrome P450monooxygenase,Sci Rep.,7:40689
Yuan P.,Li J.B.Zhou F.,Huang Q.C.,Zhang J.S.,Guo X.,Lyu Z.M.,Zhang H.X.,and Xing J.L.,2017,NPAS2 promotes cell survival of hepatocellular carci noma by transactivating CDC25A,Cell Death Dis.,8(3):e2704
Zhang Y.,Xue YB.,Li H.,Qiu D.,Wang Z.W.,and Tan S.S.,2017,Inhibition of cell survival by curcumin is associated with downregulation of cell division cycle 20(Cdc20)in pancreatic cancer cells,Nutrients.4,9(2).pii:E109
Zhao W.,Wu Z.,Li Y.,Jia H.,Chen M.,Gu X.,Liu M.,Zhang Z.,Wang P.,and Cheng W.,2016.,Pretreatment neutrophilto-lymphocyte ratio and its dynamic changes are associated with the overall survival in advanced cancer patients undergoing palliative care,Sci.Rep.,6:31394
Zou X.N.,2006,Esophageal cancer epidemiology,Zhonghua Zhongliu Yufang Zazhi(Chinese Journal of Cancer Prevention and Treatment),13(18):1-4(邹小农,2006,食管癌流行病学,中华肿瘤预防杂志,13(18):1-4)
Borsuk E.,Jachowicz J.,Kloc M.,Tassan J.P.,and Kubiak J.Z.,2017,Role of Cdc6 during oogenesis and early embryo development in mouse and xenopus laevis,Results Probl.Cell Differ.,59:201-211
Chen D.J.,Li X.S.,Zhao H.,Fu Y.,Kang H.R.,Yao F.F.,Hu J.,Qi N.,Zhang H.H.,Du.N.,and Chen W.R..,2017,Dinitrophenyl hapten with laser immunotherapy for advanced malignant melanoma:A clinical study,Oncol.Lett.,13(3):1425-1431
Chen J.R.,Chien H.P.,Chen K.S.,Hwang C.C.,Chen H.Y.,Yeh K.Y.,Hsieh T.Y.,Chang L.C.,Hsu Y.C.,Lu R.J.,and Hua C.C.,2017,Amplification of HER2 and TOP2A and deletion of TOP2A genes in a series of Taiwanese breast cancer,Medicine(Baltimore),96(2):e5582
Edfeldt K.,Hellman P.,Westin G.,and Stalberg P.,2016,A plausible role for actin gamma smooth muscle 2(ACTG2)in small intestinal neuroendocrine tumorigenesis,BMC Endocr Disord,16(1):19
Han L.,Wang W.,Ding W.,Ding W.,and Zhang L.,2017,Mi R-9is involved in TGF-β1-induced lung cancer cell invasion and adhesion by targeting SOX7,J.Cell Mol.Med.,21(9):2000-2008
Ishida H.,Nakano T.,Fujishima F.,Kamei T.,Taniyama Y.,Sakurai T.,Sato C.,Fukutomi T.,Kamiya K.,Ozawa Y.,Sasano H.,and Ohuchi N.,2015,Surgical resection and chemoradiotherapy for metachronous pulmonary metastasis of basaloid squamous cell carcinoma of the oesophagus,Int.J.Surg.Case Rep.,17:151-154
Jemal A.,Bray F.,Center M.M.,Ferlay J.J.,Ward E.,and Forman D.,2011,Global cancer statistics,CA Cancer,61:69-90
Kim T.H.,Chang J.H.,Lee H.J.,Kim J.A.,Lim Y.S.,Kim C.W.,and Han S.W.,2016,m RNA expression of CDH3,IGF2BP3,and BIRC5 in biliary brush cytology specimens is a useful adjunctive tool of cytology for the diagnosis of malignant biliary stricture.,Medicine(Baltimore),95(27):e4132
Li B.,Xu W.W.,Han L.,Chan K.T.,Tsao S.W.,Lee N.P.,Law S.,Xu L.Y.,Li E.M.,Chan K.W.,Qin Y.R.,Guan X.Y.,He Q.Y.,and Cheung A.L.,2017,Micro RNA-377 suppresses initiation and progression of esophageal cancer by inhibiting CD133 and VEGF,Oncogene,36(28):3986-4000
Li G.,Zhong Y.,Shen Q.,Zhou Y.,Deng X.F.,Li C.,Chen J.,Zhou Y.,and He M.,2017,NEK2 serves as a prognostic biomarker for hepatocellular carcinoma,Int.J.Oncol.,50(2):405-413
Luce L.N.,Abbate M.,Cotignola J.,and Giliberto F.,2017,Non-myogenic tumors display altered expression of dystrophin(DMD)and a high frequency of genetic alterations,Oncotarget,8(1):145-155
Lv L.,Pan K.,Li X.D.,She K.L.,Zhao J.J.,Wang W.,Chen J.G.,Chen Y.B.,Yun J.P.,and Xia J.C.,2011,The accumulation and prognosis value of tumor infiltrating IL-17 producing cells in esophageal squamous cell carcinoma,PLo S One,6(3):e18219
Nakasone E.S.,Askautrud H.A.,Park J.H.,Plaks V.,Ewald A.J.,Fein M.,Rasch M.G.,Tan Y.X.,Qiu J.,Park J.,Sinha P.,Bissell M.J.,Frengen E.,Werb Z.,and Egeblad M.,2012,Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance,Cancer Cell,21(4):488-503
Pakchuen S.,Ishibashi M.,Takakusagi E.,Shirahige K.,and Sutani T.,2016,Physical association of saccharomyces cerevisiae Polo-like Kinase Cdc5 with Chromosomal Cohesin Facilitates DNA Damage Response,J.Biol Chem,291(33):17228-17246
Stanilov N.S.,Miteva L.,Cirovski G.,and Stanilova S.A.,2016,Increased transforming growth factorβand interleukin 10transcripts in peripheral blood mononuclear cells of colorectalcancer patients,Contemp Oncol(Pozn),20(6):458-462
Szedlak A.,Smith N.,Liu L.,Paternostro G.,and Piermarocchi C.,2016,Evolutionary and topological properties of genes and community structures in human gene regulatory networks,PLo S.Comput.Biol.,12(6):e1005009
Toor S.M.,Syed Khaja A.S.,E Salhat H.,Faour I.,Kanbar J.,Quadri A.A.,Albashir M.,and Elkord E.,2017,Myeloid cells in circulation and tumor microenvironment of breast cancer patients,Cancer Immunol Immunother,66(6):753-764
von Mering C.,Huynen M.,Jaeggi D.,Schmidt S.,Bork P.,and Snel B.,2003,STRING:a database of predicted functional associations between proteins,Nucleic Acids Res.,31(1):258-261
Wang J.,Jia Y.,Wang N.,Zhang X.,Tan B.,Zhang G.,and Cheng Y.,2014,The clinical significance of tumor-infiltrating neutrophils and neutrophil-to-CD8+lymphocyte ratio in patients with resectable esophageal squamous cell carcinoma,Transl.Med.,12:7
Wang S.C.,Chou J.F.,Strong V.E.,Brennan M.F.,Capanu M.,and Coit D.G.,2016,Pretreatment neutrophil to lymphocyte ratio independently predicts disease-specific survival in resectable g astroesophageal junction and gastric adenocarcinoma,Ann Surg.,263(2):292-297
Wang T.L.,Ren Y.W.,Wang H.T.,Yu H.,and Zhao Y.X.,2017,Association of topoisomeraseⅡ(TOP2A)and dual-specificity phosphatase 6(DUSP6)single nucleotide polymorphisms with radiation treatment response and prognosis of lung cancer in Han Chinese,Med.Sci.Monit.,23:984-993
Xiao Q.,Zhang B.,Deng X.,Wu J.,Wang H.,Wang Y.,and Wang W.,2016,The Preoperative Neutrophil-To-Lymphocyte Ratio is a novel immune parameter for the prognosis of esophageal basaloid squamous cell carcinoma,PLo SOne,11(12):e0168299
Yu H.L.,Jiang S.H.,Bu X.L.,Wang J.H.,Weng J.Y.,Yang X.M.,He K.Y.,Zhang Z.G.,Ao P.,Xu J.,and Xu M.J.,2017,Structural diversity of anti-pancreatic cancer capsimycins identified in mangrove-derived Strep tomyces xiamenensis318 and post-modification via a novel cytochrome P450monooxygenase,Sci Rep.,7:40689
Yuan P.,Li J.B.Zhou F.,Huang Q.C.,Zhang J.S.,Guo X.,Lyu Z.M.,Zhang H.X.,and Xing J.L.,2017,NPAS2 promotes cell survival of hepatocellular carci noma by transactivating CDC25A,Cell Death Dis.,8(3):e2704
Zhang Y.,Xue YB.,Li H.,Qiu D.,Wang Z.W.,and Tan S.S.,2017,Inhibition of cell survival by curcumin is associated with downregulation of cell division cycle 20(Cdc20)in pancreatic cancer cells,Nutrients.4,9(2).pii:E109
Zhao W.,Wu Z.,Li Y.,Jia H.,Chen M.,Gu X.,Liu M.,Zhang Z.,Wang P.,and Cheng W.,2016.,Pretreatment neutrophilto-lymphocyte ratio and its dynamic changes are associated with the overall survival in advanced cancer patients undergoing palliative care,Sci.Rep.,6:31394
Zou X.N.,2006,Esophageal cancer epidemiology,Zhonghua Zhongliu Yufang Zazhi(Chinese Journal of Cancer Prevention and Treatment),13(18):1-4(邹小农,2006,食管癌流行病学,中华肿瘤预防杂志,13(18):1-4)