基于转录组数据的网络分析挖掘鼻咽癌与口腔鳞癌的共享功能模块
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摘要
鼻咽癌和口腔鳞癌是两种在临床上高度相关的疾病,从分子层面系统性研究这两种疾病的相互关系却鲜见报道。本研究通过大规模的转录组数据分析识别鼻咽癌和口腔鳞癌的共享功能模块及其核心基因(一因多效模块和基因),以期阐明这两种疾病共享的分子机制。从GEO数据库获取这两种癌症的两套转录组数据,应用倍数法和经验贝叶斯方法筛选出鼻咽癌差异表达基因1279个,口腔鳞癌差异表达基因1293个,其中两者共享基因278个。以共享基因为种子,通过蛋白质-蛋白质互作知识引导构建基因网络,其中最大子网包含1290个基因和1766互作对。应用Newman算法提取了15个共享功能模块。对这些模块进行拓扑学分析,挖掘出58个核心基因,包括已知的与鼻咽癌或口腔鳞癌相关的基因(如PCNA、CDK1、STAT1、CCL5和MMP1等)和鲜有报道的基因(如MELK、NME1、RACGAP1、INHBA和NID1等)。通路富集分析发现鼻咽癌和口腔鳞癌的共享功能模块参与多个生物学通路,包括p53信号通路、ECM受体相互作用、黏着斑、细胞周期等。本研究表明鼻咽癌和口腔鳞癌具有相似的致癌机制,所挖掘的共享模块可能是这两种疾病演化的核心分子相互作用机制。
Although nasopharyngeal carcinoma(NPC) and oral squamous cell carcinoma(OSCC) are highly correlated clinical diseases, the underling molecular mechanisms to link the two diseases remain largely unknown. The aim of thisstudy is to identify the shared functional modules for NPC and OSCC by using large-scale transcriptomic data. Gene expression profile datasets of NPC and OSCC were obtained from the GEO database. A total of 1279 differentially expressed genes(DEGs) of NPC and 1293 DEGs of OSCC were identified by fold change and empirical Bayes method, and278 DEGs were common to these two diseases. These overlapped genes were translated into a primary network consisting of 1290 nodes(genes) and 1766 edges. The primary network was then decomposed into 15 compacted modules(subnets)with high modularity by Newman's algorithm. Topological analysis of these modules identified a total of 58 hub genes,most of which(e.g., PCNA, CDK1, STAT1, CCL5, and MMP1) have been proved to be associated with NPC and/or OSCC,while the rest(e.g., MELK, NME1, RACGAP1, INHBA, and NID1) might be novel risk genes for the two diseases. Further bioinformatics analysis of KEGG databases revealed that these modules are involved in multiple pathogenic biological pathways for either NPC or OSCC(e.g., p53 signaling pathway, ECM-receptor interaction, focal adhesion, and cell cycle).This study demonstrates that NPC and OSCC have similar molecular bases, and the identified pleiotropic modules may shape the complicated molecular interplays underlying the two clinically correlated diseases.
Although nasopharyngeal carcinoma(NPC) and oral squamous cell carcinoma(OSCC) are highly correlated clinical diseases, the underling molecular mechanisms to link the two diseases remain largely unknown. The aim of thisstudy is to identify the shared functional modules for NPC and OSCC by using large-scale transcriptomic data. Gene expression profile datasets of NPC and OSCC were obtained from the GEO database. A total of 1279 differentially expressed genes(DEGs) of NPC and 1293 DEGs of OSCC were identified by fold change and empirical Bayes method, and278 DEGs were common to these two diseases. These overlapped genes were translated into a primary network consisting of 1290 nodes(genes) and 1766 edges. The primary network was then decomposed into 15 compacted modules(subnets)with high modularity by Newman's algorithm. Topological analysis of these modules identified a total of 58 hub genes,most of which(e.g., PCNA, CDK1, STAT1, CCL5, and MMP1) have been proved to be associated with NPC and/or OSCC,while the rest(e.g., MELK, NME1, RACGAP1, INHBA, and NID1) might be novel risk genes for the two diseases. Further bioinformatics analysis of KEGG databases revealed that these modules are involved in multiple pathogenic biological pathways for either NPC or OSCC(e.g., p53 signaling pathway, ECM-receptor interaction, focal adhesion, and cell cycle).This study demonstrates that NPC and OSCC have similar molecular bases, and the identified pleiotropic modules may shape the complicated molecular interplays underlying the two clinically correlated diseases.
引文
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[13]Madan M,Chandra S,Raj V,Madan R.Evaluation of cell proliferation in malignant and potentially malignant oral lesions.J Oral Maxillofac Pathol,2015,19(3):297-305.
[14]Zhai X,Yang Y,Wan J,Zhu R,Wu Y.Inhibition of LDH-Aby oxamate induces G2/M arrest,apoptosis and increases radiosensitivity in nasopharyngeal carcinoma cells.Oncol Rep,2013,30(6):2983-2991.
[15]Chen X,Zhang FH,Chen QE,Wang YY,Wang YL,He JC,Zhou J.The clinical significance of CDK1 expression in oral squamous cell carcinoma.Med Oral Patol Oral Cir Bucal,2015,20(1):e7-e12.
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[20]Kan JY,Wu DC,Yu FJ,Wu CY,Ho YW,Chiu YJ,Jian SF,Hung JY,Wang JY,Kuo PL.Chemokine(C-C motif)ligand 5 is involved in tumor-associated dendritic cellmediated colon cancer progression through non-coding RNA MALAT-1.J Cell Physiol,2015,230(8):1883-1894.
[21]Huang CY,Fong YC,Lee CY,Chen MY,Tsai HC,Hsu HC,Tang CH.CCL5 increases lung cancer migration via PI3K,Akt and NF-kappaB pathways.Biochem Pharmacol,2009,77(5):794-803.
[22]Khalid A,Wolfram J,Ferrari I,Mu C,Mai J,Yang Z,Zhao Y,Ferrari M,Ma X,Shen H.Recent advances in discovering the role of CCL5 in metastatic breast cancer.Mini Rev Med Chem,2015,15(13):1063-1072.
[23]Ma W,Feng L,Zhang S,Zhang H,Zhang X,Qi X,Zhang Y,Feng Q,Xiang T,Zeng YX.Induction of chemokine(C-C motif)ligand 5 by Epstein-Barr virus infection enhances tumor angiogenesis in nasopharyngeal carcinoma.Cancer Sci,2018,109(5):1710-1722.
[24]Rao SK,Pavicevic Z,Du Z,Kim JG,Fan M,Jiao Y,Rosebush M,Samant S,Gu W,Pfeffer LM,Nosrat C A.Pro-inflammatory genes as biomarkers and therapeutic targets in oral squamous cell carcinoma.J Biol Chem,2010,285(42):32512-32521.
[25]Chuang JY,Yang WH,Chen HT,Huang CY,Tan TW,Lin YT,Hsu CJ,Fong YC,Tang CH.CCL5/CCR5 axis promotes the motility of human oral cancer cells.J Cell Physiol,2009,220(2):418-426.
[26]Xia H,Kong SN,Chen J,Shi M,Sekar K,Seshachalam VP,Rajasekaran M,Goh B,Ooi LL,Hui KM.MELK is an oncogenic kinase essential for early hepatocellular carcinoma recurrence.Cancer Lett,2016,383(1):85-93.
[27]Kiseljak-Vassiliades K,Zhang Y,Kar A,Razzaghi R,Xu M,Gowan K,Raeburn CD,Albuja-Cruz M,Jones KL,Somerset H,Fishbein L,Leong S,Wierman ME.Elucidating the role of the maternal embryonic leucine zipper kinase in adrenocortical carcinoma.Endocrinology,2018,159(7):2532-2544.
[28]Speers C,Zhao SG,Kothari V,Santola A,Liu M,Wilder-Romans K,Evans J,Batra N,Bartelink H,Hayes DF,Lawrence TS,Brown PH,Pierce LJ,Feng FY.Maternal embryonic leucine zipper kinase(MELK)as a novel mediator and biomarker of radioresistance in human breast cancer.Clin Cancer Res,2016,22(23):5864-5875.
[29]Li S,Li Z,Guo T,Xing XF,Cheng X,Du H,Wen XZ,Ji JF.Maternal embryonic leucine zipper kinase serves as a poor prognosis marker and therapeutic target in gastric cancer.Oncotarget,2016,7(5):6266-6280.
[30]Liu H,Sun Q,Sun Y,Zhang J,Yuan H,Pang S,Qi X,Wang H,Zhang M,Zhang H,Yu C,Gu C.MELK and EZH2 cooperate to regulate medulloblastoma cancer stemlike cell proliferation and differentiation.Mol Cancer Res,2017,15(9):1275-1286.
[31]Puts GS,Leonard MK,Pamidimukkala NV,Snyder DE,Kaetzel DM.Nuclear functions of NME proteins.Lab Invest,2018,98(2):211-218.
[32]Wang C,Wang W,Liu Y,Yong M,Yang Y,Zhou H.Rac GTPase activating protein 1 promotes oncogenic progression of epithelial ovarian cancer.Cancer Sci,2018,109(1):84-93.
[33]Imaoka H,Toiyama Y,Saigusa S,Kawamura M,Kawamoto A,Okugawa Y,Hiro J,Tanaka K,Inoue Y,Mohri Y,Kusunoki M.RacGAP1 expression,increasing tumor malignant potential,as a predictive biomarker for lymph node metastasis and poor prognosis in colorectal cancer.Carcinogenesis,2015,36(3):346-354.
[34]Seder C W,Hartojo W,Lin L,Silvers A L,Wang Z,Thomas D G,Giordano T J,Chen G,Chang AC,Orringer MB,Beer DG.INHBA overexpression promotes cell proliferation and may be epigenetically regulated in esophageal adenocarcinoma.J Thorac Oncol,2009,4(4):455-462.
[35]Lyu S,Jiang C,Xu R,Huang Y,Yan S.INHBAupregulation correlates with poorer prognosis in patients with esophageal squamous cell carcinoma.Cancer Manag Res,2018,10:1585-1596.
[36]Hansen NU,Genovese F,Leeming DJ,Karsdal MA.The importance of extracellular matrix for cell function and in vivo likeness.Exp Mol Pathol,2015,98(2):286-294.
[37]Wu C.Focal adhesion:a focal point in current cell biology and molecular medicine.Cell Adh Migr,2007,1(1):13-18.
[38]He Y,Shao FY,Pi WD,Shi C,Chen YJ,Gong DP,Wang BJ,Cao ZW,Tang KL.Largescale transcriptomics analysis suggests over-expression of BGH3,MMP9 and PDIA3 in oral squamous cell carcinoma.PLoS One,2016,11(1):e146530.
[39]Brown CJ,Lain S,Verma CS,Fersht AR,Lane DP.Awakening guardian angels:drugging the p53 pathway.Nat Rev Cancer,2009,9(12):862-873.
[40]Gong Z,Yang Q,Zeng Z,Zhang W,Li X,Zu X,Deng H,Chen P,Liao Q,Xiang B,Zhou M,Li X,Li Y,Xiong W,Li G.An integrative transcriptomic analysis reveals p53regulated miRNA,mRNA,and lncRNA networks in nasopharyngeal carcinoma.Tumour Biol,2016,37(3):3683-3695.
[2]Jiang S,Dong Y.Human papillomavirus and oral squamous cell carcinoma:A review of HPV-positive oral squamous cell carcinoma and possible strategies for future.Curr Probl Cancer,2017,41(5):323-327.
[3]Stearns FW.One hundred years of pleiotropy:a retrospective.Genetics,2010,186(3):767-773.
[4]Lee YR,Chen M,Pandolfi PP.The functions and regulation of the PTEN tumour suppressor:new modes and prospects.Nat Rev Mol Cell Biol,2018,19(9):547-562.
[5]Newman ME.Modularity and community structure in networks.Proc Natl Acad Sci USA,2006,103(23):8577-8582.
[6]Clauset A,Newman ME,Moore C.Finding community structure in very large networks.Phys Rev E Stat Nonlin Soft Matter Phys,2004,70(6 pt 2):66111.
[7]Zhao XL,Zuo XY,Qin JH,Liang Y,Zhang NZ,Luan YZ,Rao SQ.A novel biological pathway expansion method based on the knowledge of protein-protein interactions.Hereditas(Beijing),2014,36(04):387-394.赵小蕾,左晓宇,覃继恒,梁岩,张乃尊,栾奕昭,饶绍奇.基于蛋白质互作知识的生物学通路扩充新方法.遗传,2014,36(4):387-394.
[8]Travers J,Milgram S.An experimental study of the small world problem.Sociometry,1969,32(4):425-443.
[9]Solovieff N,Cotsapas C,Lee PH,Purcell SM,Smoller JW.Pleiotropy in complex traits:challenges and strategies.Nat Rev Genet,2013,14(7):483-495.
[10]Wang J,Mei F,Gao X,Wang S.Identification of genes involved in Epstein-Barr virus-associated nasopharyngeal carcinoma.Oncol Lett,2016,12(4):2375-2380.
[11]Kato K,Kawashiri S,Yoshizawa K,Kitahara H,Okamune A,Sugiura S,Noguchi N,Yamamoto E.Expression form of p53 and PCNA at the invasive front in oral squamous cell carcinoma:correlation with clinicopathological features and prognosis.J Oral Pathol Med,2011,40(9):693-698.
[12]Poosarla C,Ramesh M,Ramesh K,Gudiseva S,Bala S,Sundar M.Proliferating cell nuclear antigen in premalignancy and oral squamous cell carcinoma.J Clin Diagn Res,2015,9(6):ZC39-C41.
[13]Madan M,Chandra S,Raj V,Madan R.Evaluation of cell proliferation in malignant and potentially malignant oral lesions.J Oral Maxillofac Pathol,2015,19(3):297-305.
[14]Zhai X,Yang Y,Wan J,Zhu R,Wu Y.Inhibition of LDH-Aby oxamate induces G2/M arrest,apoptosis and increases radiosensitivity in nasopharyngeal carcinoma cells.Oncol Rep,2013,30(6):2983-2991.
[15]Chen X,Zhang FH,Chen QE,Wang YY,Wang YL,He JC,Zhou J.The clinical significance of CDK1 expression in oral squamous cell carcinoma.Med Oral Patol Oral Cir Bucal,2015,20(1):e7-e12.
[16]Zhang Y,Liu Z.STAT1 in cancer:friend or foe?Discov Med,2017,24(130):19-29.
[17]Qu S,Guo Y,Huang ST,Zhu XD.Inhibition of STAT1sensitizes radioresistant nasopharyngeal carcinoma cell line CNE-2R to radiotherapy.Oncotarget,2018,9(9):8303-8310.
[18]Laimer K,Spizzo G,Obrist P,Gastl G,Brunhuber T,Schafer G,Norer B,Rasse M,Haffner MC,Doppler W.STAT1 activation in squamous cell cancer of the oral cavity:a potential predictive marker of response to adjuvant chemotherapy.Cancer,2007,110(2):326-333.
[19]Urata S,Izumi K,Hiratsuka K,Maolake A,Natsagdorj A,Shigehara K,Iwamoto H,Kadomoto S,Makino T,Naito R,Kadono Y,Lin WJ,Wufuer G,Narimoto K,Mizokami A.C-C motif ligand 5 promotes migration of prostate cancer cells in the prostate cancer bone metastasis microenvironment.Cancer Sci,2018,109(3):724-731.
[20]Kan JY,Wu DC,Yu FJ,Wu CY,Ho YW,Chiu YJ,Jian SF,Hung JY,Wang JY,Kuo PL.Chemokine(C-C motif)ligand 5 is involved in tumor-associated dendritic cellmediated colon cancer progression through non-coding RNA MALAT-1.J Cell Physiol,2015,230(8):1883-1894.
[21]Huang CY,Fong YC,Lee CY,Chen MY,Tsai HC,Hsu HC,Tang CH.CCL5 increases lung cancer migration via PI3K,Akt and NF-kappaB pathways.Biochem Pharmacol,2009,77(5):794-803.
[22]Khalid A,Wolfram J,Ferrari I,Mu C,Mai J,Yang Z,Zhao Y,Ferrari M,Ma X,Shen H.Recent advances in discovering the role of CCL5 in metastatic breast cancer.Mini Rev Med Chem,2015,15(13):1063-1072.
[23]Ma W,Feng L,Zhang S,Zhang H,Zhang X,Qi X,Zhang Y,Feng Q,Xiang T,Zeng YX.Induction of chemokine(C-C motif)ligand 5 by Epstein-Barr virus infection enhances tumor angiogenesis in nasopharyngeal carcinoma.Cancer Sci,2018,109(5):1710-1722.
[24]Rao SK,Pavicevic Z,Du Z,Kim JG,Fan M,Jiao Y,Rosebush M,Samant S,Gu W,Pfeffer LM,Nosrat C A.Pro-inflammatory genes as biomarkers and therapeutic targets in oral squamous cell carcinoma.J Biol Chem,2010,285(42):32512-32521.
[25]Chuang JY,Yang WH,Chen HT,Huang CY,Tan TW,Lin YT,Hsu CJ,Fong YC,Tang CH.CCL5/CCR5 axis promotes the motility of human oral cancer cells.J Cell Physiol,2009,220(2):418-426.
[26]Xia H,Kong SN,Chen J,Shi M,Sekar K,Seshachalam VP,Rajasekaran M,Goh B,Ooi LL,Hui KM.MELK is an oncogenic kinase essential for early hepatocellular carcinoma recurrence.Cancer Lett,2016,383(1):85-93.
[27]Kiseljak-Vassiliades K,Zhang Y,Kar A,Razzaghi R,Xu M,Gowan K,Raeburn CD,Albuja-Cruz M,Jones KL,Somerset H,Fishbein L,Leong S,Wierman ME.Elucidating the role of the maternal embryonic leucine zipper kinase in adrenocortical carcinoma.Endocrinology,2018,159(7):2532-2544.
[28]Speers C,Zhao SG,Kothari V,Santola A,Liu M,Wilder-Romans K,Evans J,Batra N,Bartelink H,Hayes DF,Lawrence TS,Brown PH,Pierce LJ,Feng FY.Maternal embryonic leucine zipper kinase(MELK)as a novel mediator and biomarker of radioresistance in human breast cancer.Clin Cancer Res,2016,22(23):5864-5875.
[29]Li S,Li Z,Guo T,Xing XF,Cheng X,Du H,Wen XZ,Ji JF.Maternal embryonic leucine zipper kinase serves as a poor prognosis marker and therapeutic target in gastric cancer.Oncotarget,2016,7(5):6266-6280.
[30]Liu H,Sun Q,Sun Y,Zhang J,Yuan H,Pang S,Qi X,Wang H,Zhang M,Zhang H,Yu C,Gu C.MELK and EZH2 cooperate to regulate medulloblastoma cancer stemlike cell proliferation and differentiation.Mol Cancer Res,2017,15(9):1275-1286.
[31]Puts GS,Leonard MK,Pamidimukkala NV,Snyder DE,Kaetzel DM.Nuclear functions of NME proteins.Lab Invest,2018,98(2):211-218.
[32]Wang C,Wang W,Liu Y,Yong M,Yang Y,Zhou H.Rac GTPase activating protein 1 promotes oncogenic progression of epithelial ovarian cancer.Cancer Sci,2018,109(1):84-93.
[33]Imaoka H,Toiyama Y,Saigusa S,Kawamura M,Kawamoto A,Okugawa Y,Hiro J,Tanaka K,Inoue Y,Mohri Y,Kusunoki M.RacGAP1 expression,increasing tumor malignant potential,as a predictive biomarker for lymph node metastasis and poor prognosis in colorectal cancer.Carcinogenesis,2015,36(3):346-354.
[34]Seder C W,Hartojo W,Lin L,Silvers A L,Wang Z,Thomas D G,Giordano T J,Chen G,Chang AC,Orringer MB,Beer DG.INHBA overexpression promotes cell proliferation and may be epigenetically regulated in esophageal adenocarcinoma.J Thorac Oncol,2009,4(4):455-462.
[35]Lyu S,Jiang C,Xu R,Huang Y,Yan S.INHBAupregulation correlates with poorer prognosis in patients with esophageal squamous cell carcinoma.Cancer Manag Res,2018,10:1585-1596.
[36]Hansen NU,Genovese F,Leeming DJ,Karsdal MA.The importance of extracellular matrix for cell function and in vivo likeness.Exp Mol Pathol,2015,98(2):286-294.
[37]Wu C.Focal adhesion:a focal point in current cell biology and molecular medicine.Cell Adh Migr,2007,1(1):13-18.
[38]He Y,Shao FY,Pi WD,Shi C,Chen YJ,Gong DP,Wang BJ,Cao ZW,Tang KL.Largescale transcriptomics analysis suggests over-expression of BGH3,MMP9 and PDIA3 in oral squamous cell carcinoma.PLoS One,2016,11(1):e146530.
[39]Brown CJ,Lain S,Verma CS,Fersht AR,Lane DP.Awakening guardian angels:drugging the p53 pathway.Nat Rev Cancer,2009,9(12):862-873.
[40]Gong Z,Yang Q,Zeng Z,Zhang W,Li X,Zu X,Deng H,Chen P,Liao Q,Xiang B,Zhou M,Li X,Li Y,Xiong W,Li G.An integrative transcriptomic analysis reveals p53regulated miRNA,mRNA,and lncRNA networks in nasopharyngeal carcinoma.Tumour Biol,2016,37(3):3683-3695.