摘要
目的:检测雌、孕激素受体不同表达状态子宫内膜样腺癌的基因表达谱特征及雌、孕激素受体作用的相关基因改变,探讨雌、孕激素受体在子宫内膜样腺癌发病中的作用并为特异性的靶向治疗提供理论基础。
方法:(1)采用人17kcDNA表达谱芯片,抽取ER(+)PR(+);ER(-)PR(-);ER(+)PR(-)子宫内膜样腺癌组织及正常子宫内膜组织RNA,经逆转录成cDNA分别进行芯片杂交实验,筛选比值大于、等于2或等于、小于.2的差异表达基因并进行差异基因功能分类;(2)通过生物信息学分析、筛选不同雌、孕激素受体子宫内膜样腺癌差异基因表达谱、凋亡信号通路及雌、孕激素受体调节相关基因;(3)RT-PCR、免疫组化验证部分基因。
结果:(1)ER(+)PR(+);ER(-)PR(-);ER(+)PR(-)子宫内膜样腺癌分别与正常子宫内膜比较,差异表达基因各有1653个、1756个、2215个;其中上、下调基因分别有902个、751个;907个、849个;1029个、1186个;基因功能分类主要有:细胞结合、凋亡、信号转导、细胞周期、转录子激活等16类。(2)ER(+)PR(+);ER(-)PR(-);ER(+)PR(-)子宫内膜样腺癌特异性差异表达基因各有571个、645个、1125个;上、下调基因分别有399个、172个;443个、202个;608个、517个。(3)雌激素受体相关差异表达基因1177个,其中上调493个,下调684个;上调的基因功能分类主要为细胞有丝分裂、胚胎发育及形态、免疫反应调节、糖代谢、DNA复制调节等31类;下调的基因类别为:T细胞增殖、血管形成、细胞迁移、细胞粘附、创伤反应、信号转导等共27类。孕激素受体相关的差异表达基因1413个,其中上调814个,下调549个;上调基因功能类别主要有巨噬细胞激活、病毒防御反应、肽及酪氨酸磷酸化正调节、氨基酸代谢调节、抗原递呈与处理等73类;下调基因类别主要有翻译、生物合成、大分子代谢3类。雌、孕激素受体相关的差异表达基因838个,其中上调466个,下调372个;雌、孕激素受体相关的上调基因类别主要有:淋巴细胞负调节、B细胞增殖、多肽抗原递呈与处理、补体经典途径、体液免疫反应、抗原递呈等65类;下调的基因类别有:气体运输、分泌、消化等4类。(4)ER(+)PR(+);ER(-)PR(-);ER(+)PR(-)子宫内膜样腺癌在经典凋亡信号通道中差异表达基因分别是:BIRC3、TNFSF10、NFκBIA;PDCD8、BIRC3、PRKACB、NFκBIA、PIK3R1、PIK3R3;ER(+)PR(-)TP53、PDCD8、BIRC3、CASP7、NFκBIA、CHUK、PIK3CD、PIK3R1、PIK3R3、IL3RA、ILlA。(5)RT-PCR实验:INHBA在正常内膜组为26.37±15.35;在ER(+)PR(+)、ER(-)PR(-)、ER(+)PR(-)内膜癌组分别为117.68±44.15,45.96±29.02,37.14±31.03,分别与正常组比较,结果除与ER(+)PR(+)内膜癌组有显著差异外(P＜0.05),余均无显著差异(P＞0.05)。FYN在正常内膜组为83.24±32.30;在ER(+)PR(+)、ER(-)PR(-)、ER(+)PR(-)内膜癌分别为48.01±38.29,18.01±19.67,20.46±16.51与正常内膜组比较,结果除与ER(+)PR(+)内膜癌组无明显差异(P＞0.05):外,余两组差异显著(P＜0.05)。Cyr61在正常内膜组织为102.63±34.83,在内膜癌ER(+)PR(+)、ER(-)PR(-)、ER(+)PR(-)组分别为25.28±28.99、55.35±44.82,10.23±11.06与正常内膜组比较,结果除与ER(-)PR(-)内膜癌组无明显差异(P＞0.05)外,余两组差异显著(P＜0.05)。(6)免疫组化:Cyr61蛋白定位于细胞膜、细胞浆,阳性表达为淡黄到棕褐色不等;Cyr61在正常组织的表达为5.10±2.64,在内膜癌手术-病理分期Ⅰ、Ⅱ、Ⅲ期分别为3.38±1.69、3.25±1.96、1.60±1.35。组间两两比较除内膜癌Ⅰ期与Ⅱ期间无显著差异外(P＞0.05),余组间均差异明显(P＜0.05);将Cyr61在不同组织学分级比较,G1为3.55±1.53,G2为3.30±1.71均高于G3的1.82±1.17(P＜0.05),但内膜癌G1与G2级间无明显差异(P＞0.05)。
结论:(1)多基因表达的变化参与了子宫内膜样腺癌的发病;(2)不同类型激素受体内膜癌不同的差异基因表达谱及凋亡信号通路是其预后差别的分子基础;各型受体特异的差异表达基因可能成为基因靶向治疗的有效靶点;(3)雌、孕激素受体能调节多种基因表达,单一雌激素受体主要通过促进有丝分裂,下调T细胞增殖分化反应;单一孕激素受体主要经刺激巨噬细胞激活,下调核糖体蛋白的转录;而雌、孕激素受体交互作用主要上调淋巴细胞负调节,下调气体运输等参与内膜癌的发病;(4)Cyr61可能成为指导临床治疗的分子指标。
Objective:Study on the profile of gene expression association with the distinct estrogen and progestogen receptor in endometrioid adenocarcinoma.so as to reveal the role of the estrogen and progestogen receptor in the pathogenesis of endometrioid adenocarcinoma and provid a special targeted therapy in rationale.
Methods:(1)By drawing the RNA from the endometrioid adenocarcinoma with estrogen receptor and progestogen receptor all positive(ER+)(PR+),estrogen receptor and progestogen receptor all negetive(ER-)(PR-),estrogen receptor positive and progestogen receptor negetive(ER+)(PR-),and normal endometrium,respectively, reversetranscription RNA to cDNA and hybridization with 17kcDNA human gene chip,screen the gene ratio equal 2 or higher than 2 and ratio eqeal -2 or lower than -2 as the difference expression genes.(2) Analysis the genetic expression and the apoptosis signal pathway and the related gene in the distincted expression of ER and PR in endometrioid adenocarcinoma by bioinformatics.(3) Verification the genes by reverse transcriptase PCR and immunohisochemistry.
Results:(1) There differential expression genes were 1653,1756, 2215 strips when the(ER+)(PR+),(ER-)(PR-),(ER+)(PR-) endometrioid adenocarcinoma comparedwith the nomor endometrium,respectively,in each group the up-regulated genes and down-regulated gens were 902、751,907、849,1029and 1186.According to the Gene Ontology(Go) classified the gene into 16 kinds:binding,apoptosis,metabolism,cell cycle,signal transduction,transcription activation,etc.(2) There were specially differential expression genes 471 in the(ER+)(PR+) endometrioid adenocarcinoma,which up-regulated genes 399 and down-regulated genes 172.The special differential expression genes 645 in(ER-)(PR-) endometrioid adenocarcinoma,the up-regulated genes were 443,the down-regulated were 202.The special differential expression genes 1125 in(ER+)(PR-) endometrioid adenocarcinoma,the up-regulated genes were 608,the down-regulated were 567.(3)The difference expression genes 1177 were relatived with the estrogen receptor in which up-regulated genes 493 and down-regulated genes 684.According to the Gene Ontology(Go) classified the up-regulated genes into 31 kinds:cell mitosis,embrynomic,cranial skeleton morphogensis,immune response regulation,glycometabolism,DNA duplicate,and so on.The down-regulation genes kinds 27:T cell proliferation,angiopioesis,cell migration,cell adhesion,wound responds,signal transduction,etc.The difference expression genes 1413 were relatived with the progestrogen receptor in which up-regulated genes 814 and down-regulated genes 549. The up-regulated genes classified into 73 kinds:macrophage activied, defence virus,positive regulated the peptide,tyrosine phosporylation, amino acid metabolism,antigen presentation,etc.The down-regulated genes classified into 3 kinds:translation,biosynthesis,macromolecule biosynthetic prosess.There were difference expression genes 838 relatived to the expression of the ER and PR,in which up-regulated genes were 466 and down-regulated genes 372.The up-regulated genes classified into 65 kinds:negative regulation of lymphocyte activation,B cell proliferation,antigen processing and presentation of peptide antigen via MHC calss I,antigen processing and presentation of peptide antigen, etc.The down-regulated genes were classified kinds 4:gas transport, excretion,digestion,etc.(4) The differencial expression genes in the apoptosis pathway in endometrioid adenocarcinoma with(ER+)(PR+) were BIRC3,TNFSF10,NFκBIA,and in endomtrioid adenocarcinoma with(ER-)(PR-) were PDCD8,BIRC3,PRKACB,NFκBIA,PIK3R1, PIK3R3.but in endometrioid adenocarcinoma with(ER+)(PR-) were TP53,PDCD8,BIRC3,CASP7,NFκBIA,CHUK,PIK3CD,PIK3R1, PIK3R3,IL3RA,IL1A.(5) Vertifercail the genes by RT-PCR.The expression of INHBA were 26.37±15.35 in the normal endometrium, and were 117.68±44.15,45.96±29.02,37.14±31.03 in the (ER+)(PR+),(ER-)(PR-),(ER+)(PR-) endometrioid adenocarcinoma, respectively,When compared the endometrioid adenocarcinoma with the normal endometrium,there were significant defference between the endometrioid adenocarcinoma with(ER+)(PR+) and the normal(p＜0.05). There were no difference in the others(p＞0.05).The expression of FYN in normal were 83.24±32.30,but in endometrioid adenocarcinoma with (ER+)(PR+);(ER-)(PR-),(ER+)(PR-) were 48.01±38.29,18.01±19.67, 20.46±16.51,respectively.Compared each other,exceptes had no difference between(ER+)(PR+) endometrioid adenocarcinoma with the normal(p＞0.05),There were significant differernce in the others (p＜0.05).The expression of Cyr61 were 102.63±34.83 in normal endometrium and in the endometrioid adenocarcinoma with (ER+)(PR+),(ER-)(PR-),(ER+)(PR-) were 25.28±28.99,55.35±44.82, 10.23±11.06,respectively.Compared with each others,excepted no significant difference between the(ER-)(PR-) endometrioid adenocarcinoma with the normal endometrium(p＞0.05),there were significant difference in the others(p＜0.05).(6) The expression of Cyr61 were located in cell membrane and cytoplasm by immunohistochemistry. The positive appearance were color changed frome yellow to brown.The expression of Cyr61 in normal endometrium were 5.10±2.64 and in endometrioid adenocarcinoma with FIGO stageⅠ,stageⅡ,stageⅢwere 3.38±1.69,3.25±1.96,1.60±1.35,respectively.There were no difference when between the stageⅠand stageⅡ(p＞0.05),but there were significants difference not only in the stageⅠwith normal but also in the stageⅡwith normal endometrium(p＜0.05).The expression of Cyr61 in the endometioid adenocarcinoma with grade 1,grade 2 and grade 3 were 3.55±1.53,3.30±1.71,1.82±1.17.There no significant difference between the G1 and G2(p＞0.05),but there were significant defference not only between G1 and G3 but also between G2 and G3(p＜0.05).
Conclusions:(1)There are many genes participated the etiopathogenisis of endometrioid adenocarcinoma(2) The various genes and the distinct apoptosis pathway along with the dictinct expression of the ER and PR played a crital roles in the prognosis of the endometrioid adenocarcinoma.(3) The ER or PR could regulate the variants gene expression.The ER up-regulated mitosis and negatived the T cell proliferation at the same time in favour the genesis of the endometrioid adenocarcinoma,the PR by up-regulated actived macrophage and down-regulated the transcription of ribosomal protein and the up-regulated negative regulate lympholyte and down-regulate the gas transport by ER and PR all participate the pathogenesis of the endometrioid adenocarcinoma.(4) The Cyr61 maybe regard as a target of the therapy in endometrioid adenocarcinoma.
引文
[1]乐杰 主编.妇产科学第七版[M].人民卫生出版社,2008,4:272-277.
[2]赵群,张淞文,王涛,等.北京地区子宫内膜癌筛查方法的研究[J].北京医学,2008;30(9):513-515.
[3]刘恩菊,项永兵,金丹,等.上海市区恶性肿瘤发病趋势分析[J].肿瘤,2004;24(1):11-15.
[4]高原,罗新.第18届FIGO世界妇产科学术会议纪要-子宫内膜癌篇[J].中国实用妇科与产科杂志,2008;24(8):536-539.
[5]Jemal A,Thomas A,Murray T,et al.Cancer staistics[J].CA Cancer J Clin,2002;52(1):23-47.
[6]易晓芳,郑文新.子宫内膜癌的分型及其临床意义.中国使用妇科与产科杂志,2008:24(1):15-17.
[7]王文军,杨冬梓,范顺家,等.232例子宫内膜癌发病年龄趋势和确诊时间[J].中山大学学报(医学科学版),2004;25(S2):142-144.
[8]David M.Epidemiology of endometrial cancer[J].Reviews in Gynaecological pratice,2003;3(5):217-220.
[9]Kim,J.Protective effrcts of Asian dietary iems on cancers-soy and ginseng[J].Asian Pac J cancer prev,2008;9(4):543-548.
[10]李小平,商宇红,魏丽惠,等.子宫内膜癌肿瘤家族聚集性研究[J].中国妇产科临床.2000:8(1):15-17.
[11]David WS.Endometrial cancer and HRT[J].Gynaecol Pract,2005;5:51-56.
[12]Omar R,Karen P,David G,et al.Expression profiling of mouse endometrial cancers microdissected from the fixed parnffin-embedded tissues[J].American J Patho,2003;162(3):755-762.
[13]Lina A,Mark BC,Suzy D,et al.Consequences of the loss of P53、RB1、PTEN:Relationship to gefitinib resistance in endometrial cancer[J].Gyneco onco,2007;106(1):94-104.
[14]Doll A,Abel M,Rigan M,et al.Novel molecular profiles of endometrial cancer new light through old windows[J].J Steroid Biochem Mol Biol,2008;108(3):221-229.
[15]宋英娜,郎景和.子宫内膜癌的微卫星不稳定性与临床病理和雌、孕激素受体水平的关系[J].中华妇产科杂志,2000;35(5):273-276.
[16]李华,杨兴升,曲迅,等.CYP1A1基因多态性与子宫内膜腺癌发生的关系研究[J].实用妇产科杂志,2006;22(3):151-154.
[17]Cerolyn KM,David GM,Randall KG,et al.Body mass index:Relationship to clinical pathologic and features of microsatellite instability in endometrial cancer[J].Gynecol Oncol,2007;104(13):535-539.
[18]陈美霞,孟元光,韩为东,等.DNA甲基化在子宫内膜癌中的研究进展[J].国外医学.妇产科学分册,2007;34(6):421-424.
[19]刘曼华,陶潜,郑艳莉,等.Surivin、雌、孕激素受体在子宫内膜癌中的表达的意义[J].南通大学学报,2007;27(5):346-348.
[20]戴钟英.子宫内膜癌的激素治疗[J].实用妇产科杂志,2008;24(5):268-269.
[21]赵晓东,张毅.子宫内膜癌的治疗[J].中国肿瘤临床,2007;34(1):56-59.
[22]Nahta R,Esteva FJ.Herceptin:mechanisme of action and resistance[J].Cancer Lett,2006;232(2):123-138.
[23]茆勇军,张佩璇,田广辉,等.血管内皮生长因子受体酪氨酸激酶抑制剂的研究进展[J].中国新药杂志,2008;17(7):544-560.
[24]Asco in the 21st century:challeges and opportunities-Asco presidential address[J].J Clin Oncol,2006;24(13):1967-1971.
[25]李世君,元娇娇.雌激素受体、孕激素受体在子宫内膜癌中的表达与预后的关系.包头医学院学报,2003;19(3):177-178.
[26]李海萍.雌、孕激素受体与子宫内膜癌的预后[J].青海医学院学报,2006;27(3):212-214.
[27]陈雅卿,楼洪坤.甾体激素受体PR、ER表达与子宫内膜癌淋巴结转移关系的研究[J].肿瘤防治杂志,2002;9(5):478-479.
[28]万正东,陆飞飞,刘志明.mmp-2、mmp-7在甲状腺乳头状癌中的表达及其临床意义[J].广西医科大学学报,2008;25(5):677-679.
[29]刘广寅,刘琳,盛树海,等.基质溶解素在乳腺癌组织中的表达及其临床意义[J].华北煤炭医学院学报,2008;10(5):599-601.
[30]Espen A,Maria P,Bjarne J,et al.Regulation of MAPK-activated protein kinase 5 activity and subcellulor localization by the atypical MAPK ERK4/MAPK4[J].J Biology Chemist,2006;28(46):35499-35510.
[31]Lee S,Kang J,Cho M,et al.Profiling of teanscripts and proteins modulated by K-ras oncogene in the lung tissues of K-ras transgenic mice by omits approaches[J].Int J Oncol,2009;34(1):161-172.
[32]王志启,王建六,魏丽慧.子宫内膜癌合并症146例临床分析[J].中华妇产科杂志,2003;38(6):350-353.
[33]Zhi-Min Liu,Geoge GC,Cathy kys,et al.Induction of functional MT1 and MT2:isoforms by calcium in anaplastic thyroid carcinoma cells[J].FEBS Letters,2007;581(13):2465-2472.
[34]Trevor S,Kanwaldeep KR,Michael JR,et al.The chemokine CXCL14(BRAK)stimulates activated NK cell migration:implications for the downregulation of CXCL14 in malignancy[J].Experi Hematology,2006;34(8):1101-1105.
[35]Frederick MJ,Henderson Y,Xu X,et al.In vivo expression of novel CXC chemokine BRAK in nomal and cancers human tissue[J].Am J Pahol,2000;156(6):1937-1950.
[36]Shigeyuki O,Yasumas K,Reika K,et al.BRAK/CXCL14 expression suppresses tumor growth in vivo in human oral carcinoma cells[J].Biochem Biophy Res Communi,2006;348(2):406-412.
[37]Yang LL,Ping C,Luo S,et al.CXCL10 gene therapy efficiently inhibited the growth of cervical carcinoma based on the antiangiogenic and antiviral activity[J].Biotechnol appl Biolchem,2009;[Epub ahead of print].
[38] Persano L, Moserie L, Esposito G, et al. Interferon-alpha counteracts the angiogenic switch and reduces tumor cell proliferation in a spontaneous model of prostatic cancer[J]. Cercinogenesis, 2009; [Epub ahead of print].
[39] Mei K, Wang L, Tian L, et al. Antitumor efficacy of combination of interferon-gamma-inducible protein 10 gene with gemcitabine a study in murine model[J]. J Exp Clin Cancer Res, 2008; 27:63.
[40] Wendel M, Galani IE, Suri-Payer E, et al. Natural killer cell accumulation in tumors is dependent on IFN-gamma and CXCR3 ligands[J]. Cancer Res, 2008; 68(20): 8437-8445.
[41] Sato E, Fujimoto J, Tamaya T, et al. Expression of interferon-gamma-inducible protein 10 related to angiogenesis in uterine endometrial cancers[J]. Oncology, 2007; 73(3-4): 246-251.
[42] Preussat K, Beetz C, Schrey M, et al. Expression of voltaget-gated potassium chanmels kv1.3 and kv1.5 in human glimas[J]. Neurosci Letee, 2003; 346(1-2): 33-36.
[43] Abduc M, Hoosein N. Expression and activity of postassium ion channels in human prostate cancer[J]. Cancer Lett, 2002; 86(1): 99-105.
[44] Fraser SP, Grimes JA, Diss JK, et al. Predominant expression of KV1.3 voltage-gated K~+ channel subunit in rat prostate cancer cell lines: electrophysiological pahamacological and molecular characteristation[J]. Pflugers Arch, 2003; 446(5): 559-571.
[45] Tschritter O, Machicao F, Stefan N, et al. A new variant in the human Kv1.3 gene is associated with low insulin sensitivity and impaired glucose tolerance[J]. J Clin Endocrinol Metab, 2006; 91(2): 654-658.
[46] Kinney EL, Tanida S, Rodrigue AA, et al. Adenovirus El A oncoprotein liberates c-myc activity to promote cell proliferation through abating Binl expression via and Rb/E2F1-dependent mechanism[J]. J CellPhysial, 2008; 216(3): 621-631.
[47] Kuinetsova EB, Kekeeva TV, Larin SS, et al. Methylation of the BIN1 gene promoter CPG island associated with breast and prostate cancer[J]. J Carcinog, 2007; 6(9):1-6.
[48] Ghaneie A, Zemba-palko V, Itoh H, et al. BIN1 attenuation in breast cancer is correlated to nodal metastsis and reduced survival[J]. Cancer Bio Ther, 2007; 6(2): 192-194.
[49] Chang MY, Boulden J, Katz JB, et al. Binl ablation increases susceptibility to cancer during ageing particularly lung cancer[J]. Cancer Res, 2007; 67(16): 7605-7612.
[50] Yu W, Su Z, Wu Z, et al. cDNA clone prokaryotic expression and purification of human interleukin-13 receptor alpha2 chain[J]. Cancer Immunol Immunother, 2009; 58(3): 409-413.
[51] Zhang K, Hu S, Wu J, et al. Overexpression of RRM2 dereases thrombspondin-1 and increase VEGF production in human cancer cells in vitro and in vivo:omplication of RRM2 in angiogensis[J]. Mol Cancer, 2009; 28(1): 8-11.
[52] Kolesar J, Huang W, Eickhoff J, et al. Evaluation of Mrna by Q-RTPCR and protein expression by AQUA of the M2 subunit of ribonucleotide reductase (RRM2) in human tumors[J]. Cancer Chemother Ptharrmacol, 2008; [Epub ahead of print].
[53] Souglakos J, Boukovinas I, Taron M, et al. Ribonuceotide reductase subunits Ml and M2 Mrna expression levels and clinical outcone of lung adenocarcinoma patients treated with deocetaXEL/genicitabine[J] Br J Cancer, 2008; 98(10): 1710-1715.
[54] Penning TM, Byrns MC. Steroid hormone transforming aldo-keto reduced and cancer[J]. Ann NY Acad Sci, 2009; 1155: 33-42.
[55] Wang S, Yang Q, Fung KM, et al. AKR1C2 and AKR1C3 mediated prostaglandin D2 metabolism augments eht PI3K/AKT proliferatve signaling pathway in human prostate cancer cells[J]. Mol Cell Endocrinol, 2008; 289(1-2): 60-66.
[56] Lu DD. AKR1C2 small interfering RNA (SiRNA) inhibited beta-catenin expression and transcriptional activation in human liver cancer cell Liue QGY7701[J].Hepatogastrogenterology,2007;54(79):2088-2091.
[57]Riekenberg S,Ferhat K,Debarry J,et al.Regulators of G-protein signaling are modulated by bacterial lipopetides and lipopolysaccharide[J].FEBS J,2009;276(3):649-659.
[58]Park BC,Park SY,Lee JS,et al.The anti-angiogenic effects of 1-furan-2-yl-3-pyridin-2-yl-propenone are mediated through the suppression of both VEGF-production and VEGF-induced signaling[J].Vascul Pharmaco L,2009;50(3-4):123-131.
[59]Yang Z,Pun J.A novel role for tissue factor pathway inhibitor-2(TFPI-2) in the therapy of human esophageal carcinoma[J].Hum Gen Ther,2008;(epub ahead of print).
[60]Kempaiah,Kisiel W.Human tissue factor pathway inhibitor-2 induces caspase-mediated apoptosis in a human fibrosarcoma cell line[J].Apoptosis,2008;13(5):702-715.
[61]Fu Y,Zhang Q,Kang L,et al.Inhibitory effects of adenovirus mediated AKT1and PIK3R1 shRNA on the growth of malignant tumor cells in vitro and in vivo[J].Cancer Bion Ther,2009;8(11):[Epub ahead of print].
[62]Wee S,Wiederschain D,Maira SM,et al.PTEN-deficient cancers depend on PI3KCB[J].Proc Natl Acad Sci USA,2008;105(35):13057-13062.
[63]Derek CR,Mina JB.NFκB links oestrogen receptor signailing and EMT[J].Nature Cell Bio,2007;9(4):361-364.
[64]Veronique B,Michael K.Is NFκB a:good target for cancer therapy? Hope and Pitfalls[J].Nature,2009;8(1):33-40.
[65]Anwesha D,Vinay T,David PL.Double-edged swords as cancer therapeutics:simultaneously targeting P53 and NFκB Pathways[J].Nature.2008;7(12):1031-1040.
[66]Ma O,Cai WW,Zender L,et al.MMP-13、Birc2(cIAP1) ando Birc3(cIAP2)amplified on chromosome 9 collaborate with P53 deficiency in mouse oateosarcoma progression[J].Cancer Res,2009;69(6):2559-2567.
[67]Daigeler A,Chromik AM,Geisler A,et al.Synergistic apoptotic effects of faurolidice and TRIL on squamous carcinoma cells of the esophagus[J].Int J Oncol,2008;32(6):1205-1220.
[68]Hess CJ,Berkhof J,Denkers F,et al.Activated intrinsic apoptosis pathway is a key related prognostic parameter in acute myeloid leukemia[J].J Clin Oncol,2007;25(10):1209-1215.
[69]Zhu H,Lu W,Laurent C,et al.Genes oncoding catalytic subunits of protein kinase A and risk of spina bifida[J].Birth Defects Res A Clin Mol Teratol,2005;73(9):591-596.
[70]Aldinucci D,Olivo K,Corenzon D,et al.The role of interleukin-3 in classical Hodgkin's disease[J].Leuk Lymphona,2005;6(3):303-311.
[71]杨兴升,孔北华.子宫内膜癌预后及影响因素[J].实用妇产科杂志,2008;24(5):272-273.
[72]Keisuke I,Eiki O,Fumiaki T,et al.Identification of overexprssed genes in hepatocellular carcinoma with special referce to ubiquitin-conjugating enzyme E2C gene expression[J].Int J Cancer,2007;121(1):33-38.
[73]Yoshiaki O,Toshinori O,Kou M,et al.Ubah10 2s the cancer-related E2ubiquitin-conjugating Euzyme[J].Cancer resear,2003;63(3):4167-4173.
[74]Yasuo T,Yukimoto I,Yayoi N,et al.Detection of aberrations of ubiquitin-conjugating enzyme E2C gene(UBE2C) in advanced colon cancer with liver metastases by DNA microaaray and Two-Color FISH[J].Cancer Genetics and cytogentics.2006;168(1):30-35.
[75]Keisuke I,Eiki O,Fumiaki T,et al.Identification of overexpressed genes in hepatocellular carcinoma with special reference to ubiquitin-conjugationg enzymeE2C gene expression[J].Int J Cancer,2007;121(1):33-38.
[76]Graeme W,Kennth M,Alistair RWW,et al.Estrogen-regulated gene expression predicts response to endocrine therapy in patients with ovarian cancer[J].Gynecologic Oncology,2007;106(3):461-468.
[77]Bredel M,Bredel C,Juric D,et al.Functional network analysis reveals extended giomagenesis pathway maps and three novel myc-interacting gene in human giomas[J]. Cancer Res, 2005; 65(19): 8679-8689.
[78] Erkani S, Kayasecuk F, Kuscu E, et al. Cox-2 and surviving are overexpressed and positively correlated in endometrial carcinoma[J]. Gynecol Oncol, 2007; 104(2): 320-325.
[79] Ai Z, Yin L, Zhou X, et al. Inhibition of surviving reduces cell profiferation and induces apoptosis in human endometrial cancer[J]. Cancer, 2006; 107(4): 746-756.
[80] Pallares J, Martines-Guiltarte TL, Dolcet X, et al. Survivin expression in endometrial cancinoma:a tissue microarry study with cooelation with PTEN and STAT3[J] . Int J Gynecol Pathol, 2005; 24(3): 247-253.
[81] Blad F, Aippersbach E, GelkopS, et al. The murine NCK SH2/SH3 adaptors are omportant for the development of mesoderum-derived embryomic structures and for regulating the cellular actin network[J]. Mol Cell Bio, 2003; 23(13): 4586-4597.
[82] Rajesh K, Iyer A, Suragani RW, et al. Intersubunit and interprotein inferations of alpha-and beta-subunits of human e2F2:Effect of phosphorylation[J]. Biochem Biophys Res Commun,2008; 374(2): 336-340.
[83] Li C, Sohibli D, Li SS. The XLP syndrome protein SAP interacts with SH3 proteins to regulate T cell signaling and proliferation[J]. Cell Signal, 2009; 21(1): 111-119.
[84] Miyamoto Y, Yamanchi J, Mizuno N, et al. The adaptor protein NCK1 mediates endothelin A receptor-regulated cell migration through the Cdc42-dependendt c-Jun N-terinal Kinase pathway[J]. J Bio Chem, 2004; 279(33): 34736-34742.
[85] Saito J, Takayama T, Osaki T,et al. Combined mobilization and stimulation of tumor-infiltrating dendrictic cells and natural killer cells with FLT3 ligand and IL-18 in vivo induces systemic antitumor immunity[J]. Cancer Sci, 2008; 99(10): 2028-2036.
[86] Kang HS, Jim SJ, Myung CS, et al. Deliery of interleukin-18 gene to lung cancer cells using catiomic emulsion[J].J Drug Target,2009;17(1):19-28.
[87]Shimada M,Ando T,Peek RM,et al.Helilobacter pylori infection upregulates interleukin-18 production from gastric epithelia cells[J].Eur Gastroentera Hepatol,2008;20(12):1144-1150.
[88]Thog ND,Tangkijvanich P,Lerknimit R,et al.Diagnostic role of serum interleukin-18 in gastric cancer patients[J].World Gastrogenterol,2006;12(28):4473-4477.
[89]Sumamura M,Sun L,Lozonschi L,et al.The antiangiogenesis effect of interleukin-12 during early growth of human pancreatic cancer in SCID mice[J].Pancreas,2000;20(3):227-233.
[90]Meyer-Siegler KL,Leifheit EC,Vera PL.Inhibition of macrophage migration inhibitory factor decreases proliferation and cytokine expression in bladder cancer cells[J].Bmc Cancer,2004;12(4):24-34.
[91]Beatriz ER,Sharon SW,Wayne Z,et al.Mechanisms of macrophage migration inhibitory factor(MIF)-dependent tumor microenviamental adaptation[J].Experiental Molecular pathology,2008;[Epub ahead of print].
[92]Ellen JB,Zrina VP,Giovanni S,et al.Helicobacter pylofi CagA-dependent macrophage migration inhilitory factor produced by Gastric epithelial cells binds to CD74 and stimulations procarcinogenic events[J].J Immu,2006;176(7):6794-6801.
[93]杨斌,郝飞.线粒体核糖体蛋白与线粒体疾病[J].中国优生与遗传,2005;13(7):1-3.
[94]聂轶飞,王凯娟,代丽萍,等.肝癌相关抗原血清学自身抗体反应分析[J].中国公共卫生,2007;23(7):801-802.
[95]曾锦章,洪毅,王红阳,等.核糖体蛋白L26基因克隆及其在肝癌中的表达[J].中华实验外科杂志,2001;18(2):108-109.
[96]Karan D,Kelly DL,Rizzino A,et al.Expression profile of differentially-regulated genes during progression of androgen-independent growth in human prostate cencer cells[J].Cancinogenesisi,2002;23(6):967-975.
[97]张寒,郜慧芳,郑丽镛.转录因子RunX1对RPL4启动子的调节作用[J].中国肿瘤生物治疗杂志,2008;15(3):412-416.
[98]吴峰,王清明,范国才,等.紫杉醇诱导MCF-7乳腺癌细胞凋亡的蛋白组学研究[J],2006;28(6):418-421.
[99]陈宏,姜浩,张志伟.人核糖体蛋白L6对白血病K562/A02细胞耐药的影响[J].实用癌症杂志,2006;21(2):117-119.
[100]曹漫明,张秋仁,周媛,等.人卵巢癌顺铂耐药细胞中核糖体蛋白的基因的表达谱分析[J].肿瘤,2005;25(6):555-559.
[101]Mari L,Pirjo K,Eeva-riitta S,et al.The expression of carbonic DahydraseⅡ in hematological mallignncies[J].Clin Cancer Res.2002;2240(8):2240-2245.
[102]Deng HK,Hei-cheul J,Chan HP,et al.Whole genome analysisi for liver metastasis gene signatures in colorectial cancer[J].Int J Cancer,2007;121(9):2005-2012.
[103]Elizabeth A W,Neil AC,Jenifer ML,et al.The antibody MAB8051 directed aganist osteoprotegerin detects carbonic anhydrase Ⅱ:implication for association studies with human cancers[J].Inc J Cancer,2007;21(4):1958-1966.
[104]Juliac M,Gerard C,Amelia O,et al.Anovel proup of genes regulates susceptibility to antineoplastic drugs in highly tumorigenic breast cancer cells[J].Mol Pharmacol,2005;68(6):1747-1756.
[105]Marounan R,Jean-Yves W,Alessio I,et al.Carbonic anhydrase inhibiters:copper(Ⅱ) complexes of polyamino-polycarboxylamido aromatic/heterocyclic sulfonamides are very potent inhibitors of the tumor-associated isoforms Ⅸ and Ⅻ[J].Bioorganic Medicine Chemistyr Leters,2008;18(2):836-841.
[106]Shimizu S,Seki N,Sugimoto T,et al.Identification of molecular targets in head and neck squamous cell carcinomas based on genome-wide gene expreesion[J].Oncol Rep.2007;18(6):1489-1497.
[107]Seder CW,Hartojo W,Lin L,et al.INHBA overexpression promotes cell proliferation and may be epigenetically regulated in esophageal adenocarcino[J].J Thoral Oncol,2009;4(1):455-462.
[108]Takeno A,Takemasa I,Doki Y,et al.Integrative approach for differentially overexpressed genes in gaseric cancer by combining large-scale gene expression profiling and network analysis[J].Br J Cancer,2008;99(8):1307-1315.
[109]Ye H,Yu J,Teman S,et al.Transcriptomic dissection of tongue squamous cell carcinoma[J].Bmc Genomics,2008;6(9):69.
[110]Labbe E,Lock L,Letamendia A,et al.Transcription cooperation between the transforming growth factor-beta and wnt pathways in mamany and intestinas tumorigenesis[J].Cancer Res,2007;67(1):75-84.
[111]Salmond RT,Fiby A,Qureshi I,et al.T-cell receptor proximal signaling via the Src-family kinase LCK FYN influences T-cellactivation differerntion and tolerance[J].Immunol Rev,2009;228(1):9-22.
[112]Hwang MK,Kang NJ,Heo YS,et al.FYN kinase is a direct molecular target of decphnidin for the inhibiton of cyclooxygenase-2 expression induced by tumor necrosis factor-alpha[J].Biochen Phamacol,2009;77(7):1213-1222.
[113]Karahan N,Guney M,Baspinar S,et al.Expression gelatinase(mmp-2 and mmp-9) and cyclooxygenasse-2(cox-2) in endometrial carcimona[J].Eur J Gynaecol Oncol,2007;28(3):184-188.
[114]王红,赵逵,王建立,等.COX-2、E6FR和KI67在大肠癌组织中的表达及其意义[J].山东医药,2008;48(31):1-3.
[115]环氧合酶-2在甲状腺乳头状癌中的表达及其对淋巴管生成的影响[J].实用肿瘤杂志,2008;23(4):833-836.
[116]Hongsachart P,Huang-Liu R,Sinchaikus S,et al.Glycoproteomic anclysis of WGA-bound glycoprotein biomarkers in sera from pations with lung adenocarcinoma.Electrophoresis[J].2009;17[Epub ahead of print].
[117]曾志军,杨连粤,王伟,等.Cyr61、CTGF和NOV基因在肝细胞癌中的表达及其与临床病理特征的关系[J].中华肝胆外科杂志,2005;11(7):452-454.
[118]Lin MT,Zuon CY,Chang CL.Cyr61 induces gastric cancer cell motility /invasion via activation of the integrin/nuclear factor-kapaB/cyclooxygenase-2 signaling pathway[J].Clin Cancer Res.2005;11(6):5809-5820.
[119]Nguyen N,Kulipalos A,Gruham RA,et al.Tumor-derived Cyr61 promotes stromal matrix metalloproteinase-1 prodction and protease-activated receptor 1-dependent migration of brease cancer cells[J].Cancer Res.2006;66(5):2658-2665.
[120]崔玲玲,王旗,赵松,等.肺癌组织中Cyr61、WISP-1基因表达及意义[J].山东医药,2007;47(20):1-3.
[121]牛志宏,高德轩,丁森泰,等.Cyr61、CTGF、NOV、WISP-1基因在肾癌中的表达[J].山东大学学报(医学版),2008;46(7):701-704.
[122]Wenwen C,Taksh K,Carl WM,et al.Cyr61 suppresses growth of human endometrial cancer cell[J].J Bio Chem,2004,279(51):53087-53096.
[123]Risinger JI,Maxwell GL,Chandremaili GVR,et al.Microarray analysis reveal distinct gene expression profiles among different histologic types of endometrial cancer[J].Cancer Res,2003;63(1):6-11.
[1]乐杰 主编.妇产科学第七版[M].人民卫生出版社,2008,4:272-277.
[2]赵群,张淞文,王涛,等.北京地区子宫内膜癌筛查方法的研究[J].北京医学,2008;30(9):513-515.
[3]高原,罗新.第18届FIGO世界妇产科学术会议纪要-子宫内膜癌篇[J].中国实用妇科与产科杂志,2008;24(8):536-539.
[4]Jemal A,Thomas A,Murray T,et al.Cancer staistics.CA Cancer J Clin,2002;52(1):23-47.
[5]Larry M,Ohandramouli G,Lou D,et al.Microarray analysis of endometrial carcinomas and mixed mullerian tumors reveals distinct gene expression profiles associated with different histologic type of uerine cancer[J].Clin Cancer Res,2005;11(11):4056-4066.
[6]Roes L,Melbert D,Krapoho M,et al.SEER cancer statisitics review.2007;internet website Available from:http//SEER,gov/csr/1075-2004.
[7]Allard JE,Maxwell GL.Race disparities between black and white women in the incidence treatment and prognosis of endometrial cancer[J].Cancer Control,2009;16(1):53-56.
[8]陈美霞,孟元光,韩为东,等.DNA甲基化在子宫内膜癌中的研究进展[J].国外医学.妇产科学分册,2007;314(6):421-424.
[9]张阳德.编著.生物信息学[M].北京:科学出版社,2004年9月第一版,248-262.
[10]周怀君,石一复,李娟清,等.子宫内膜腺癌基因表达谱的初步研究[J].中华肿瘤杂志,2003;25(5):464-467.
[11]Oehler MK,Mackenzie IZ,Walluiener D,et al.Wnt-7 is upregulated by nerethisterone in human endometrial epthelia cells:a possible mechanism by which progesterons reduce the tisk of estrogen-induce endometrial neoplasia.Cancer Lett,2002;186(1):75-81.
[12]孟元光,韩为东,黄柯,等.雌激素调控子宫内膜癌Ishikawa细胞中LRP16 基因表达及其意义[J].第四军医大学学报,2006;27(11):980-984.
[13]Omar R,Karen R David G,et al.Expression profiling of mouse endometrial cancers microdissected from the fixed parnffin-embedded tissues[J].American J Patho,2003;162(3):755-762.
[14]Sarah EF,Robert AS,Alison A,et al.Comparision of uterine malignanlies that develop during and following tamoxifen therapy.Gynecol Oncolo,2006;101(3):322-326.
[15]Gielen SC,Santegoets LA,Kuhne LC,et al.Genomic and nongenomic effects of estrogen signaling in human endometrial cells:involvement of the growth factor receptor signaling downstream AKT pathway.Reprod Sci,2007;14(7):646-654.
[16]Angela M D,Jiude M,Bushra N,et al.Comparative effects of estradiol,methyl-piperidino-pyrazole,raloxifene,and ICI 182 780 on gene expression in the murine uterus J Molec Endocri,2008;41(4):205-217d.Bokhman JV.Two pathogenetic type of endometrial carcinoma[J].Gynecol Oncol,1983,15(1):10-17.
[17]Ferguson SE,Olshen AB,Levine BA,et al.Moleculai profiling of endometrial cancer from African-American and Caucasian women.Gynecol Oncol,2006;101(2):209-213.
[18]Bokhman JV.Two pathogenetic type of endometrial carcinoma[J].Gynecol Oncol,1983,15(1):10-17.
[19]Gema M B,Carolina SE,Raul C,et al.Differerntial Gene expression profile in endometroid and nonendometrioid endometrial carcinoma[J].Cancer Res,2003;63(18):5697-5702.
[20]郭遂群,刑福祺,庞战军,等.基因芯片筛选CFTR基因作为雌激素依赖性子宫内膜癌预后标志物的研究[J].广东医学,2007;28(3):369-371.
[21]皱果芳,胡江波,胡卫忠,等.子宫内膜癌预后相关因素的多元回归分析[J].实用肿瘤学杂志,2008;22(3):452-456.
[22]李萍,罗来敏.子宫内膜癌手术前后分期的相关性.肿瘤,2005;25(5):481-483.
[23]蔡斌,万小平,刘玲,等.应用cDNA表达谱芯片研究子宫内膜癌基因的表 达谱[J].现代妇产科进展,2006;15(3):177-181.
[24]Ferguson SE,Olshen AB,Viale A,et al.Stratification of intermediate-risk endometrial cancer patients into groups at high risk of low risk for recurrence based on tumor gene expression profiles[J].Clin Cancer Res,2005;11(6):2252-2257.
[25]Bidus MA,Risinger JI,Chandramouli GR,et al.Prediction of lympa node metastasis in patients with endometrioid endometrial cancer using expression microarray[J].Clin Cancer Res,2006;12(1):83-88.
[26]Israel I,Parl JG,Amy P S,et al.Differentional methlation Hybridization array of endometrial cancer reveals two novel cancer-specific methylation markers[J].Clin Cancer Res,2007;13(10):2882-2889.
[27]孟元光,魏丽惠,李春海,等.应用mRNA差异显示技术筛选子宫内膜癌相关基因片段[J].中华妇产科杂志,2001;36(6):364-367.
[28]Du XL,Jiang T,Zhao WB,et al.Gene alterations in tumor-associated endothelial cells from endometrial cancer[J].Int J Med,2008;22(5):619-632.
[29]Jesus P,Maria DF,Antonio GM,et al.A differentia Gene expression protile reveals overexprssion RUNX1/AML1 in invasive endometrial carcinoma[J].Cancer Research,2004;64(24):8846-8853.
[30]Koistionen H,Sepppala MS,Wagy B,et al.Glycodelin reduces carcinoma-associated gene expression in endometrial edenocarcinoma cells[J].Am J Obstet Gynecol.2005;193(6):1955-1960.
[31]Peng L,Broaddus RR,MC-Campben A,et al.Identification of a novel estrogen-regulated gene EIG121,induced by hormone replacement therapr and differentioal expressed in type Ⅰ and type Ⅱ endometrial cancer[J].Clin Cancer Res.2005;11(23):8258-8264.
[32]Aparecide AC,Silva ID,Villanova FE,et al.Differential gene expression profile reveals overexpression of MAP3K8 in invasive endometrioid carcinoma[J].Eur J Gynaecol Oncol,2006;27(6):589-593.
[33]Lagos QM,Rauhu R,Lendeckel W,et al.Identification of novel genes coding for small expressed RNAs.Science,2001;294(5543):853-858.
[34] Rajewsky N, Socei N O. Computational identification of microRNA targets. Dev Biol, 2004; 267(2): 529-535.
[35] Calin GA, Sevignani C, Dan Dumitru C, et al. Human microRNA gene are frequently located at fragile sites and genomic regions involved in cancers[J]. Proc Natl Acad Sci USA.2004; 101(9): 2999-3004.
[36] Chen CZ. MicroRNAs as oncogenes and tumor suppressors[J]. N Engl J Med, 2005; 353(17): 1768-1771.
[37] Wu WG, Lin IQ, Zhuang ZQ, et al. Expression profile of mammalian microRNAs in endometrioid adenocarcinoma[J]. European J Cancer Prevet, 2009; 18(1): 50-56.
[38] Boren J, Xiong Y, Hakam A, et al. MicroRNAs and their target messenger RNAs assiociated with endometrial carcingenesis[J]. Gynecol Oncol, 2008; 110(2): 206-215.
[39] Chung T K, Cheunq T H, Huen NY, et al. Dysregulated microRNAs and their predicted targets associated with endometrioid endometrial adenocarcinoma in Hong Kong Women[J]. Int J Cancer , 2009; 124(6): 1358-1365.
[40] Luthra R, Silqh RR, Luthra MG, et al. MicroRNA-196a targets annexin Al: a microRNA-mediated mechanism of annexin A1 downregulation in cancers[J]. Oncogene, 2008; 27(5): 6667-6678.
[41] Daikoku T, Hirota Y, Tranquch S, et al. Conditional loss fo uterine pten unfailingly and rapidly induces endometrial cancer in mice[J]. Cancer Res, 2008; 68(14): 5619-5627.