STAT3及其磷酸化、SOCS3及其DNA甲基化在食管鳞癌中的表达及其意义
|
摘要
目的检测食管鳞癌组织中信号转导子和转录激活子3(STAT3)在mRNA、蛋白质和蛋白质磷酸化3种水平的表达,探讨其在食管鳞癌发生、发展、浸润、转移中作用。
方法应用Real-Time PCR和Western Blot法分别检测43例食管鳞癌组织中STAT3mRNA、STAT3和磷酸化STAT3(pSTAT3)的表达,并与癌旁正常食管组织进行对照研究,分析STAT3mRNA、STAT3和pSTAT3的表达与临床病理参数的关系。
结果⑴食管鳞癌组织中STAT3 mRNA相对表达强度比值(1.43±0.59)较癌旁组织的比值(0.98±0.47)明显增高(P<0.05);食管鳞癌组织中STAT3、pSTAT3表达(2.16±0.39;1.40±0.15)也都显著高于癌旁组织(1.87±0.29;1.25±0.13)(P <0.05);⑵食管鳞癌组织中STAT3mRNA、STAT3和pSTAT3在肿瘤不同分化级别中有表达差异,分化级别越低,表达水平越高(P<0.05),与肿瘤分化级别呈负相关(-10.05)。
结论食管鳞癌组织中STAT3和pSTAT3高表达,尤其活化状态的pSTAT3更为显著,并与食管鳞癌的分化、浸润、转移相关。推断pSTAT3可为食管癌的基因治疗提供理想靶点。
目的检测食管鳞癌组织中细胞因子信号转导负调控因子3(SOCS3)的DNA甲基化、mRNA及蛋白表达水平,探讨其在食管鳞癌发生、发展、浸润和转移中的作用。
方法应用MSP、Real-Time PCR和Western Blot法分别检测43例食管鳞癌组织中SOCS3的DNA甲基化、mRNA和蛋白表达水平,并与相应的癌旁正常食管组织进行对照研究,分析其与临床病理参数的相关性。
结果本组43例实验样本中⑴食管鳞癌组织SOCS3 DNA甲基化的阳性率(79.1%)明显高于癌旁组织(14.0%)(P<0.01);⑵食管鳞癌组织SOCS3mRNA相对表达强度比值(0.53±0.30)明显低于癌旁组织(1.15±0.44)(P<0.01),食管鳞癌组织中甲基化组的SOCS3 mRNA表达(0.45±0.24)显著低于非甲基化组(0.86±0.29) (P<0.05);食管鳞癌组织SOCS3蛋白表达(1.66±0.22)显著低于癌旁组织(1.83±0.15)(P<0.01),食管鳞癌组织中甲基化组SOCS3蛋白表达(1.61±0.21)显著低于非甲基化组(1.87±0.15)(P<0.01);⑶食管鳞癌组织中SOCS3mRNA表达及其蛋白表达水平与肿瘤分化级别呈正相关(0.3010.05)。结论食管鳞癌组织中SOCS3 DNA甲基化阳性率高,导致SOCS3基因表达下调,与食管鳞癌的
分化、浸润和转移密切相关;检测食管鳞癌组织中SOCS3及其DNA甲基化程度可作为判断食管鳞癌恶性程度及生物学行为的重要指标。
Objective By testing the expression of signal transducer and activator of transcription 3 (STAT3) in esophageal squamous cell carcinoma (ESCC) tissue at mRNA, protein and protein phosphorylation levels, we studied the function of STAT3 in the occurrence, development, invasion and metastasis of ESCC.
Methods By using adjacent normal esophageal tissue as control, the expression of STAT3mRNA, STAT3 and phosphorylated STAT3 (pSTAT3) in 43 cases of ESCC was studied by Real-Time PCR and Western Blot, and subsequently analyzed to find out the correlation with Clinical Pathological Parameters.
Results (1) Remarkably higher relative expression intensity of STAT3 at mRNA was found in ESCC tissue( 1.43±0.59) , compared with normal esophageal tissue(0.98±0.47)(P<0.05);STAT3 and pSTAT3 expression in ESCC (2.16±0.39;1.40±0.15)was also significantly higher than normal tissue( 1.87±0.29;1.25±0.13)(P<0.05). (2) Statistical differences were found in different differentiation degrees of tumor for the expression of STAT3mRNA, STAT3 and pSTAT3 in ESCC. The lower differentiation degree, the higher the expression( P< 0.05) . The expression was negatively correlated with differentiation degree of tumor( -1< r<-0.301,P<0.05), while it had a positive relationship with TNM staging and lymph node metastasis( 0.301< r< 1,P< 0.05).In TNM staging, higher expression was found in StageⅢthan both StageⅠand StageⅡ( P< 0.05), and the expression in the group with lymph node metastasis was higher than that in the group without lymph node metastasis( P< 0.05). No obvious connection was found with the age, gender, family history and smoking history of patients( P> 0.05) .
Conclusion Higher expression of STAT3 and pSTAT3 in ESCC tissue indicated close correlation with the differentiation, invasion and metastasis of ESCC. pSTAT3 is more significant.Testing of pSTAT3 might provide ideal target for gene therapy of esophageal cancer.
Objective By testing the expression of suppressor of cytokine signaling 3 (SOCS3) in esophageal squamous cell carcinoma (ESCC) tissue at DNA methylation, mRNA and protein levels, we studied the function of SOCS3 in the occurrence, development, invasion and metastasis of ESCC.
Methods In this study, by using adjacent normal esophageal tissue as control, the expression of SOCS3 DNA methylation, SOCS3 mRNA and SOCS3 protein in 43 cases of ESCC was detected by MSP, Real-Time PCR and Western Blot, and subsequently analyzed to find out the correlation with Clinical Pathological Parameters.
Results (1) The positive rate of SOCS3 DNA methylation in ESCC( 79.1%) was significantly higher than normal tissue( 14.0%)( P< 0.01). (2) Remarkably lower relative expression intensity of SOCS3 mRNA was found in ESCC tissue (0.53±0.30), compared with normal esophageal tissue(1.15±0.44)( P﹤0.01) . In ESCC, the SOCS3mRNA expression was notably lower in methylation group(0.45±0.24) than non-methylation group(0.86±0.29)( P<0.05). (3) SOCS3 protein expression in ESCC(1.66±0.22) was also evidently lower than adjacent normal tissue (1.83±0.15)( P <0.01). In ESCC, the SOCS3 expression was notably lower in methylation group(1.61±0.21) than non-methylation group(1.87±0.15)( P <0.01). (4) Expression of both SOCS3mRNA and SOCS3 in ESCC was positively correlated with differentiation degree ( P < 0.05 ) , while it had a negative correlation with TNM staging and lymph node metastasis( P< 0.05) . No obvious connection was found with the age, gender, family history and smoking history of patients( P> 0.05) .
Conclusion The decrease of SOCS3 gene expression in ESCC was caused by the high positive rate of SOCS3 DNA methylation, which was closely connected with the differentiation, invasion and metastasis of ESCC. The detection of SOCS3 DNA methylation,SOCS3mRNA and SOCS3 expression in ESCC could provide important index in diagnosis of the malignant degree and biological behavior of esophageal squamous cell carcinoma.
方法应用Real-Time PCR和Western Blot法分别检测43例食管鳞癌组织中STAT3mRNA、STAT3和磷酸化STAT3(pSTAT3)的表达,并与癌旁正常食管组织进行对照研究,分析STAT3mRNA、STAT3和pSTAT3的表达与临床病理参数的关系。
结果⑴食管鳞癌组织中STAT3 mRNA相对表达强度比值(1.43±0.59)较癌旁组织的比值(0.98±0.47)明显增高(P<0.05);食管鳞癌组织中STAT3、pSTAT3表达(2.16±0.39;1.40±0.15)也都显著高于癌旁组织(1.87±0.29;1.25±0.13)(P <0.05);⑵食管鳞癌组织中STAT3mRNA、STAT3和pSTAT3在肿瘤不同分化级别中有表达差异,分化级别越低,表达水平越高(P<0.05),与肿瘤分化级别呈负相关(-1
结论食管鳞癌组织中STAT3和pSTAT3高表达,尤其活化状态的pSTAT3更为显著,并与食管鳞癌的分化、浸润、转移相关。推断pSTAT3可为食管癌的基因治疗提供理想靶点。
目的检测食管鳞癌组织中细胞因子信号转导负调控因子3(SOCS3)的DNA甲基化、mRNA及蛋白表达水平,探讨其在食管鳞癌发生、发展、浸润和转移中的作用。
方法应用MSP、Real-Time PCR和Western Blot法分别检测43例食管鳞癌组织中SOCS3的DNA甲基化、mRNA和蛋白表达水平,并与相应的癌旁正常食管组织进行对照研究,分析其与临床病理参数的相关性。
结果本组43例实验样本中⑴食管鳞癌组织SOCS3 DNA甲基化的阳性率(79.1%)明显高于癌旁组织(14.0%)(P<0.01);⑵食管鳞癌组织SOCS3mRNA相对表达强度比值(0.53±0.30)明显低于癌旁组织(1.15±0.44)(P<0.01),食管鳞癌组织中甲基化组的SOCS3 mRNA表达(0.45±0.24)显著低于非甲基化组(0.86±0.29) (P<0.05);食管鳞癌组织SOCS3蛋白表达(1.66±0.22)显著低于癌旁组织(1.83±0.15)(P<0.01),食管鳞癌组织中甲基化组SOCS3蛋白表达(1.61±0.21)显著低于非甲基化组(1.87±0.15)(P<0.01);⑶食管鳞癌组织中SOCS3mRNA表达及其蛋白表达水平与肿瘤分化级别呈正相关(0.301
分化、浸润和转移密切相关;检测食管鳞癌组织中SOCS3及其DNA甲基化程度可作为判断食管鳞癌恶性程度及生物学行为的重要指标。
Objective By testing the expression of signal transducer and activator of transcription 3 (STAT3) in esophageal squamous cell carcinoma (ESCC) tissue at mRNA, protein and protein phosphorylation levels, we studied the function of STAT3 in the occurrence, development, invasion and metastasis of ESCC.
Methods By using adjacent normal esophageal tissue as control, the expression of STAT3mRNA, STAT3 and phosphorylated STAT3 (pSTAT3) in 43 cases of ESCC was studied by Real-Time PCR and Western Blot, and subsequently analyzed to find out the correlation with Clinical Pathological Parameters.
Results (1) Remarkably higher relative expression intensity of STAT3 at mRNA was found in ESCC tissue( 1.43±0.59) , compared with normal esophageal tissue(0.98±0.47)(P<0.05);STAT3 and pSTAT3 expression in ESCC (2.16±0.39;1.40±0.15)was also significantly higher than normal tissue( 1.87±0.29;1.25±0.13)(P<0.05). (2) Statistical differences were found in different differentiation degrees of tumor for the expression of STAT3mRNA, STAT3 and pSTAT3 in ESCC. The lower differentiation degree, the higher the expression( P< 0.05) . The expression was negatively correlated with differentiation degree of tumor( -1< r<-0.301,P<0.05), while it had a positive relationship with TNM staging and lymph node metastasis( 0.301< r< 1,P< 0.05).In TNM staging, higher expression was found in StageⅢthan both StageⅠand StageⅡ( P< 0.05), and the expression in the group with lymph node metastasis was higher than that in the group without lymph node metastasis( P< 0.05). No obvious connection was found with the age, gender, family history and smoking history of patients( P> 0.05) .
Conclusion Higher expression of STAT3 and pSTAT3 in ESCC tissue indicated close correlation with the differentiation, invasion and metastasis of ESCC. pSTAT3 is more significant.Testing of pSTAT3 might provide ideal target for gene therapy of esophageal cancer.
Objective By testing the expression of suppressor of cytokine signaling 3 (SOCS3) in esophageal squamous cell carcinoma (ESCC) tissue at DNA methylation, mRNA and protein levels, we studied the function of SOCS3 in the occurrence, development, invasion and metastasis of ESCC.
Methods In this study, by using adjacent normal esophageal tissue as control, the expression of SOCS3 DNA methylation, SOCS3 mRNA and SOCS3 protein in 43 cases of ESCC was detected by MSP, Real-Time PCR and Western Blot, and subsequently analyzed to find out the correlation with Clinical Pathological Parameters.
Results (1) The positive rate of SOCS3 DNA methylation in ESCC( 79.1%) was significantly higher than normal tissue( 14.0%)( P< 0.01). (2) Remarkably lower relative expression intensity of SOCS3 mRNA was found in ESCC tissue (0.53±0.30), compared with normal esophageal tissue(1.15±0.44)( P﹤0.01) . In ESCC, the SOCS3mRNA expression was notably lower in methylation group(0.45±0.24) than non-methylation group(0.86±0.29)( P<0.05). (3) SOCS3 protein expression in ESCC(1.66±0.22) was also evidently lower than adjacent normal tissue (1.83±0.15)( P <0.01). In ESCC, the SOCS3 expression was notably lower in methylation group(1.61±0.21) than non-methylation group(1.87±0.15)( P <0.01). (4) Expression of both SOCS3mRNA and SOCS3 in ESCC was positively correlated with differentiation degree ( P < 0.05 ) , while it had a negative correlation with TNM staging and lymph node metastasis( P< 0.05) . No obvious connection was found with the age, gender, family history and smoking history of patients( P> 0.05) .
Conclusion The decrease of SOCS3 gene expression in ESCC was caused by the high positive rate of SOCS3 DNA methylation, which was closely connected with the differentiation, invasion and metastasis of ESCC. The detection of SOCS3 DNA methylation,SOCS3mRNA and SOCS3 expression in ESCC could provide important index in diagnosis of the malignant degree and biological behavior of esophageal squamous cell carcinoma.
引文
[1]D.M.Parkin,F.Bray,J.Ferlay and P.Pisani.Global cancer statistics.CA Cancer J Clin,2005,55,74-108
[2]A.M.Mandard,P.Hainaut and M.Hollstein.Genetic steps in the development of squamous cell carcinoma of the esophagus.Mutat.Res,2000,462:335-342
[3]Campbell.CL,Jiang.Z,Savarese.DM,et al.Increased expression of the interleukin-11receptor and evidence ofSTAT 3 activation in prostate carcinoma [J].Am J Pathol,2001,158(1) :25-32
[4]Bowman.T,Caroia.R,Turkson.J,et al.STATs in oncogenesis[J].Oncogene, 2000,19(21) :2474-2488
[5]谢宏霞,曾凤辉,刘鸿,等.磷酸化和乙酞化修饰对STAT3功能的调节.中国细胞生物学学报.2010,32(1):115-120
[6]Murray.P.J.Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti- inflammatory response.Curr Opin Pharmacol,2006,6:379-386
[7]Fu.X.Y.STAT3 in immune responses and inflammatory bowel diseases.Cell Res,2006,16:214-219
[8]邱志兵,陈鑫,万松,等.STAT3信号通路与血管重塑中平滑肌细胞表型转化及增殖关系.中华实验外科杂志,2008,25:1624-1626
[9]郝怀勇,王永广,程峰,等.JAK2/STAT3信号通路调节骨髓间充质干细胞神经定向分化.中华实验外科杂志,2010,27:400
[10]J.V.Alvarez,P.G.Febbo,S.Ramaswamy,M.Loda,A.Richardson and D.A.Frank.Identification of a genetic signature of activated signal transducer and activator of transcription 3 in human tumors.Cancer Res.2005,65,5054-5062
[11]L.Li and P.E.Shaw.Autocrine-mediated activation of STAT3 correlates with cell proliferation in breast carcinoma lines.Biol.Chem,2002,277:17397-17405
[12]D.Wei,X.Le,L.Zheng,L.Wang,J.A.Frey and A.C.Gao,et al.Stat3 activation regulates the expres- sion of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis.Oncogene,2003,22:319-329
[13]T.X..Xie, F.J.Huang, K.D.Aldape, S.H.Kang,M.Liu and J.E.Gershenwald et al. Activation of stat3 in human melanoma promotes brain metastasis.Cancer Res.2006,66:3188-3196
[14]Benekli.M,Baer.MR,Baumann.H,et al.Signal transducer and activator of transcription proteins in leukemias[J].Blood, 2003,101(8):2940-2954
[15]Grandis.JR,Drenning.SD,Zeng.Q,et al.Constitutive activation of Stat3 signaling abrogates apoptosis in squamouscell carcinogenesis in viv o[J].Proc Natl Acad Sci USA,2000,97(8):4227-4232
[16]Catlett-Falcone.R,Landowski.TH,Oshiro.MM,et al.Constitutive activation of STAT3 signaling confers resistance to apoptosis in human U266 myeloma cells [J].Immunity,1999,10(1):105-115
[17]Burdelya.L,K.ujawski.M,Niu.G,et al.Stat3 activity in melanoma cells affects migration of immu- ne effector cells and nitricoxide-mediated antitumor effects[J].Immunol,2005,174(7): 3925-3931
[18]Leong.PL,Andrews.G.A,Johnson.DE,et al.Targeted inhibition of STAT3 with a decoy oligo nucleotide abrogates head and neck cancer cell growth[J].Proc Natl Acad Sci USA, 2003,100(7): 4138-4143
[19]Garcia.R,Bowman.T.L,Niu.G,et al.Constitutive activation of STAT3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells [J].Oncogene, 2001,20(20) : 2499-2513
[20]Zhang.L,Gao.L.F, Zhao.L.J,et al.Intratumoral delivery and suppression of prostate tumor growth by attenuated Salmonella enterica serovar typhimurium carrying plasmid-based small interfering RNAs[J].Cancer Res,2007,67(12):5859-5864
[21]Hung.K,Liu.H.J,Tu.Y.T.STAT3 and related skin diseases[J].Int J Dermatol Venereol,2006,32(3): 182-184
[22]邓立力,邓洪滨,吕慧芳,等.STAT3和p38在胃癌组织中的表达及意义[J].中国肿瘤临床,2008, 35(4):202 -205
[23]Kramer.OH,Knauer.SK,Greiner.G,et al.A phosphorylation-acetylation switch regulates STAT3 signaling.Genes Dev.2009;23(2):223-235
[24]GRITSKO.T,WILLIAMS.A,TURKSON.J,et al.Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells.Clin Cancer Res,2006,12 :11-19.
[25]马中州,黄壮士,付东宏.食管鳞癌中磷酸化STAT3与Ki67的表达与意义.河南外科学杂志,2009,15 :14-16.
[26]杨俊波,毛志福,蔡享道.STAT3在食管鳞状细胞癌中的表达和意义.消化外科,2006,5:220-222
[27]梁斌,王彬,祝学光,等.转录信号传导子和激活分子在人胃癌组织中的表达及意义.中华实验外科杂志,2001,18:313-314
[28]Redell.MS,Tweardy.DJ.Targeting transcription factors for cancer therapy.Curr Pharm Des, 2005,11: 2873-2887
[1]D.M.Parkin,F.Bray,J.Ferlay and P.Pisani.Global cancer statistics.CA Cancer J.Clin,2005,55:74-108
[2]陈克能,师晓天,程邦昌.食管癌、胃癌基因分子水平的研究进展.中华实验外科杂志,1996,13: 383-384
[3]YOSH.IMURA.A,OHKUBO.T,KIGUCH.I.T,et al.A novel cytokine-inducible gene CIS encodes an SH22containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors.EMBO J,1995,14:2816-2826
[4]Kebs.DLHilton.DJ.SOCS:Physiologieal suppressors of eytokine signaling[J]Cell Sci.2000;113: 2813-2819
[5]Marine.JC,Mckay.C,Wang.D,et al.SOCS3 is essential in the regulation of fetal liver erythropoiesis Cell,1999,98:617-627
[6]Lo.HW,Cao.X,Zhu.H,et al.Constitutively activated STAT3 frequently coexpresses with epidermal growth factor receptor in high-grade gliom as and targeting STAT3 sensitizes them to Iressa and alkylators.Clin Cancer Res,2008;14(19):6042-6054
[7]Zhu.BM,Ishida.Y,Robinson.GW,et al.SOCS3 negatively regulates the gp130-STAT3 pathway in mouse skin wound healing.[J].Invest Derm atol,2008;128(7):1821-1829
[8]Stevenson.NJ,Haan.S,Mc.Clurg.AE,et al.The chemoattractants,IL-8 and form ylmethinony lleucylpheny lalanine,regulate granuloco tyecolony-stimulating factor signaling by inducing supperssor of ctyokine signaling-1 expression. Jimmunol,2004;173 (5):3243-3249
[9]Wong.PK,Egan.PJ,Croker.BA,et al.SOCS-3 negatively regulates innate and adaptive immun emechanisms in acute IL-1 dependent inflamm atory arthritis.[J].Clin Invest,2006;116(6):1571-1581
[10]Tokita.T,Maesawa.C,Kimura.T, et al.Methylation status of the SOCS3 gene in human malignant melanomas. Int J Oncol, 2007,3:689-694
[11]He.B,You.L,Xu.Z,er al.Activity of the suppressor of eytokine signaling-3 promoterin human non-small-cell lung caneer.Clin Lung Caneer.2004;5:366-370
[12]Weber.A,Hengge.UR,Bardenheuer.W,et al.SOCS-3 is frequently methylated in head and neck squamous cell carcinoma and its precursor lesions and causes growth inhibition. Oncogene,2005, 24 (44):6699-6708
[13]Calvisi.DF,Lad.US,Gordena,et al.Ubiquitous activation of Ras and jak/stat Pathways in human HCC. Gastroen-terology,2006,130,(4):1117-1128
[14]Sutherlangd.KD,Lindeman.GJ,Choong.DY,et al.Differential hyper-methylation of SOCS genesin ovarian and breast carcinomas.Oncogene,2004,23(46):7726-7733
[15]Brender.C,Lovato.P,Sommer.VH,et al.Constitutive SOCS-3 expression Proteets T-cell lymPho- ma against growth inhibition by IFNalpha. Leukemia,2005,19(2):209-213
[16]He.B,You.L,Uemasu.K,et a l..SOCS3 is frequently silenced by hype rmethylation and supprsses cell growth in hum an lung cance r[J].Proc Natl Acad Sci USA ,2003,100(24):14133-14138.
[17]Rigby.RJ,Simmons.JG,Greenhalgy.CJ,et al.Suppressor of cytokine signaling 3(SOCS3) limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon. Oncogene,2007,26:4833-4841
[18]刘细国,袁先厚,江普查,等.STAT3和Cyclin D1在人脑胶质瘤中的表达及其意义.中华实验外科杂志,2010,27 :1389-1391.
[19]Ogata.H,Kobayashi.T,Chinen.T,et al.Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis.Gastroenterology,2006,131:179-193
[20]Dimitriadis.E,Stoikos.C,Tan.Y.L,et al.Interleukin 11 signaling components signal transducer and activator of transcrip tion 3 ( STAT3) and supp ressor of cytokine signaling 3 ( SOCS3) regulate human endometrial stromal cell differentiation.Endocrinology,2006,147:3809-3817
[21]毛煜侃,张伟,郑立君.SOCS-3基因在结肠癌中的表达及甲基化测定.同济大学学报,2010,31:41-44
[22]Berclaz.G,Altermal.HJ,Robrobacb.V,et al.EGFR dependent expression of STAT 3(but not STAT1)in breast cancer.Int J Oncol,2001,19:1155-1162
[23]马中州,黄壮士,付东宏.食管鳞癌中磷酸化STAT3与Ki67的表达与意义.河南外科学杂志,2009,15:14-16
[24]Niwa.Y,Kanda.H,Shikauchi.Y,et al.Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Oncogene,2005,24:6406-6417
[1] Kim.DJ,Chan.KS,Sano.S,et a1.Signal transducer and activator of transcription3 (Stat3) in epithelial carcinogenesis.Mol Carcinoq,2007,46;725-731
[2]Pellegrini.S,Dusanter-Fout.I.The structure,regulation and function of theJAKs and STATs[J].EurJ Biochem,1997,248:615-633
[3]Caldenhoven.E,van.Dijk.TB,Solari.R,et al.STAT3β,a splice variant oftranscription factor STAT3, is a dominant negative regulator ofTranscription[J].J Bio Chem,1996,271(21):13221-13227.
[4]Novak.U,Ji.H,Kanagasundaram.V,et al.STAT3 forms sable homodimers in thepresence of divalentcations prior to activation[J].Biochemical and BiophysicalResearch Communications,1998, 247(3):558-563
[5]Becher.S,Groner.B,Mfller.CW,et al.Three-dimensional structure of the STAT3βhomodimer bound to DNA[J].Nature,1998,349(9):145-151
[6]Darnell,JE,Jr.STATs and gene regulation[J].Science,1997,277(12):1630-1635
[7]Atreva.R,Neurath.M.F.Signaling molecules:the pathogenic role of the IL6/STAT3 transsignaling pathway in intestinal inflammation and in colonic cancer.Curr Drug Targets,2008, 9:369-374
[8]Takeda.K,Clausen.BE,Kaisho.T,et al.Enhanced Th1 activity and development of chronic entero- colitis in mice devoid of STAT3 inmacro-phages and neutrophils[J].Immunity,1999,10:39-49
[9] Steven.Fletcher,James.Turkson,Patrick.T,et a1.Molecular approaches towards the inhibition of the signal transducer and activator of transcription3(Star3) protein.Chem Med Chen.2008,3:1159-1168
[10]Zhong.Z,Wen.Z,Darnell.JE,et al.STAT3 and STAT4:Members of the family of signal transducers and activators of transcription[J].PNAS,2004,91:4806-4810
[11]Chakraborty.A,Dyer.KF,Cascio.M,et al.Identification of a novel STAT3 recruitment and active- tion motif within the G-CSFR[J].Blood,1999,93(1): 15-24
[12]Subramaniam.SV,Cooper.RS,Adunyah.SE,et al.Evidence for the involvementof JAK/STAT path- way in the signaling mechanism of interleukin-17[J].Biochemical and Biophysical Research Comu- nications,1999,262:14-19
[13]Rico.K.HL,Helen.C,Yung.H.W,et al.Constitutively Active G 16 StimulatesSTAT3 via a c-Src/ JAK-and ERK-dependent Mechanism[J].J Biol Chem,2003,278(52),52154-52165
[14]谢宏霞,曾凤辉,刘鸿,等.磷酸化和乙酞化修饰对STAT3功能的调节.中国细胞生物学学报.2010,32(1):115-120
[15]Weber-Norlt.RM,Riley.JK,Greenland.AC,et al.STAT3 recruitment by twodistinct ligand-induced ,tyrosine-phosphorylated docking sites in the interlukin-10 receptor intracellular domain[J].J Biol Chem,1996, 87(2):439-446
[16]刘细国,袁先厚,江普查,等.STAT3和Cyclin D1在人脑胶质瘤中的表达及其意义.中华实验外科杂志, 2010,27:1389-1391
[17]华天凤,张妍蓓.瘦素通过激活STAT3信号通路刺激人肺腺癌细胞增殖.安徽医科大学学报.2011,46(1):100-102
[18] Chen.Z,Han,ZC.STAT3:a critical transcription activator in angiogenesis.M edRes Rev,2008,28:85-200.
[19] Frank.DA.STAT 3 as a central mediator of neoplastic cellular transformation.Cancer Iett,2007, 251:199 210
[20]Stefan.F,William.B,David.M,et al.APCK110,a Novel and Potent Inhibitor of c-Kit,Blocks Phosphorylation of AKT and STAT3,Induces Apoptosis,and Inhibits Proliferation of Acute Myeloid Leukemia (AML)Cells[J].Blood,(ASH Annual Meeting Abstracts),2006,108-153
[21]Takemoto.S,Mulloy.JC,Cereseto.A,et al.Proliferation of adult T cell leukemia/ lymphoma cells is associated with the constitutive activation of JAK/STAT proteins[J].PNAS,1997,94:13897-13902
[22]Frank.DA,Mahajan.S,Ritz.J,et al.Blymphocytes from patients with chronic lymphocytic leuke- mia contain signal transducer and activator of Transcription STAT1 and STAT3 constitutively phosphorylated on serine residues[J].J Clin Invest,2007,100(12):3140-3148
[23]Yukio.T,Yukinori.M,Ying.CB,et al.A GTPase-activating protein binds STAT3 and is required for IL-6–induced STAT3 activation and for differentiation of a leukemic cell line[J].Blood,2004,104(12) 3550-3557
[24]Zhenfeng.D,Rosemary.F,Debra.AB,et al.Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer[J].Clin Cancer Res,2006,12:5055-5063
[25]Dieterk.STAT3 is constitutively activated in Hodgkin cell lines[J].Blood,2001,98:762-768
[26]Chong.SS,John.HK.Pyk2 Amplifies Epidermal Growth Factor and c-Src-induced Stat3 Activation[J].J Biol Chem,2004,279(17):17224-17231
[27]Berclaz.G,Altermal.HJ,Robrobacb.V,et al.EGFR dependent expression of STAT 3(but not STAT1)in breast cancer[J].Int J Oncol,2001,19(6):1155-1162
[28]Frank.D.A,Mahajan.S,Ritz.J.B,et al.Lymphocytes from patients with chronic lymphocyticleukemia contains STAT1 and STAT3 constitutively on serine residues[J].J Clin Investig,1997,100: 3140-3144
[29]Steve.A,Benjamin.B,Rituximab.inactivates STAT3 activity in B-Non-Hodgkin's Lymphoma through inhibition of the interleukinl0 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxin drugs[J].Cancer Res,2001,61:5137-5140
[30]Epling-Burnette.PK,Liu.J.H,Catlett-Falcone.R,et al.Inhibition of STAT3 signaling leads to apoptosis of leukemia large granular lymphoma and decreased Mcl-1 expression[J].J Clin Invest,2001,351-356
[31]Lin.J,Jin.X,Rothman.K,et al.Modulation of STAT3 activates by p53 tumor suppressor in breast cancer cell[J].Cancer Res,2002,62(2):376-385
[32]Udayakumar.TS,Stratton.Me,Nagle.RB,et al.Fibroblast growth factor-1 induced promatrilysin expression through the activation of extra cellular regulate kinases and STAT3[J].Neoplasia,2002, 41: 60-70
[33]Jenkins.BJ,Grail.D,Nheu.T,et al.Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling[J].Nat Med,2005,11(8):845-852
[34] Kim.BH,Yin.CH,Guo.Q,et a1.A small molecule compound identified through a cell based screening inhibits JAK/STAT pathway signaling in human cancer cells. Mol Cancer Ther,2008,7: 2672-2680
[35]Sasaki.A.et al.J Biol Chem.2003,278(4):2432-2436
[36]Wailboci.LW,Ahmed.CM,Mujtaba.MG,et al.Both the suppressor of cytokine signaling 1 (SOCS1) kinase inhibitory region and SOCS1 mimetic bind to JAK2 autophosphorylation site: implications for the development of a SOCS1 an tagonist.J.Immuno, 2007; 178(8):5058- 5068
[37]Ben.A,Sandra.E.SOCS regulation of the JAK/STAT signalling pathway.Sem in Cell Dev Biol, 2008;19(4):414 - 422
[38]He.B,You.L,Uematsu.K,et al.SOCS3 is frequently silenced by hyperme- thylation and suppress- es cell growth in human lung cancer [J]. ProcNatlAcad SciUSA, 2003, 100(24):14133- 14138
[39]秦伟.细胞因子信号转导抑制蛋白3与骨髓增殖性肿瘤关系的研究进展.中国实验血液学杂志, 2010;18(4):1101-1104
[40]孙洋,李珊珊,王新华,王小军,阎爱华.转化生长因子p1与食管鳞状细胞癌上皮间质转化的关系中华病理学杂志,2008,37:542-546
[2]A.M.Mandard,P.Hainaut and M.Hollstein.Genetic steps in the development of squamous cell carcinoma of the esophagus.Mutat.Res,2000,462:335-342
[3]Campbell.CL,Jiang.Z,Savarese.DM,et al.Increased expression of the interleukin-11receptor and evidence ofSTAT 3 activation in prostate carcinoma [J].Am J Pathol,2001,158(1) :25-32
[4]Bowman.T,Caroia.R,Turkson.J,et al.STATs in oncogenesis[J].Oncogene, 2000,19(21) :2474-2488
[5]谢宏霞,曾凤辉,刘鸿,等.磷酸化和乙酞化修饰对STAT3功能的调节.中国细胞生物学学报.2010,32(1):115-120
[6]Murray.P.J.Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti- inflammatory response.Curr Opin Pharmacol,2006,6:379-386
[7]Fu.X.Y.STAT3 in immune responses and inflammatory bowel diseases.Cell Res,2006,16:214-219
[8]邱志兵,陈鑫,万松,等.STAT3信号通路与血管重塑中平滑肌细胞表型转化及增殖关系.中华实验外科杂志,2008,25:1624-1626
[9]郝怀勇,王永广,程峰,等.JAK2/STAT3信号通路调节骨髓间充质干细胞神经定向分化.中华实验外科杂志,2010,27:400
[10]J.V.Alvarez,P.G.Febbo,S.Ramaswamy,M.Loda,A.Richardson and D.A.Frank.Identification of a genetic signature of activated signal transducer and activator of transcription 3 in human tumors.Cancer Res.2005,65,5054-5062
[11]L.Li and P.E.Shaw.Autocrine-mediated activation of STAT3 correlates with cell proliferation in breast carcinoma lines.Biol.Chem,2002,277:17397-17405
[12]D.Wei,X.Le,L.Zheng,L.Wang,J.A.Frey and A.C.Gao,et al.Stat3 activation regulates the expres- sion of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis.Oncogene,2003,22:319-329
[13]T.X..Xie, F.J.Huang, K.D.Aldape, S.H.Kang,M.Liu and J.E.Gershenwald et al. Activation of stat3 in human melanoma promotes brain metastasis.Cancer Res.2006,66:3188-3196
[14]Benekli.M,Baer.MR,Baumann.H,et al.Signal transducer and activator of transcription proteins in leukemias[J].Blood, 2003,101(8):2940-2954
[15]Grandis.JR,Drenning.SD,Zeng.Q,et al.Constitutive activation of Stat3 signaling abrogates apoptosis in squamouscell carcinogenesis in viv o[J].Proc Natl Acad Sci USA,2000,97(8):4227-4232
[16]Catlett-Falcone.R,Landowski.TH,Oshiro.MM,et al.Constitutive activation of STAT3 signaling confers resistance to apoptosis in human U266 myeloma cells [J].Immunity,1999,10(1):105-115
[17]Burdelya.L,K.ujawski.M,Niu.G,et al.Stat3 activity in melanoma cells affects migration of immu- ne effector cells and nitricoxide-mediated antitumor effects[J].Immunol,2005,174(7): 3925-3931
[18]Leong.PL,Andrews.G.A,Johnson.DE,et al.Targeted inhibition of STAT3 with a decoy oligo nucleotide abrogates head and neck cancer cell growth[J].Proc Natl Acad Sci USA, 2003,100(7): 4138-4143
[19]Garcia.R,Bowman.T.L,Niu.G,et al.Constitutive activation of STAT3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells [J].Oncogene, 2001,20(20) : 2499-2513
[20]Zhang.L,Gao.L.F, Zhao.L.J,et al.Intratumoral delivery and suppression of prostate tumor growth by attenuated Salmonella enterica serovar typhimurium carrying plasmid-based small interfering RNAs[J].Cancer Res,2007,67(12):5859-5864
[21]Hung.K,Liu.H.J,Tu.Y.T.STAT3 and related skin diseases[J].Int J Dermatol Venereol,2006,32(3): 182-184
[22]邓立力,邓洪滨,吕慧芳,等.STAT3和p38在胃癌组织中的表达及意义[J].中国肿瘤临床,2008, 35(4):202 -205
[23]Kramer.OH,Knauer.SK,Greiner.G,et al.A phosphorylation-acetylation switch regulates STAT3 signaling.Genes Dev.2009;23(2):223-235
[24]GRITSKO.T,WILLIAMS.A,TURKSON.J,et al.Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells.Clin Cancer Res,2006,12 :11-19.
[25]马中州,黄壮士,付东宏.食管鳞癌中磷酸化STAT3与Ki67的表达与意义.河南外科学杂志,2009,15 :14-16.
[26]杨俊波,毛志福,蔡享道.STAT3在食管鳞状细胞癌中的表达和意义.消化外科,2006,5:220-222
[27]梁斌,王彬,祝学光,等.转录信号传导子和激活分子在人胃癌组织中的表达及意义.中华实验外科杂志,2001,18:313-314
[28]Redell.MS,Tweardy.DJ.Targeting transcription factors for cancer therapy.Curr Pharm Des, 2005,11: 2873-2887
[1]D.M.Parkin,F.Bray,J.Ferlay and P.Pisani.Global cancer statistics.CA Cancer J.Clin,2005,55:74-108
[2]陈克能,师晓天,程邦昌.食管癌、胃癌基因分子水平的研究进展.中华实验外科杂志,1996,13: 383-384
[3]YOSH.IMURA.A,OHKUBO.T,KIGUCH.I.T,et al.A novel cytokine-inducible gene CIS encodes an SH22containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors.EMBO J,1995,14:2816-2826
[4]Kebs.DLHilton.DJ.SOCS:Physiologieal suppressors of eytokine signaling[J]Cell Sci.2000;113: 2813-2819
[5]Marine.JC,Mckay.C,Wang.D,et al.SOCS3 is essential in the regulation of fetal liver erythropoiesis Cell,1999,98:617-627
[6]Lo.HW,Cao.X,Zhu.H,et al.Constitutively activated STAT3 frequently coexpresses with epidermal growth factor receptor in high-grade gliom as and targeting STAT3 sensitizes them to Iressa and alkylators.Clin Cancer Res,2008;14(19):6042-6054
[7]Zhu.BM,Ishida.Y,Robinson.GW,et al.SOCS3 negatively regulates the gp130-STAT3 pathway in mouse skin wound healing.[J].Invest Derm atol,2008;128(7):1821-1829
[8]Stevenson.NJ,Haan.S,Mc.Clurg.AE,et al.The chemoattractants,IL-8 and form ylmethinony lleucylpheny lalanine,regulate granuloco tyecolony-stimulating factor signaling by inducing supperssor of ctyokine signaling-1 expression. Jimmunol,2004;173 (5):3243-3249
[9]Wong.PK,Egan.PJ,Croker.BA,et al.SOCS-3 negatively regulates innate and adaptive immun emechanisms in acute IL-1 dependent inflamm atory arthritis.[J].Clin Invest,2006;116(6):1571-1581
[10]Tokita.T,Maesawa.C,Kimura.T, et al.Methylation status of the SOCS3 gene in human malignant melanomas. Int J Oncol, 2007,3:689-694
[11]He.B,You.L,Xu.Z,er al.Activity of the suppressor of eytokine signaling-3 promoterin human non-small-cell lung caneer.Clin Lung Caneer.2004;5:366-370
[12]Weber.A,Hengge.UR,Bardenheuer.W,et al.SOCS-3 is frequently methylated in head and neck squamous cell carcinoma and its precursor lesions and causes growth inhibition. Oncogene,2005, 24 (44):6699-6708
[13]Calvisi.DF,Lad.US,Gordena,et al.Ubiquitous activation of Ras and jak/stat Pathways in human HCC. Gastroen-terology,2006,130,(4):1117-1128
[14]Sutherlangd.KD,Lindeman.GJ,Choong.DY,et al.Differential hyper-methylation of SOCS genesin ovarian and breast carcinomas.Oncogene,2004,23(46):7726-7733
[15]Brender.C,Lovato.P,Sommer.VH,et al.Constitutive SOCS-3 expression Proteets T-cell lymPho- ma against growth inhibition by IFNalpha. Leukemia,2005,19(2):209-213
[16]He.B,You.L,Uemasu.K,et a l..SOCS3 is frequently silenced by hype rmethylation and supprsses cell growth in hum an lung cance r[J].Proc Natl Acad Sci USA ,2003,100(24):14133-14138.
[17]Rigby.RJ,Simmons.JG,Greenhalgy.CJ,et al.Suppressor of cytokine signaling 3(SOCS3) limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon. Oncogene,2007,26:4833-4841
[18]刘细国,袁先厚,江普查,等.STAT3和Cyclin D1在人脑胶质瘤中的表达及其意义.中华实验外科杂志,2010,27 :1389-1391.
[19]Ogata.H,Kobayashi.T,Chinen.T,et al.Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis.Gastroenterology,2006,131:179-193
[20]Dimitriadis.E,Stoikos.C,Tan.Y.L,et al.Interleukin 11 signaling components signal transducer and activator of transcrip tion 3 ( STAT3) and supp ressor of cytokine signaling 3 ( SOCS3) regulate human endometrial stromal cell differentiation.Endocrinology,2006,147:3809-3817
[21]毛煜侃,张伟,郑立君.SOCS-3基因在结肠癌中的表达及甲基化测定.同济大学学报,2010,31:41-44
[22]Berclaz.G,Altermal.HJ,Robrobacb.V,et al.EGFR dependent expression of STAT 3(but not STAT1)in breast cancer.Int J Oncol,2001,19:1155-1162
[23]马中州,黄壮士,付东宏.食管鳞癌中磷酸化STAT3与Ki67的表达与意义.河南外科学杂志,2009,15:14-16
[24]Niwa.Y,Kanda.H,Shikauchi.Y,et al.Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Oncogene,2005,24:6406-6417
[1] Kim.DJ,Chan.KS,Sano.S,et a1.Signal transducer and activator of transcription3 (Stat3) in epithelial carcinogenesis.Mol Carcinoq,2007,46;725-731
[2]Pellegrini.S,Dusanter-Fout.I.The structure,regulation and function of theJAKs and STATs[J].EurJ Biochem,1997,248:615-633
[3]Caldenhoven.E,van.Dijk.TB,Solari.R,et al.STAT3β,a splice variant oftranscription factor STAT3, is a dominant negative regulator ofTranscription[J].J Bio Chem,1996,271(21):13221-13227.
[4]Novak.U,Ji.H,Kanagasundaram.V,et al.STAT3 forms sable homodimers in thepresence of divalentcations prior to activation[J].Biochemical and BiophysicalResearch Communications,1998, 247(3):558-563
[5]Becher.S,Groner.B,Mfller.CW,et al.Three-dimensional structure of the STAT3βhomodimer bound to DNA[J].Nature,1998,349(9):145-151
[6]Darnell,JE,Jr.STATs and gene regulation[J].Science,1997,277(12):1630-1635
[7]Atreva.R,Neurath.M.F.Signaling molecules:the pathogenic role of the IL6/STAT3 transsignaling pathway in intestinal inflammation and in colonic cancer.Curr Drug Targets,2008, 9:369-374
[8]Takeda.K,Clausen.BE,Kaisho.T,et al.Enhanced Th1 activity and development of chronic entero- colitis in mice devoid of STAT3 inmacro-phages and neutrophils[J].Immunity,1999,10:39-49
[9] Steven.Fletcher,James.Turkson,Patrick.T,et a1.Molecular approaches towards the inhibition of the signal transducer and activator of transcription3(Star3) protein.Chem Med Chen.2008,3:1159-1168
[10]Zhong.Z,Wen.Z,Darnell.JE,et al.STAT3 and STAT4:Members of the family of signal transducers and activators of transcription[J].PNAS,2004,91:4806-4810
[11]Chakraborty.A,Dyer.KF,Cascio.M,et al.Identification of a novel STAT3 recruitment and active- tion motif within the G-CSFR[J].Blood,1999,93(1): 15-24
[12]Subramaniam.SV,Cooper.RS,Adunyah.SE,et al.Evidence for the involvementof JAK/STAT path- way in the signaling mechanism of interleukin-17[J].Biochemical and Biophysical Research Comu- nications,1999,262:14-19
[13]Rico.K.HL,Helen.C,Yung.H.W,et al.Constitutively Active G 16 StimulatesSTAT3 via a c-Src/ JAK-and ERK-dependent Mechanism[J].J Biol Chem,2003,278(52),52154-52165
[14]谢宏霞,曾凤辉,刘鸿,等.磷酸化和乙酞化修饰对STAT3功能的调节.中国细胞生物学学报.2010,32(1):115-120
[15]Weber-Norlt.RM,Riley.JK,Greenland.AC,et al.STAT3 recruitment by twodistinct ligand-induced ,tyrosine-phosphorylated docking sites in the interlukin-10 receptor intracellular domain[J].J Biol Chem,1996, 87(2):439-446
[16]刘细国,袁先厚,江普查,等.STAT3和Cyclin D1在人脑胶质瘤中的表达及其意义.中华实验外科杂志, 2010,27:1389-1391
[17]华天凤,张妍蓓.瘦素通过激活STAT3信号通路刺激人肺腺癌细胞增殖.安徽医科大学学报.2011,46(1):100-102
[18] Chen.Z,Han,ZC.STAT3:a critical transcription activator in angiogenesis.M edRes Rev,2008,28:85-200.
[19] Frank.DA.STAT 3 as a central mediator of neoplastic cellular transformation.Cancer Iett,2007, 251:199 210
[20]Stefan.F,William.B,David.M,et al.APCK110,a Novel and Potent Inhibitor of c-Kit,Blocks Phosphorylation of AKT and STAT3,Induces Apoptosis,and Inhibits Proliferation of Acute Myeloid Leukemia (AML)Cells[J].Blood,(ASH Annual Meeting Abstracts),2006,108-153
[21]Takemoto.S,Mulloy.JC,Cereseto.A,et al.Proliferation of adult T cell leukemia/ lymphoma cells is associated with the constitutive activation of JAK/STAT proteins[J].PNAS,1997,94:13897-13902
[22]Frank.DA,Mahajan.S,Ritz.J,et al.Blymphocytes from patients with chronic lymphocytic leuke- mia contain signal transducer and activator of Transcription STAT1 and STAT3 constitutively phosphorylated on serine residues[J].J Clin Invest,2007,100(12):3140-3148
[23]Yukio.T,Yukinori.M,Ying.CB,et al.A GTPase-activating protein binds STAT3 and is required for IL-6–induced STAT3 activation and for differentiation of a leukemic cell line[J].Blood,2004,104(12) 3550-3557
[24]Zhenfeng.D,Rosemary.F,Debra.AB,et al.Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer[J].Clin Cancer Res,2006,12:5055-5063
[25]Dieterk.STAT3 is constitutively activated in Hodgkin cell lines[J].Blood,2001,98:762-768
[26]Chong.SS,John.HK.Pyk2 Amplifies Epidermal Growth Factor and c-Src-induced Stat3 Activation[J].J Biol Chem,2004,279(17):17224-17231
[27]Berclaz.G,Altermal.HJ,Robrobacb.V,et al.EGFR dependent expression of STAT 3(but not STAT1)in breast cancer[J].Int J Oncol,2001,19(6):1155-1162
[28]Frank.D.A,Mahajan.S,Ritz.J.B,et al.Lymphocytes from patients with chronic lymphocyticleukemia contains STAT1 and STAT3 constitutively on serine residues[J].J Clin Investig,1997,100: 3140-3144
[29]Steve.A,Benjamin.B,Rituximab.inactivates STAT3 activity in B-Non-Hodgkin's Lymphoma through inhibition of the interleukinl0 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxin drugs[J].Cancer Res,2001,61:5137-5140
[30]Epling-Burnette.PK,Liu.J.H,Catlett-Falcone.R,et al.Inhibition of STAT3 signaling leads to apoptosis of leukemia large granular lymphoma and decreased Mcl-1 expression[J].J Clin Invest,2001,351-356
[31]Lin.J,Jin.X,Rothman.K,et al.Modulation of STAT3 activates by p53 tumor suppressor in breast cancer cell[J].Cancer Res,2002,62(2):376-385
[32]Udayakumar.TS,Stratton.Me,Nagle.RB,et al.Fibroblast growth factor-1 induced promatrilysin expression through the activation of extra cellular regulate kinases and STAT3[J].Neoplasia,2002, 41: 60-70
[33]Jenkins.BJ,Grail.D,Nheu.T,et al.Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling[J].Nat Med,2005,11(8):845-852
[34] Kim.BH,Yin.CH,Guo.Q,et a1.A small molecule compound identified through a cell based screening inhibits JAK/STAT pathway signaling in human cancer cells. Mol Cancer Ther,2008,7: 2672-2680
[35]Sasaki.A.et al.J Biol Chem.2003,278(4):2432-2436
[36]Wailboci.LW,Ahmed.CM,Mujtaba.MG,et al.Both the suppressor of cytokine signaling 1 (SOCS1) kinase inhibitory region and SOCS1 mimetic bind to JAK2 autophosphorylation site: implications for the development of a SOCS1 an tagonist.J.Immuno, 2007; 178(8):5058- 5068
[37]Ben.A,Sandra.E.SOCS regulation of the JAK/STAT signalling pathway.Sem in Cell Dev Biol, 2008;19(4):414 - 422
[38]He.B,You.L,Uematsu.K,et al.SOCS3 is frequently silenced by hyperme- thylation and suppress- es cell growth in human lung cancer [J]. ProcNatlAcad SciUSA, 2003, 100(24):14133- 14138
[39]秦伟.细胞因子信号转导抑制蛋白3与骨髓增殖性肿瘤关系的研究进展.中国实验血液学杂志, 2010;18(4):1101-1104
[40]孙洋,李珊珊,王新华,王小军,阎爱华.转化生长因子p1与食管鳞状细胞癌上皮间质转化的关系中华病理学杂志,2008,37:542-546