DUSP6在肝细胞肝癌中的表达及其与MAPK信号通路、临床病理学特征和预后相关性研究
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摘要
目的：探讨DUSP6在肝细胞肝癌(hepatocellular carcinoma,HCC)中的表达及其与MAPK信号通路、临床病理学特征和预后相关性。
方法：1)305例HCC组织芯片,免疫组化EnVision法检测DUSP6,p-ERK,p-JNK, p-P38α,CyclinDl和Ki-67表达,将以上结果进行统计学相关性分析。2)将DUSP6表达结果同临床病理学特征及术后随访资料进行统计学相关性及预后生存分析。
结果：1)HCC肿瘤组织、癌旁组织和正常肝组织DUSP6表达存在显著性差异(P<0.001);p-ERK,p-JNK和Ki-67肿瘤组织与癌旁组织表达存在显著性差异(P<0.001)：p-P38α和CyclinDl肿瘤组织与癌旁组织表达没有显著性差异(P=0.271,P=0.828).Spearman相关性分析,在HCC肿瘤组织中DUSP6和p-ERK的表达呈显著正相关(r=0.179,P<0.01),DUSP6和1p-JNK的表达无显著相关性(r=0.074,P>0.05),DUSP6和p-P38α的表达无显著相关性(r=0.095,P>0.05),DUSP6和CyclinDl的表达呈显著正相关(r=0.213,P<0.01),DUSP6和Ki-67的表达呈显著正相关(r=0.137,P<0.05)。2)不同DUSP6肿瘤组织表达分组间临床病理学特征均未见显著性差异(P>0.05)：而相对癌旁DUSP6肿瘤组织表达分组间,患者有乙肝和肝硬化病史者不同分组间均存在显著性差异(P<0.05),而其它临床病理学特征均未见显著性差异(P>0.05)。Kaplan-Meier生存曲线分析,不同DUSP6肿瘤组织表达分组间总体生存率(P=0.505)及无瘤生存率(P=0.057)没有显著差异；相对癌旁DUSP6肿瘤组织表达分组间总体生存率(P=0.504)没有显著差异,而无瘤生存率(P=0.004)存在显著性差异。单因素生存分析,肿瘤大小,肿瘤数目,癌栓,肿瘤病理学分级,TNM分期与总体生存率和无瘤生存率均具有显著相关性(P<0.05),而血AFP值只与总体生存率呈显著相关性(P<0.05),肿瘤细胞DUSP6表达和相对癌旁肿瘤细胞DUSP6表达只与无瘤生存率呈显著相关性(P<0.05)。多因素Cox回归模型生存分析,肿瘤大小和肿瘤病理学分级为总体生存率的独立预后风险因素(P<0.001；P=0.006)；肿瘤大小、肿瘤数目和相对癌旁肿瘤细胞DUSP6表达为无瘤生存率的独立预后风险因素(P<0.001；P=0.039：P=0.006)。
结论：1)DUSP6在HCC中肿瘤组织较癌旁组织和正常肝组织表达上调,说明HCC发生发展过程中DUSP6可能为逐渐上调表达过程。p-ERK和p-JNK在HCC肿瘤组织较癌旁组织表达明显上调而p-P38α肿瘤组织较癌旁组织表达没有显著性差异,说明MAPK信号通路中p-ERK和p-JNK上调表达与HCC的发生发展有关,而P38α可能与HCC的发生发展无关；CyclinDl在HCC肿瘤组织较癌旁组织表达没有显著性差异,说明其与HCC的发生发展可能无关；Ki-67肿瘤组织较癌旁组织平均细胞增殖指数明显增加,说明HCC肿瘤细胞增殖活性较癌旁肝硬化组织或正常肝组织明显增加。DUSP6和p-ERK的表达呈显著正相关而DUSP6与p-JNK或p-P38α的表达均无显著相关性,提示DUSP6对p-ERK上调表达起负反馈调节作用。DUSP6和CyclinDl的表达呈显著正相关提示两者关系较为密切,具体关系有待进一步研究；DUSP6和Ki-67的表达呈显著正相关,可能由于ERK信号通路激活导致细胞增殖活性活性升高。2)HBV感染或肝硬化形成与DUSP6表达可能存在一定相关性；相对癌旁DUSP6高表达HCC患者术后更易复发；相对癌旁肿瘤组织DUSP6表达可以作为HCC术后复发风险最佳预测指标；DUSP6作为HCC术后辅助治疗靶点具有一定前景。
Objective:To investigate the correlation of expression of DUSP6 with clinicopathological features, MAPK signaling pathway and prognosis in hepatocellular carcinoma (HCC).
Methods:1)The Expressions of DUSP6, p-ERK, p-JNK, p-P38a, CyclinDl and Ki-67 were assessed by immunohistochemistry in tissue microarrays containing paired tumor and peritumoral liver tissue from 305 patients who had undergone hepatectomy for HCC.Statistical analysis was performed to assess the relationship between DUSP6 and others.2) Prognostic value of DUSP6 and other clinicopathologic factors were evaluated.
Results:1) The expression of DUSP6 was significant different among tumor, peritumor and normal liver tissue (P<0.001).The expression of p-ERK,p-JNK and Ki-67 was significant different between tumor and peritumor respectively (P<0.001); the expression of p-P38αand CyclinDl was no significant difference between tumor and peritumor respectively (P=0.271,P=0.828).The results of Spearman correlation analysis demonstrated that DUSP6 and p-ERK remained significant positive correlation (r=0.179,P<0.01);there was no significant correlation between DUSP6 and p-JNK(r=0.074,P>0.05),between DUSP6 and p-P38a (r=0.095,P>0.05); DUSP6 and CyclinDl remained significant positive correlation (r=0.213,P<0.01); DUSP6 and Ki-67 remained significant positive correlation (r=0.137,P<0.05).2) DUSP6 expression was not associated with clinicopathological features in group of tumor expression and relative tumor expression (P>0.05),except hepatitis B and liver cirrhosis history in group of relative tumor expression (P<0.05).Kaplan-Meier analyzed, tumor DUSP6 expression was not associated with overall survival (OS) or disease-free survival (DFS);relative tumor DUSP6 expression was not associated with OS but was significantly associated with DFS (P=0.004).With univariate Analyses, tumor size, intrahepatic metastasis, microvascular invasion,tumor differentiation, TNM stage were associated with OS and DFS;but AFP was only associated with OS, and tumor DUSP6 expression and relative tumor DUSP6 expression were only associated with DFS.With multivariate analyses of Cox proportional hazards regression model, tumor size and tumor differentiation were independent prognostic factors for OS (P<0.001 and P=0.006, respectively); tumor size, intrahepatic metastasis and relative tumor DUSP6 expression were independent prognostic factors for DFS (P<0.001,P=0.039 and P=0.006, respectively).
Conclusions:1)The expression of DUSP6 in tumor is up-regulated compared with peritumor and normal liver tissue, which indicates that DUSP6 may be gradually up-regulated during genesis and development of HCC.The expression of p-ERK and p-JNK in tumor is significantly up-regulated compared with peritumor, but there is no significant difference between tumor and peritumor for p-P38a, that explains up-regulated expression of p-ERK and p-JNK is concerned with genesis and development of HCC but P38a is not; there is no significant difference between tumor and peritumor about the expression of CyclinDl,which indicates that CyclinDl may have nothing to do with genesis and development of HCC;the expression of Ki-67 in tumor is significantly increased compared with peritumor, which indicates that the proliferation of HCC is higher than peritumor cirrhosis and normal liver tissue. DUSP6 and p-ERK remain significant positive correlation but there is no significant correlation between DUSP6 and p-JNK or p-P38a, so DUSP6 maybe assume negative feedback regulation to overexpression of p-ERK.The positive correlation between DUSP6 and CyclinDl hints the closer relationship between them and further study is needed.The positive correlation between DUSP6 and Ki-67 maybe result from the activation of ERK signaling pathway.2) HBV infection or cirrhosis may be associated with DUSP6;high relative tumor DUSP6 expression is associated with recurrence after curative resection of HCC;relative tumor DUSP6 expression can have a best power to predict the recurrence of HCC;DUSP6 may be a target of postoperative adjuvant therapy.
方法：1)305例HCC组织芯片,免疫组化EnVision法检测DUSP6,p-ERK,p-JNK, p-P38α,CyclinDl和Ki-67表达,将以上结果进行统计学相关性分析。2)将DUSP6表达结果同临床病理学特征及术后随访资料进行统计学相关性及预后生存分析。
结果：1)HCC肿瘤组织、癌旁组织和正常肝组织DUSP6表达存在显著性差异(P<0.001);p-ERK,p-JNK和Ki-67肿瘤组织与癌旁组织表达存在显著性差异(P<0.001)：p-P38α和CyclinDl肿瘤组织与癌旁组织表达没有显著性差异(P=0.271,P=0.828).Spearman相关性分析,在HCC肿瘤组织中DUSP6和p-ERK的表达呈显著正相关(r=0.179,P<0.01),DUSP6和1p-JNK的表达无显著相关性(r=0.074,P>0.05),DUSP6和p-P38α的表达无显著相关性(r=0.095,P>0.05),DUSP6和CyclinDl的表达呈显著正相关(r=0.213,P<0.01),DUSP6和Ki-67的表达呈显著正相关(r=0.137,P<0.05)。2)不同DUSP6肿瘤组织表达分组间临床病理学特征均未见显著性差异(P>0.05)：而相对癌旁DUSP6肿瘤组织表达分组间,患者有乙肝和肝硬化病史者不同分组间均存在显著性差异(P<0.05),而其它临床病理学特征均未见显著性差异(P>0.05)。Kaplan-Meier生存曲线分析,不同DUSP6肿瘤组织表达分组间总体生存率(P=0.505)及无瘤生存率(P=0.057)没有显著差异；相对癌旁DUSP6肿瘤组织表达分组间总体生存率(P=0.504)没有显著差异,而无瘤生存率(P=0.004)存在显著性差异。单因素生存分析,肿瘤大小,肿瘤数目,癌栓,肿瘤病理学分级,TNM分期与总体生存率和无瘤生存率均具有显著相关性(P<0.05),而血AFP值只与总体生存率呈显著相关性(P<0.05),肿瘤细胞DUSP6表达和相对癌旁肿瘤细胞DUSP6表达只与无瘤生存率呈显著相关性(P<0.05)。多因素Cox回归模型生存分析,肿瘤大小和肿瘤病理学分级为总体生存率的独立预后风险因素(P<0.001；P=0.006)；肿瘤大小、肿瘤数目和相对癌旁肿瘤细胞DUSP6表达为无瘤生存率的独立预后风险因素(P<0.001；P=0.039：P=0.006)。
结论：1)DUSP6在HCC中肿瘤组织较癌旁组织和正常肝组织表达上调,说明HCC发生发展过程中DUSP6可能为逐渐上调表达过程。p-ERK和p-JNK在HCC肿瘤组织较癌旁组织表达明显上调而p-P38α肿瘤组织较癌旁组织表达没有显著性差异,说明MAPK信号通路中p-ERK和p-JNK上调表达与HCC的发生发展有关,而P38α可能与HCC的发生发展无关；CyclinDl在HCC肿瘤组织较癌旁组织表达没有显著性差异,说明其与HCC的发生发展可能无关；Ki-67肿瘤组织较癌旁组织平均细胞增殖指数明显增加,说明HCC肿瘤细胞增殖活性较癌旁肝硬化组织或正常肝组织明显增加。DUSP6和p-ERK的表达呈显著正相关而DUSP6与p-JNK或p-P38α的表达均无显著相关性,提示DUSP6对p-ERK上调表达起负反馈调节作用。DUSP6和CyclinDl的表达呈显著正相关提示两者关系较为密切,具体关系有待进一步研究；DUSP6和Ki-67的表达呈显著正相关,可能由于ERK信号通路激活导致细胞增殖活性活性升高。2)HBV感染或肝硬化形成与DUSP6表达可能存在一定相关性；相对癌旁DUSP6高表达HCC患者术后更易复发；相对癌旁肿瘤组织DUSP6表达可以作为HCC术后复发风险最佳预测指标；DUSP6作为HCC术后辅助治疗靶点具有一定前景。
Objective:To investigate the correlation of expression of DUSP6 with clinicopathological features, MAPK signaling pathway and prognosis in hepatocellular carcinoma (HCC).
Methods:1)The Expressions of DUSP6, p-ERK, p-JNK, p-P38a, CyclinDl and Ki-67 were assessed by immunohistochemistry in tissue microarrays containing paired tumor and peritumoral liver tissue from 305 patients who had undergone hepatectomy for HCC.Statistical analysis was performed to assess the relationship between DUSP6 and others.2) Prognostic value of DUSP6 and other clinicopathologic factors were evaluated.
Results:1) The expression of DUSP6 was significant different among tumor, peritumor and normal liver tissue (P<0.001).The expression of p-ERK,p-JNK and Ki-67 was significant different between tumor and peritumor respectively (P<0.001); the expression of p-P38αand CyclinDl was no significant difference between tumor and peritumor respectively (P=0.271,P=0.828).The results of Spearman correlation analysis demonstrated that DUSP6 and p-ERK remained significant positive correlation (r=0.179,P<0.01);there was no significant correlation between DUSP6 and p-JNK(r=0.074,P>0.05),between DUSP6 and p-P38a (r=0.095,P>0.05); DUSP6 and CyclinDl remained significant positive correlation (r=0.213,P<0.01); DUSP6 and Ki-67 remained significant positive correlation (r=0.137,P<0.05).2) DUSP6 expression was not associated with clinicopathological features in group of tumor expression and relative tumor expression (P>0.05),except hepatitis B and liver cirrhosis history in group of relative tumor expression (P<0.05).Kaplan-Meier analyzed, tumor DUSP6 expression was not associated with overall survival (OS) or disease-free survival (DFS);relative tumor DUSP6 expression was not associated with OS but was significantly associated with DFS (P=0.004).With univariate Analyses, tumor size, intrahepatic metastasis, microvascular invasion,tumor differentiation, TNM stage were associated with OS and DFS;but AFP was only associated with OS, and tumor DUSP6 expression and relative tumor DUSP6 expression were only associated with DFS.With multivariate analyses of Cox proportional hazards regression model, tumor size and tumor differentiation were independent prognostic factors for OS (P<0.001 and P=0.006, respectively); tumor size, intrahepatic metastasis and relative tumor DUSP6 expression were independent prognostic factors for DFS (P<0.001,P=0.039 and P=0.006, respectively).
Conclusions:1)The expression of DUSP6 in tumor is up-regulated compared with peritumor and normal liver tissue, which indicates that DUSP6 may be gradually up-regulated during genesis and development of HCC.The expression of p-ERK and p-JNK in tumor is significantly up-regulated compared with peritumor, but there is no significant difference between tumor and peritumor for p-P38a, that explains up-regulated expression of p-ERK and p-JNK is concerned with genesis and development of HCC but P38a is not; there is no significant difference between tumor and peritumor about the expression of CyclinDl,which indicates that CyclinDl may have nothing to do with genesis and development of HCC;the expression of Ki-67 in tumor is significantly increased compared with peritumor, which indicates that the proliferation of HCC is higher than peritumor cirrhosis and normal liver tissue. DUSP6 and p-ERK remain significant positive correlation but there is no significant correlation between DUSP6 and p-JNK or p-P38a, so DUSP6 maybe assume negative feedback regulation to overexpression of p-ERK.The positive correlation between DUSP6 and CyclinDl hints the closer relationship between them and further study is needed.The positive correlation between DUSP6 and Ki-67 maybe result from the activation of ERK signaling pathway.2) HBV infection or cirrhosis may be associated with DUSP6;high relative tumor DUSP6 expression is associated with recurrence after curative resection of HCC;relative tumor DUSP6 expression can have a best power to predict the recurrence of HCC;DUSP6 may be a target of postoperative adjuvant therapy.
引文
[1]Parkin DM,Bray F, Ferlay J,et al.Global cancer statistics,2002. CA Cancer J Clin,2005,55:74-108.
[2]Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet, 2003,362:1907-1917.
[3]Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol, 2001,2:533-543.
[4]Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of 25 major cancers in 1990. Int J Cancer,1999,80:827-841.
[5]Tang ZY, Ye SL, Liu YK, et al.A decade's studies on metastasis of hepatocellular carcinoma. J Cancer Res Clin Oncol,2004,130:187-196.
[6]Alonso A, Sasin J, Bottini N, et al.Protein tyrosine phosphatases in the human genome. Cell,2004,117:699-711.
[7]Camps M,Nichols A, Arkinstall S. Dual specificity phosphatases:A gene family for control of MAP kinase function. FASEB Journal,2000, 14:6-16.
[8]Dickinson RJ, Keyse SM. Diverse physiological functions for dual-specificity MAP kinase phosphatases.Journal of Cell Science,2006, 119(22):4607-4615.
[9]Kondoh K, Nishida E. Regulation of MAP kinases by MAP kinase phosphatases.Biochim Biophys Acta,2006,1773(8):1227-1237.
[10]Theodosiou A, Ashworth A. MAP kinase phosphatases.Genome Biology, 2002,3(7):REVIEWS3009.
[11]Davis RJ. Signal transduction by the JNK group of MAP kinases.Cell, 2000,103:239-252.
[12]Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases.Science,2002,298: 1911-1912.
[13]Pearson G, Robinson F, Beers Gibson T, et al.Mitogen-activated protein (MAP)kinase pathways:Regulation and physiological functions. Endocrine Reviews,2001,22:153-183.
[14]Chang L, Karin M. Mammalian MAP kinase signalling cascades.Nature, 2001,410:37-40.
[15]Kennedy NJ, Davis RJ. Role of JNK in tumor development.Cell Cycle, 2003,2:199-201.
[16]Reth M. Hydrogen peroxide as second messenger in lymphocyte activation. Nature Immunol,2002,3:1129-1134.
[17]Wu GS.Role of mitogen-activated protein kinase phosphatases(MKPs) in cancer. Cancer Metastasis Rev,2007,26:579-585.
[18]Jeffrey KL, Camps M, Rommel C,et al.Targeting dual-specificity phosphatases:manipulating MAP kinase signalling and immune responses. Nat Rev Drug Discov,2007,6(5):391-403.
[19]Mourey RJ,Mourey RJ, Vega QC,et al.A novel cytoplasmic dual specificity protein tyrosine phosphatase implicated in muscle and neuronal differentiation. J Biol Chem,1996,271:3795-3802(1996).
[20]Muda M, Boschert U, Dickinson R, et al.MKP-3, a novel cytosolic protein-tyrosine phosphatase that exemplifies a new class of mitogen-activated protein kinase phosphatase.J Biol Chem,1996,271: 4319-4326.
[21]Groom LA, Sneddon AA, Alessi DR, et al.Differential regulation of the MAP,SAP and RK/p38 kinases by Pystl, a novel cytosolic dual-specificity phosphatase.EMBO J,1996,15:3621-3632.
[22]Smith TG, Karlsson M, Lunn JS, et al. Negative feedback predominates over cross-regulation to control ERK MAPK activity in response to FGF signalling in embryos. FEBS Lett,2006,580:4242-4245.
[23]Pascoal S, Andrade RP, Bajanca F,et al.Progressive mRNA decay establishes an MKP-3 expression gradient in the chick limb bud. Biochem Biophys Res Commun,2007,352:153-157.
[24]Vieira C,Martinez S.Experimental study of MAP kinase phosphatase-3 (MKP-3)expression in the chick neural tube in relation to Fgf8 activity. Brain Res Brain Res Rev,2005,49:158-166.
[25]Tsang M, Maegawa S, Kiang A, et al.A role for MKP-3 in axial patterning of the zebrafish embryo. Development,2004,131:2769-2779.
[26]Kim M, Cha GH, Kim S, et al.MKP-3 has essential roles as a negative regulator of the Ras/mitogen-activated protein kinase pathway during Drosophila development.Mol Cell Biol,2004,24:573-583.
[27]Li C, Scott DA, Hatch E, et al.DUSP6 (MKP-3)is a negative feedback regulator of FGF-stimulated ERK signaling during mouse development. Development,2007,134:167-176.
[28]Maillet M, Purcell NH, Sargent MA, et al.DUSP6 (MKP3) null mice show enhanced ERK1/2 phosphorylation at baseline and increased myocyte proliferation in the heart affecting disease susceptibility. J Biol Chem, 2008,283:31246-31255.
[29]Furukawa T, Tanji E, Xu S, et al.Feedback regulation of DUSP6 transcription responding to MAPK1 via ETS2 in human cells.Biochem Biophys Res Commun,2008,377:317-320.
[30]Marchetti S, Gimond C, Chambard JC,et al.(2005).Extracellular signal-regulated kinases phosphorylate mitogen-activated protein kinase phosphatase 3/DUSP6 at serines 159 and 197, two sites critical for its proteasomal degradation.Mol Cell Biol,2005,25:854-864.
[31]Bermudez 0, Marchetti S, Pages G,et al.Post-translational regulation of the ERK phosphatase DUSP6/MKP3 by the mTOR pathway. Oncogene,2008,27:3685-3691.
[32]Furukawa T, Yatsuoka T, Youssef EM,et al.Genomic analysis of DUSP6, a dual specificity MAP kinase phosphatase, in pancreatic cancer. Cytogenetics and Cell Genetics,1998,82(3-4):156-159.
[33]Furukawa T, Sunamura M, Motoi F,et al.Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer.American Journal of Pathology,2003,162(6):1807-1815.
[34]Xu S, Furukawa T, Kanai N,et al. Abrogation of DUSP6 by hypermethylation in human pancreatic cancer. Journal of Human Genetics, 2005,50(4):159-167.
[35]Furukawa T, Fujisaki R, Yoshida Y,et al.Distinct progression pathways involving the dysfunction of DUSP6/MKP-3 in pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms of the pancreas.Modern Pathology,2005,18(8):1034-1042.
[36]Chan DW, Liu VW, Tsao GS, et al.Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells.Carcinogenesis,2008,29:1742-1750.
[37]Okudela K, Yazawa T,Woo T,et al.Down-regulation of DUSP6 expression in lung cancer:its mechanism and potential role in carcinogenesis.Am J Pathol,2009,175:867-881.
[38]Chen HY, Yu SL, Chen CH, et al.A five-gene signature and clinical outcome in non-small-cell lung cancer.New England Journal of Medicine, 2007,356(1):11-20.
[39]Leung AC, Wong VC, Yang LC,et al.Frequent decreased expression of candidate tumor suppressor gene,DEC1,and its anchorage-independent growth properties and impact on global gene expression in esophageal carcinoma. Int J Cancer,2008,122:587-594.
[40]Hakansson P, Nilsson B, Andersson A,et al.Gene expression analysis of BCR/ABL1-dependent transcriptional response reveals enrichment for genes involved in negative feedback regulation. Genes Chromosomes Cancer, 2008,47:267-275.
[41]Ramnarain DB, Park S, Lee DY,et al.Differential gene expression analysis reveals generation of an autocrine loop by a mutant epidermal growth factor receptor in glioma cells.Cancer Res,2006,66:867-874.
[42]Bloethner S,Chen B,Hemminki K,et al.Effect of common B-RAF and N-RAS mutations on global gene expression in melanoma cell lines. Carcinogenesis,2005,26:1224-1232.
[43]Vogt A,Cooley KA, Brisson M,et al.Cell-active dual specificity phosphatase inhibitors identified by high-content screening. Chemistry and Biology,2003,10(8):733-742.
[44]Hui LJ,Bakiri L,Mairhorfer A,et al.p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway. Nat Genet,2007,39:741-749.
[45]Owens DM,Keyse SM. Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases.Oncogene,2007,26:3203-3213.
[46]Gailhouste L,Ezan F,Bessard A,et al.RNAi-mediated MEK1 knock-down prevents ERK1/2 activation and abolishes human hepatocarcinoma growth in vitro and in vivo. Int J Cancer,2010,126:1367-1377.
[47]Bessard A,Fremin C,Ezan F,et al.RNAi-mediated ERK2 knockdown inhibits growth of tumor cells in vitro and in vivo. Oncogene,2008,27: 5315-5325.
[48]Schmitz KJ, Wohlschlaeger J, Lang H,et al.Activation of the ERK and AKT signalling pathway predicts poor prognosis in hepatocellular carcinoma and ERK activation in cancer tissue is associated with hepatitis C virus infection. Journal of Hepatology,2008,48:83-90.
[49]Tsuboi Y, Ichida T, Sugitani S, et al.Overexpression of extracellular signal-regulated protein kinase and its correlation with proliferation in human hepatocellular carcinoma. Liver Int,2004,24: 432-436.
[50]Chang Q, Zhang Y, Beezhold KJ, et al.Sustained JNK1 activation is associated with altered histone H3 methylations in human liver cancer. Journal of Hepatology,2009,50:323-333.
[51]Chang Q, Chen J, Beezhold KJ, et al.JNK1 activation predicts the prognostic outcome of the human hepatocellular carcinoma. Mol Cancer, 2009,8:64.
[52]Chen X, Cheung ST, So S, Fan ST, Barry C, Higgins J, Lai K-M, Ji J, Dudoit S, Ng IOL, van de Rijn M, Botstein D, Brown PO:Gene Expression Patterns in Human Liver Cancers,Mol.Biol.Cell 2002,13:1929-1939
[53]Ju-Seog L, In-Sun C, Jeonghoon H, Diego FC, Zongtang S, Tania R, Anne D, Anthony JD, Snorri ST:Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling, Hepatology 2004, 40:667-676
[54]Lee J-S, Heo J, Libbrecht L, Chu I-S, Kaposi-Novak P, Calvisi DF, Mikaelyan A, Roberts LR, Demetris AJ, Sun Z, Nevens F, Roskams T, Thorgeirsson SS:A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells, Nat Med 2006,12:410-416
[55]Boyault S,Rickman DS, de Reynies A, Balabaud C,Rebouissou S,Jeannot E, Herault A, Saric J, Belghiti J, Franco D, Bioulac-Sage P, Laurent-Puig P, Zucman-Rossi J:Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets, Hepatology 2007,45:42-52
[56]Ye Q-H, Qin L-X, Forgues M, He P, Kim JW, Peng AC, Simon R, Li Y, Robles Al,Chen Y, Ma Z-C, Wu Z-Q, Ye S-L, Liu Y-K, Tang Z-Y, Wang XW: Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning, Nat Med 2003,9:416-423
[57]Llovet JM, Ricci S, Mazzaferro V,et al.Sorafenib in advanced hepatocellular carcinoma, N Engl J Med,2008,359:378-390.
[58]Parekh P, Rao KV. Overexpression of cyclin Dl is associated with elevated levels of MAP kinases, Akt and Pakl during diethylnitrosamine-induced progressive liver carcinogenesis.Cell Biol Int,2007,31:35-43.
[1]Mourey RJ,Mourey RJ, Vega QC,et al.A novel cytoplasmic dual specificity protein tyrosine phosphatase implicated in muscle and neuronal differentiation. J Biol Chem,1996,271:3795-3802(1996).
[2]Muda M, Boschert U, Dickinson R, et al.MKP-3, a novel cytosolic protein-tyrosine phosphatase that exemplifies a new class of mitogen-activated protein kinase phosphatase. J Biol Chem,1996,271: 4319-4326.
[3]Groom LA, Sneddon AA, Alessi DR, et al.Differential regulation of the MAP,SAP and RK/p38 kinases by Pystl, a novel cytosolic dual-specificity phosphatase. EMBO J,1996,15:3621-3632.
[4]Jeffrey KL, Camps M, Rommel C, et al.Targeting dual-specificity phosphatases:manipulating MAP kinase signalling and immune responses. Nat Rev Drug Discov,2007,6(5):391-403.
[5]Hunter T. Protein kinases and phosphatases:the yin and yang of protein phosphorylation and signaling. Cell,1995,80:225-236.
[6]Alonso A, Sasin J, Bottini N, et al.Protein tyrosine phosphatases in the human genome. Cell,2004,117:699-711.
[7]Stoker AW. Protein tyrosine phosphatases and signalling. J Endocrinol,2005,185:19-33.
[8]Tonks NK,Neel BG.(1996) From form to function:signaling by protein tyrosine phosphatases.Cell,1996,87:365-368.
[9]Charbonneau H, Tonks NK, Kumar S, et al. Human placenta protein-tyrosinephosphatase:amino acid sequence and relationship to a family of receptor-like proteins. Proc Natl Acad Sci U.S.A.1989,86: 5252-5256.
[10]Guan KL, Haun RS, Watson SJ, et al.Cloning and expression of a protein-tyrosine-phosphatase. Proc Natl Acad Sci U.S.A.1990,87: 1501-1505.
[11]Czernilofsky AP, Levinson AD, Varmus HE, et al.Nucleotide sequence of an avian sarcoma virus oncogene(src)and proposed amino acid sequence for gene product.Nature,1980,287:198-203.
[12]Heinrich R, Neel BG,Rapoport TA. Mathematical models of protein kinase signal transduction. Mol Cell,2002,9:957-970.
[13]Russell P,Nurse P. cdc25+ functions as an inducer in the mitotic control of fission yeast.Cell,1986,45:145-153.
[14]Karlsson-Rosenthal C,Millar JB. Cdc25:mechanisms of checkpoint inhibition and recovery. Trends Cell Biol,2006,16:285-292.
[15]Moorhead GB,Trinkle-Mulcahy L,Ulke-Lemee A. Emerging roles of nuclear protein phosphatases.Nat.Rev. Mol.Cell Biol,2007,8:234-244.
[16]Gohla A, Birkenfeld J,Bokoch GM. Chronophin, a novel HAD-type serine protein phosphatase,regulates cofilin-dependent actin dynamics.Nat Cell Biol,2005,7:21-29.
[17]Yeo M, Lin PS, Dahmus ME,et al.A novel RNA polymerase II C-terminal domain phosphatase that preferentially dephosphorylates serine 5.J Biol Chem,2003,278:26078-26085.
[18]Roberts SJ, Stewart AJ, Sadler PJ,et al.Human PHOSPH01 exhibits high specific phosphoethanolamine and phosphocholine phosphatase activities. Biochem J,2004,382:59-65.
[19]Allegrini S, Scaloni A, Careddu MG, et al.Mechanistic studies on bovine cytosolic 5'-nucleotidase Ⅱ, an enzyme belonging to the HAD superfamily. Eur J Biochem,2004,271:4881-4891.
[20]Denu JM,Dixon JE. Protein tyrosine phosphatases:mechanisms of catalysis and regulation. Curr Opin Chem Biol,1998,2:633-641.
[21]Denu JM,Dixon JE. A catalytic mechanism for the dual-specific phosphatases. Proc Natl Acad Sci U.S.A.1995,92:5910-5914.
[22]Camps M,Nichols A, Arkinstall S. Dual specificity phosphatases:A gene family for control of MAP kinase function. FASEB Journal,2000, 14:6-16.
[23]Dickinson RJ, Keyse SM. Diverse physiological functions for dual-specificity MAP kinase phosphatases.Journal of Cell Science,2006, 119(22):4607-4615.
[24]Kondoh K, Nishida E. Regulation of MAP kinases by MAP kinase phosphatases.Biochim Biophys Acta,2006,1773(8):1227-1237.
[25]Zhan XL, Wishart MJ, Guan KL. Nonreceptor tyrosine phosphatases in cellular signaling:Regulation of mitogen-activated protein kinases. Chemical Reviews,2001,101(8):2477-2496.
[26]Theodosiou A, Ashworth A. MAP kinase phosphatases.Genome Biology, 2002,3(7):REVIEWS3009.
[27]Davis RJ. Signal transduction by the JNK group of MAP kinases.Cell, 2000,103:239-252.
[28]Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science,2002,298: 1911-1912.
[29]Pearson G, Robinson F, Beers Gibson T, et al.Mitogen-activated protein (MAP)kinase pathways:Regulation and physiological functions. Endocrine Reviews,2001,22:153-183.
[30]Chang L, Karin M. Mammalian MAP kinase signalling cascades.Nature, 2001,410:37-40.
[31]Kennedy NJ, Davis RJ. Role of JNK in tumor development.Cell Cycle, 2003,2:199-201.
[32]Reth M. Hydrogen peroxide as second messenger in lymphocyte activation. Nature Immunol,2002,3:1129-1134.
[33]Wu GS.Role of mitogen-activated protein kinase phosphatases(MKPs) in cancer. Cancer Metastasis Rev,2007,26:579-585.
[34]Karlsson M, Mathers J,Dickinson RJ, et al.Both nuclear-cytoplasmic shuttling of the dual specificity phosphatase MKP-3 and its ability to anchor MAP kinase in the cytoplasm are mediated by a conserved nuclear export signal.J Biol Chem,2004,279:41882-41891.
[35]Smith TG, Karlsson M, Lunn JS, et al.Negative feedback predominates over cross-regulation to control ERK MAPK activity in response to FGF signalling in embryos.FEBS Lett,2006,580:4242-4245.
[36]Pascoal S, Andrade RP, Bajanca F,et al.Progressive mRNA decay establishes an MKP-3 expression gradient in the chick limb bud. Biochem Biophys Res Commun,2007,352:153-157.
[37]Vieira C,Martinez S.Experimental study of MAP kinase phosphatase-3 (MKP-3)expression in the chick neural tube in relation to Fgf8 activity. Brain Res Brain Res Rev,2005,49:158-166.
[38]Tsang M, Maegawa S, Kiang A, et al.A role for MKP-3 in axial patterning of the zebrafish embryo. Development,2004,131:2769-2779.
[39]Kim M, Cha GH, Kim S, et al.MKP-3 has essential roles as a negative regulator of the Ras/mitogen-activated protein kinase pathway during Drosophila development.Mol Cell Biol,2004,24:573-583.
[40]Li C, Scott DA, Hatch E, et al.DUSP6 (MKP-3)is a negative feedback regulator of FGF-stimulated ERK signaling during mouse development. Development,2007,134:167-176.
[41]Maillet M, Purcell NH, Sargent MA, et al.DUSP6 (MKP3) null mice show enhanced ERK1/2 phosphorylation at baseline and increased myocyte proliferation in the heart affecting disease susceptibility. J Biol Chem, 2008,283:31246-31255.
[42]Rossig L, Hermann C, Haendeler J,et al.Angiotensin Ⅱ-induced upregulation of MAP kinase phosphatase-3 mRNA levels mediates endothelial cell apoptosis, Basic Res Cardiol,2002,97:1-8.
[43]Xu H, Yang Q, Shen M, et al.Dual specificity MAPK phosphatase 3 activates PEPCK gene transcription and increases gluconeogenesis in rat hepatoma cells.J Biol Chem,2005,280:36013-36018.
[44]Furukawa T, Tanji E, Xu S, et al.Feedback regulation of DUSP6 transcription responding to MAPK1 via ETS2 in human cells.Biochem Biophys Res Commun,2008,377:317-320.
[45]Ekerot M, Stavridis MP, Delavaine L,et al.Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter. Biochem J,2008,412:287-298.
[46]Jurek A, Amagasaki K, Gembarska A,et al.Negative and positive regulation of MAPK phosphatase 3 controls platelet-derived growth factor-induced Erk activation. Biol Chem,2009,284:4626-4634.
[47]Marchetti S, Gimond C, Chambard JC,et al.(2005).Extracellular signal-regulated kinases phosphorylate mitogen-activated protein kinase phosphatase 3/DUSP6 at serines 159 and 197, two sites critical for its proteasomal degradation. Mol Cell Biol,2005,25:854-864.
[48]Bermudez 0, Marchetti S, Pages G,et al.Post-translational regulation of the ERK phosphatase DUSP6/MKP3 by the mTOR pathway. Oncogene,2008,27:3685-3691.
[49]Zeliadt NA, Mauro LJ, Wattenberg EV. Reciprocal regulation of extracellular signal regulated kinase 1/2 and mitogen activated protein kinase phosphatase-3.Toxicol Appl Pharmacol,2008,232:408-417.
[50]Furukawa T, Yatsuoka T, Youssef EM,et al.Genomic analysis of DUSP6, a dual specificity MAP kinase phosphatase, in pancreatic cancer. Cytogenetics and Cell Genetics,1998,82(3-4):156-159.
[51]Furukawa T, Sunamura M, Motoi F,et al.Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer. American Journal of Pathology,2003,162(6):1807-1815.
[52]Xu S, Furukawa T, Kanai N,et al.Abrogation of DUSP6 by hypermethylation in human pancreatic cancer. Journal of Human Genetics, 2005,50(4):159-167.
[53]Furukawa T, Fujisaki R, Yoshida Y,et al.Distinct progression pathways involving the dysfunction of DUSP6/MKP-3 in pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms of the pancreas.Modern Pathology,2005,18(8):1034-1042.
[54]Chan DW, Liu VW, Tsao GS, et al.Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells.Carcinogenesis,2008,29:1742-1750.
[55]Okudela K, Yazawa T, Woo T,et al.Down-regulation of DUSP6 expression in lung cancer:its mechanism and potential role in carcinogenesis.Am J Pathol,2009,175:867-881.
[56]Sato M, Vaughan MB, Girard L, et al.Multiple oncogenic changes (K-RAS(V12),p53 knockdown, mutant EGFRs,p16 bypass, telomerase)are not sufficient to confer a full malignant phenotype on human bronchial epithelial cells.Cancer Res,2006,66:2116-2128.
[57]Chen HY, Yu SL, Chen CH, et al.A five-gene signature and clinical outcome in non-small-cell lung cancer. New England Journal of Medicine, 2007,356(1):11-20.
[58]Leung AC, Wong VC, Yang LC,et al.Frequent decreased expression of candidate tumor suppressor gene, DEC1,and its anchorage-independent growth properties and impact on global gene expression in esophageal carcinoma. Int J Cancer,2008,122:587-594.
[59]Hakansson P, Nilsson B, Andersson A,et al.Gene expression analysis of BCR/ABL1-dependent transcriptional response reveals enrichment for genes involved in negative feedback regulation.Genes Chromosomes Cancer, 2008,47:267-275.
[60]Ramnarain DB, Park S, Lee DY,et al.Differential gene expression analysis reveals generation of an autocrine loop by a mutant epidermal growth factor receptor in glioma cells.Cancer Res,2006,66:867-874.
[61]Bloethner S,Chen B,Hemminki K,et al.Effect of common B-RAF and N-RAS mutations on global gene expression in melanoma cell lines. Carcinogenesis,2005,26:1224-1232.
[62]Croonquist PA, Linden MA, Zhao F,et al.Gene profiling of a myeloma cell line reveals similarities and unique signatures among IL-6 response, N-ras-activating mutations,and coculture with bone marrow stromal cells. Blood,2003,102:2581-2592.
[63]Cui Y, Parra I, Zhang M,et al.Elevated expression of mitogen-activated protein kinase phosphatase 3 in breast tumors:a mechanism of tamoxifen resistance,Cancer Res,2006,66:5950-5959.
[64]Vogt A,Cooley KA, Brisson M,et al.Cell-active dual specificity phosphatase inhibitors identified by high-content screening. Chemistry and Biology,2003,10(8):733-742.
[2]Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet, 2003,362:1907-1917.
[3]Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol, 2001,2:533-543.
[4]Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of 25 major cancers in 1990. Int J Cancer,1999,80:827-841.
[5]Tang ZY, Ye SL, Liu YK, et al.A decade's studies on metastasis of hepatocellular carcinoma. J Cancer Res Clin Oncol,2004,130:187-196.
[6]Alonso A, Sasin J, Bottini N, et al.Protein tyrosine phosphatases in the human genome. Cell,2004,117:699-711.
[7]Camps M,Nichols A, Arkinstall S. Dual specificity phosphatases:A gene family for control of MAP kinase function. FASEB Journal,2000, 14:6-16.
[8]Dickinson RJ, Keyse SM. Diverse physiological functions for dual-specificity MAP kinase phosphatases.Journal of Cell Science,2006, 119(22):4607-4615.
[9]Kondoh K, Nishida E. Regulation of MAP kinases by MAP kinase phosphatases.Biochim Biophys Acta,2006,1773(8):1227-1237.
[10]Theodosiou A, Ashworth A. MAP kinase phosphatases.Genome Biology, 2002,3(7):REVIEWS3009.
[11]Davis RJ. Signal transduction by the JNK group of MAP kinases.Cell, 2000,103:239-252.
[12]Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases.Science,2002,298: 1911-1912.
[13]Pearson G, Robinson F, Beers Gibson T, et al.Mitogen-activated protein (MAP)kinase pathways:Regulation and physiological functions. Endocrine Reviews,2001,22:153-183.
[14]Chang L, Karin M. Mammalian MAP kinase signalling cascades.Nature, 2001,410:37-40.
[15]Kennedy NJ, Davis RJ. Role of JNK in tumor development.Cell Cycle, 2003,2:199-201.
[16]Reth M. Hydrogen peroxide as second messenger in lymphocyte activation. Nature Immunol,2002,3:1129-1134.
[17]Wu GS.Role of mitogen-activated protein kinase phosphatases(MKPs) in cancer. Cancer Metastasis Rev,2007,26:579-585.
[18]Jeffrey KL, Camps M, Rommel C,et al.Targeting dual-specificity phosphatases:manipulating MAP kinase signalling and immune responses. Nat Rev Drug Discov,2007,6(5):391-403.
[19]Mourey RJ,Mourey RJ, Vega QC,et al.A novel cytoplasmic dual specificity protein tyrosine phosphatase implicated in muscle and neuronal differentiation. J Biol Chem,1996,271:3795-3802(1996).
[20]Muda M, Boschert U, Dickinson R, et al.MKP-3, a novel cytosolic protein-tyrosine phosphatase that exemplifies a new class of mitogen-activated protein kinase phosphatase.J Biol Chem,1996,271: 4319-4326.
[21]Groom LA, Sneddon AA, Alessi DR, et al.Differential regulation of the MAP,SAP and RK/p38 kinases by Pystl, a novel cytosolic dual-specificity phosphatase.EMBO J,1996,15:3621-3632.
[22]Smith TG, Karlsson M, Lunn JS, et al. Negative feedback predominates over cross-regulation to control ERK MAPK activity in response to FGF signalling in embryos. FEBS Lett,2006,580:4242-4245.
[23]Pascoal S, Andrade RP, Bajanca F,et al.Progressive mRNA decay establishes an MKP-3 expression gradient in the chick limb bud. Biochem Biophys Res Commun,2007,352:153-157.
[24]Vieira C,Martinez S.Experimental study of MAP kinase phosphatase-3 (MKP-3)expression in the chick neural tube in relation to Fgf8 activity. Brain Res Brain Res Rev,2005,49:158-166.
[25]Tsang M, Maegawa S, Kiang A, et al.A role for MKP-3 in axial patterning of the zebrafish embryo. Development,2004,131:2769-2779.
[26]Kim M, Cha GH, Kim S, et al.MKP-3 has essential roles as a negative regulator of the Ras/mitogen-activated protein kinase pathway during Drosophila development.Mol Cell Biol,2004,24:573-583.
[27]Li C, Scott DA, Hatch E, et al.DUSP6 (MKP-3)is a negative feedback regulator of FGF-stimulated ERK signaling during mouse development. Development,2007,134:167-176.
[28]Maillet M, Purcell NH, Sargent MA, et al.DUSP6 (MKP3) null mice show enhanced ERK1/2 phosphorylation at baseline and increased myocyte proliferation in the heart affecting disease susceptibility. J Biol Chem, 2008,283:31246-31255.
[29]Furukawa T, Tanji E, Xu S, et al.Feedback regulation of DUSP6 transcription responding to MAPK1 via ETS2 in human cells.Biochem Biophys Res Commun,2008,377:317-320.
[30]Marchetti S, Gimond C, Chambard JC,et al.(2005).Extracellular signal-regulated kinases phosphorylate mitogen-activated protein kinase phosphatase 3/DUSP6 at serines 159 and 197, two sites critical for its proteasomal degradation.Mol Cell Biol,2005,25:854-864.
[31]Bermudez 0, Marchetti S, Pages G,et al.Post-translational regulation of the ERK phosphatase DUSP6/MKP3 by the mTOR pathway. Oncogene,2008,27:3685-3691.
[32]Furukawa T, Yatsuoka T, Youssef EM,et al.Genomic analysis of DUSP6, a dual specificity MAP kinase phosphatase, in pancreatic cancer. Cytogenetics and Cell Genetics,1998,82(3-4):156-159.
[33]Furukawa T, Sunamura M, Motoi F,et al.Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer.American Journal of Pathology,2003,162(6):1807-1815.
[34]Xu S, Furukawa T, Kanai N,et al. Abrogation of DUSP6 by hypermethylation in human pancreatic cancer. Journal of Human Genetics, 2005,50(4):159-167.
[35]Furukawa T, Fujisaki R, Yoshida Y,et al.Distinct progression pathways involving the dysfunction of DUSP6/MKP-3 in pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms of the pancreas.Modern Pathology,2005,18(8):1034-1042.
[36]Chan DW, Liu VW, Tsao GS, et al.Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells.Carcinogenesis,2008,29:1742-1750.
[37]Okudela K, Yazawa T,Woo T,et al.Down-regulation of DUSP6 expression in lung cancer:its mechanism and potential role in carcinogenesis.Am J Pathol,2009,175:867-881.
[38]Chen HY, Yu SL, Chen CH, et al.A five-gene signature and clinical outcome in non-small-cell lung cancer.New England Journal of Medicine, 2007,356(1):11-20.
[39]Leung AC, Wong VC, Yang LC,et al.Frequent decreased expression of candidate tumor suppressor gene,DEC1,and its anchorage-independent growth properties and impact on global gene expression in esophageal carcinoma. Int J Cancer,2008,122:587-594.
[40]Hakansson P, Nilsson B, Andersson A,et al.Gene expression analysis of BCR/ABL1-dependent transcriptional response reveals enrichment for genes involved in negative feedback regulation. Genes Chromosomes Cancer, 2008,47:267-275.
[41]Ramnarain DB, Park S, Lee DY,et al.Differential gene expression analysis reveals generation of an autocrine loop by a mutant epidermal growth factor receptor in glioma cells.Cancer Res,2006,66:867-874.
[42]Bloethner S,Chen B,Hemminki K,et al.Effect of common B-RAF and N-RAS mutations on global gene expression in melanoma cell lines. Carcinogenesis,2005,26:1224-1232.
[43]Vogt A,Cooley KA, Brisson M,et al.Cell-active dual specificity phosphatase inhibitors identified by high-content screening. Chemistry and Biology,2003,10(8):733-742.
[44]Hui LJ,Bakiri L,Mairhorfer A,et al.p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway. Nat Genet,2007,39:741-749.
[45]Owens DM,Keyse SM. Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases.Oncogene,2007,26:3203-3213.
[46]Gailhouste L,Ezan F,Bessard A,et al.RNAi-mediated MEK1 knock-down prevents ERK1/2 activation and abolishes human hepatocarcinoma growth in vitro and in vivo. Int J Cancer,2010,126:1367-1377.
[47]Bessard A,Fremin C,Ezan F,et al.RNAi-mediated ERK2 knockdown inhibits growth of tumor cells in vitro and in vivo. Oncogene,2008,27: 5315-5325.
[48]Schmitz KJ, Wohlschlaeger J, Lang H,et al.Activation of the ERK and AKT signalling pathway predicts poor prognosis in hepatocellular carcinoma and ERK activation in cancer tissue is associated with hepatitis C virus infection. Journal of Hepatology,2008,48:83-90.
[49]Tsuboi Y, Ichida T, Sugitani S, et al.Overexpression of extracellular signal-regulated protein kinase and its correlation with proliferation in human hepatocellular carcinoma. Liver Int,2004,24: 432-436.
[50]Chang Q, Zhang Y, Beezhold KJ, et al.Sustained JNK1 activation is associated with altered histone H3 methylations in human liver cancer. Journal of Hepatology,2009,50:323-333.
[51]Chang Q, Chen J, Beezhold KJ, et al.JNK1 activation predicts the prognostic outcome of the human hepatocellular carcinoma. Mol Cancer, 2009,8:64.
[52]Chen X, Cheung ST, So S, Fan ST, Barry C, Higgins J, Lai K-M, Ji J, Dudoit S, Ng IOL, van de Rijn M, Botstein D, Brown PO:Gene Expression Patterns in Human Liver Cancers,Mol.Biol.Cell 2002,13:1929-1939
[53]Ju-Seog L, In-Sun C, Jeonghoon H, Diego FC, Zongtang S, Tania R, Anne D, Anthony JD, Snorri ST:Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling, Hepatology 2004, 40:667-676
[54]Lee J-S, Heo J, Libbrecht L, Chu I-S, Kaposi-Novak P, Calvisi DF, Mikaelyan A, Roberts LR, Demetris AJ, Sun Z, Nevens F, Roskams T, Thorgeirsson SS:A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells, Nat Med 2006,12:410-416
[55]Boyault S,Rickman DS, de Reynies A, Balabaud C,Rebouissou S,Jeannot E, Herault A, Saric J, Belghiti J, Franco D, Bioulac-Sage P, Laurent-Puig P, Zucman-Rossi J:Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets, Hepatology 2007,45:42-52
[56]Ye Q-H, Qin L-X, Forgues M, He P, Kim JW, Peng AC, Simon R, Li Y, Robles Al,Chen Y, Ma Z-C, Wu Z-Q, Ye S-L, Liu Y-K, Tang Z-Y, Wang XW: Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning, Nat Med 2003,9:416-423
[57]Llovet JM, Ricci S, Mazzaferro V,et al.Sorafenib in advanced hepatocellular carcinoma, N Engl J Med,2008,359:378-390.
[58]Parekh P, Rao KV. Overexpression of cyclin Dl is associated with elevated levels of MAP kinases, Akt and Pakl during diethylnitrosamine-induced progressive liver carcinogenesis.Cell Biol Int,2007,31:35-43.
[1]Mourey RJ,Mourey RJ, Vega QC,et al.A novel cytoplasmic dual specificity protein tyrosine phosphatase implicated in muscle and neuronal differentiation. J Biol Chem,1996,271:3795-3802(1996).
[2]Muda M, Boschert U, Dickinson R, et al.MKP-3, a novel cytosolic protein-tyrosine phosphatase that exemplifies a new class of mitogen-activated protein kinase phosphatase. J Biol Chem,1996,271: 4319-4326.
[3]Groom LA, Sneddon AA, Alessi DR, et al.Differential regulation of the MAP,SAP and RK/p38 kinases by Pystl, a novel cytosolic dual-specificity phosphatase. EMBO J,1996,15:3621-3632.
[4]Jeffrey KL, Camps M, Rommel C, et al.Targeting dual-specificity phosphatases:manipulating MAP kinase signalling and immune responses. Nat Rev Drug Discov,2007,6(5):391-403.
[5]Hunter T. Protein kinases and phosphatases:the yin and yang of protein phosphorylation and signaling. Cell,1995,80:225-236.
[6]Alonso A, Sasin J, Bottini N, et al.Protein tyrosine phosphatases in the human genome. Cell,2004,117:699-711.
[7]Stoker AW. Protein tyrosine phosphatases and signalling. J Endocrinol,2005,185:19-33.
[8]Tonks NK,Neel BG.(1996) From form to function:signaling by protein tyrosine phosphatases.Cell,1996,87:365-368.
[9]Charbonneau H, Tonks NK, Kumar S, et al. Human placenta protein-tyrosinephosphatase:amino acid sequence and relationship to a family of receptor-like proteins. Proc Natl Acad Sci U.S.A.1989,86: 5252-5256.
[10]Guan KL, Haun RS, Watson SJ, et al.Cloning and expression of a protein-tyrosine-phosphatase. Proc Natl Acad Sci U.S.A.1990,87: 1501-1505.
[11]Czernilofsky AP, Levinson AD, Varmus HE, et al.Nucleotide sequence of an avian sarcoma virus oncogene(src)and proposed amino acid sequence for gene product.Nature,1980,287:198-203.
[12]Heinrich R, Neel BG,Rapoport TA. Mathematical models of protein kinase signal transduction. Mol Cell,2002,9:957-970.
[13]Russell P,Nurse P. cdc25+ functions as an inducer in the mitotic control of fission yeast.Cell,1986,45:145-153.
[14]Karlsson-Rosenthal C,Millar JB. Cdc25:mechanisms of checkpoint inhibition and recovery. Trends Cell Biol,2006,16:285-292.
[15]Moorhead GB,Trinkle-Mulcahy L,Ulke-Lemee A. Emerging roles of nuclear protein phosphatases.Nat.Rev. Mol.Cell Biol,2007,8:234-244.
[16]Gohla A, Birkenfeld J,Bokoch GM. Chronophin, a novel HAD-type serine protein phosphatase,regulates cofilin-dependent actin dynamics.Nat Cell Biol,2005,7:21-29.
[17]Yeo M, Lin PS, Dahmus ME,et al.A novel RNA polymerase II C-terminal domain phosphatase that preferentially dephosphorylates serine 5.J Biol Chem,2003,278:26078-26085.
[18]Roberts SJ, Stewart AJ, Sadler PJ,et al.Human PHOSPH01 exhibits high specific phosphoethanolamine and phosphocholine phosphatase activities. Biochem J,2004,382:59-65.
[19]Allegrini S, Scaloni A, Careddu MG, et al.Mechanistic studies on bovine cytosolic 5'-nucleotidase Ⅱ, an enzyme belonging to the HAD superfamily. Eur J Biochem,2004,271:4881-4891.
[20]Denu JM,Dixon JE. Protein tyrosine phosphatases:mechanisms of catalysis and regulation. Curr Opin Chem Biol,1998,2:633-641.
[21]Denu JM,Dixon JE. A catalytic mechanism for the dual-specific phosphatases. Proc Natl Acad Sci U.S.A.1995,92:5910-5914.
[22]Camps M,Nichols A, Arkinstall S. Dual specificity phosphatases:A gene family for control of MAP kinase function. FASEB Journal,2000, 14:6-16.
[23]Dickinson RJ, Keyse SM. Diverse physiological functions for dual-specificity MAP kinase phosphatases.Journal of Cell Science,2006, 119(22):4607-4615.
[24]Kondoh K, Nishida E. Regulation of MAP kinases by MAP kinase phosphatases.Biochim Biophys Acta,2006,1773(8):1227-1237.
[25]Zhan XL, Wishart MJ, Guan KL. Nonreceptor tyrosine phosphatases in cellular signaling:Regulation of mitogen-activated protein kinases. Chemical Reviews,2001,101(8):2477-2496.
[26]Theodosiou A, Ashworth A. MAP kinase phosphatases.Genome Biology, 2002,3(7):REVIEWS3009.
[27]Davis RJ. Signal transduction by the JNK group of MAP kinases.Cell, 2000,103:239-252.
[28]Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science,2002,298: 1911-1912.
[29]Pearson G, Robinson F, Beers Gibson T, et al.Mitogen-activated protein (MAP)kinase pathways:Regulation and physiological functions. Endocrine Reviews,2001,22:153-183.
[30]Chang L, Karin M. Mammalian MAP kinase signalling cascades.Nature, 2001,410:37-40.
[31]Kennedy NJ, Davis RJ. Role of JNK in tumor development.Cell Cycle, 2003,2:199-201.
[32]Reth M. Hydrogen peroxide as second messenger in lymphocyte activation. Nature Immunol,2002,3:1129-1134.
[33]Wu GS.Role of mitogen-activated protein kinase phosphatases(MKPs) in cancer. Cancer Metastasis Rev,2007,26:579-585.
[34]Karlsson M, Mathers J,Dickinson RJ, et al.Both nuclear-cytoplasmic shuttling of the dual specificity phosphatase MKP-3 and its ability to anchor MAP kinase in the cytoplasm are mediated by a conserved nuclear export signal.J Biol Chem,2004,279:41882-41891.
[35]Smith TG, Karlsson M, Lunn JS, et al.Negative feedback predominates over cross-regulation to control ERK MAPK activity in response to FGF signalling in embryos.FEBS Lett,2006,580:4242-4245.
[36]Pascoal S, Andrade RP, Bajanca F,et al.Progressive mRNA decay establishes an MKP-3 expression gradient in the chick limb bud. Biochem Biophys Res Commun,2007,352:153-157.
[37]Vieira C,Martinez S.Experimental study of MAP kinase phosphatase-3 (MKP-3)expression in the chick neural tube in relation to Fgf8 activity. Brain Res Brain Res Rev,2005,49:158-166.
[38]Tsang M, Maegawa S, Kiang A, et al.A role for MKP-3 in axial patterning of the zebrafish embryo. Development,2004,131:2769-2779.
[39]Kim M, Cha GH, Kim S, et al.MKP-3 has essential roles as a negative regulator of the Ras/mitogen-activated protein kinase pathway during Drosophila development.Mol Cell Biol,2004,24:573-583.
[40]Li C, Scott DA, Hatch E, et al.DUSP6 (MKP-3)is a negative feedback regulator of FGF-stimulated ERK signaling during mouse development. Development,2007,134:167-176.
[41]Maillet M, Purcell NH, Sargent MA, et al.DUSP6 (MKP3) null mice show enhanced ERK1/2 phosphorylation at baseline and increased myocyte proliferation in the heart affecting disease susceptibility. J Biol Chem, 2008,283:31246-31255.
[42]Rossig L, Hermann C, Haendeler J,et al.Angiotensin Ⅱ-induced upregulation of MAP kinase phosphatase-3 mRNA levels mediates endothelial cell apoptosis, Basic Res Cardiol,2002,97:1-8.
[43]Xu H, Yang Q, Shen M, et al.Dual specificity MAPK phosphatase 3 activates PEPCK gene transcription and increases gluconeogenesis in rat hepatoma cells.J Biol Chem,2005,280:36013-36018.
[44]Furukawa T, Tanji E, Xu S, et al.Feedback regulation of DUSP6 transcription responding to MAPK1 via ETS2 in human cells.Biochem Biophys Res Commun,2008,377:317-320.
[45]Ekerot M, Stavridis MP, Delavaine L,et al.Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter. Biochem J,2008,412:287-298.
[46]Jurek A, Amagasaki K, Gembarska A,et al.Negative and positive regulation of MAPK phosphatase 3 controls platelet-derived growth factor-induced Erk activation. Biol Chem,2009,284:4626-4634.
[47]Marchetti S, Gimond C, Chambard JC,et al.(2005).Extracellular signal-regulated kinases phosphorylate mitogen-activated protein kinase phosphatase 3/DUSP6 at serines 159 and 197, two sites critical for its proteasomal degradation. Mol Cell Biol,2005,25:854-864.
[48]Bermudez 0, Marchetti S, Pages G,et al.Post-translational regulation of the ERK phosphatase DUSP6/MKP3 by the mTOR pathway. Oncogene,2008,27:3685-3691.
[49]Zeliadt NA, Mauro LJ, Wattenberg EV. Reciprocal regulation of extracellular signal regulated kinase 1/2 and mitogen activated protein kinase phosphatase-3.Toxicol Appl Pharmacol,2008,232:408-417.
[50]Furukawa T, Yatsuoka T, Youssef EM,et al.Genomic analysis of DUSP6, a dual specificity MAP kinase phosphatase, in pancreatic cancer. Cytogenetics and Cell Genetics,1998,82(3-4):156-159.
[51]Furukawa T, Sunamura M, Motoi F,et al.Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer. American Journal of Pathology,2003,162(6):1807-1815.
[52]Xu S, Furukawa T, Kanai N,et al.Abrogation of DUSP6 by hypermethylation in human pancreatic cancer. Journal of Human Genetics, 2005,50(4):159-167.
[53]Furukawa T, Fujisaki R, Yoshida Y,et al.Distinct progression pathways involving the dysfunction of DUSP6/MKP-3 in pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms of the pancreas.Modern Pathology,2005,18(8):1034-1042.
[54]Chan DW, Liu VW, Tsao GS, et al.Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells.Carcinogenesis,2008,29:1742-1750.
[55]Okudela K, Yazawa T, Woo T,et al.Down-regulation of DUSP6 expression in lung cancer:its mechanism and potential role in carcinogenesis.Am J Pathol,2009,175:867-881.
[56]Sato M, Vaughan MB, Girard L, et al.Multiple oncogenic changes (K-RAS(V12),p53 knockdown, mutant EGFRs,p16 bypass, telomerase)are not sufficient to confer a full malignant phenotype on human bronchial epithelial cells.Cancer Res,2006,66:2116-2128.
[57]Chen HY, Yu SL, Chen CH, et al.A five-gene signature and clinical outcome in non-small-cell lung cancer. New England Journal of Medicine, 2007,356(1):11-20.
[58]Leung AC, Wong VC, Yang LC,et al.Frequent decreased expression of candidate tumor suppressor gene, DEC1,and its anchorage-independent growth properties and impact on global gene expression in esophageal carcinoma. Int J Cancer,2008,122:587-594.
[59]Hakansson P, Nilsson B, Andersson A,et al.Gene expression analysis of BCR/ABL1-dependent transcriptional response reveals enrichment for genes involved in negative feedback regulation.Genes Chromosomes Cancer, 2008,47:267-275.
[60]Ramnarain DB, Park S, Lee DY,et al.Differential gene expression analysis reveals generation of an autocrine loop by a mutant epidermal growth factor receptor in glioma cells.Cancer Res,2006,66:867-874.
[61]Bloethner S,Chen B,Hemminki K,et al.Effect of common B-RAF and N-RAS mutations on global gene expression in melanoma cell lines. Carcinogenesis,2005,26:1224-1232.
[62]Croonquist PA, Linden MA, Zhao F,et al.Gene profiling of a myeloma cell line reveals similarities and unique signatures among IL-6 response, N-ras-activating mutations,and coculture with bone marrow stromal cells. Blood,2003,102:2581-2592.
[63]Cui Y, Parra I, Zhang M,et al.Elevated expression of mitogen-activated protein kinase phosphatase 3 in breast tumors:a mechanism of tamoxifen resistance,Cancer Res,2006,66:5950-5959.
[64]Vogt A,Cooley KA, Brisson M,et al.Cell-active dual specificity phosphatase inhibitors identified by high-content screening. Chemistry and Biology,2003,10(8):733-742.