DUSP6在肝细胞肝癌中的表达与MAPK信号通路及临床病理学特征相关性研究

目的:探讨DUSP6在肝细胞肝癌(hepatocellular carcinoma,HCC)中的表达及其与MAPK信号通路和临床病理学特征相关性。方法:查询复旦大学附属中山医院肝癌研究所2005年1月至2006年12月HCC临床病理资料数据库,筛选出305例HCC制作组织芯片,免疫组化检测DUSP6、p-ERK、P-JNK、p-P38α、CyclinD1和Ki-67表达,将以上结果同临床病理学特征进行统计学相关性分析。结果: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)。Spearman相关性分析,在HCC肿瘤组织中DUSP6和p-ERK,CyclinD1及Ki-67的表达呈显著正相关(r=0.179,P<0.01;r=0.213,P<0.01;r=0.137,P<0.05)。相对癌旁,各组肿瘤组织DUSP6表达、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)。结论:DUSP6在HCC中肿瘤组织较癌旁组织和正常肝组织过表达,DUSP6对p-ERK过表达可能起负反馈调节作用。DUSP6过表达可能与HCC细胞周期调节及促进肿瘤增殖活性有关。

人参皂苷Rg3调控ERK通路抑制Lewis小鼠肺癌生长的研究

目的:通过人参皂苷Rg3对Lewis肺癌小鼠模型及其细胞模型的抑制研究,探讨ERK信号通路及相关基因在抗肿瘤中的作用。方法:建立Lewis肺癌小鼠荷瘤动物模型,通过口饲法给予定量人参皂苷,连续3周,处死动物后,比较各组荷瘤小鼠肿瘤体积。含药动物血清作用于Lewis肺癌细胞,MTT法检测各组细胞抑制效率。Realtime-PCR法检测荷瘤鼠Dusp6、Bax、Bcl-2基因表达变化,Western blot法检测荷瘤鼠ERK、p-ERK蛋白表达变化。结果:人参皂苷Rg3对Lewis肺癌细胞及荷瘤小鼠的肿瘤生长均有明显抑制作用(P<0.01)。Western blot显示ERK在Rg3处理组中的表达明显比对照组低,Realtime-PCR结果显示,在动物肿瘤标本中,Dusp6、Bax基因药物处理组比对照组高表达(P<0.01),Bcl-2基因药物处理组比对照组低表达(P<0.01)。结论:人参皂苷Rg3在Lewis肺癌体内外模型中具有一定的肿瘤抑制效果,ERK信号通路及Dusp6基因与Rg3的抑制作用有关,Rg3诱导的细胞凋亡也参与了抗肿瘤的作用。

Higher intratumor than peritumor expression of DUSP6/MKP-3 is associated with recurrence after curative resection of hepatocellular carcinoma

Background The MAPK phosphatases （MKPs） are a family of dual-specificity phosphatases （DUSPs） that can dephosphorylate both phosphothreonine and phosphotyrosine residues,thus inactivating MAPK signaling.DUSP6 is a cytoplasmic MKP that can inactivate ERK.DUSP6 has been implicated in the development of some tumors.The aim of this research was to investigate the expression of DUSP6 in hepatocellular carcinoma （HCC） and the correlation of DUSP6 with mitogen-activated protein kinases （MAPKs）,clinicopathological characteristics,and prognosis.Methods Tissues from 305 patients who had undergone hepatectomy for HCC was used in this study.The expression of DUSP6,p-ERK,p-JNK,and p-p38a was determined using tissue microarrays for immunohistochemical analysis.The prognostic value of DUSP6 and other clinicopathological factors were evaluated.Results The expression of DUSP6 was significantly higher in the tumor tissue when compared to the peritumor or normal liver tissue （P ＜0.001）.Tumor DUSP6 expression was significantly associated with disease-free survival （DFS） （P=0.013）.Tumor DUSP6 expression was an independent prognostic factor for DFS （Hazard ratio =1.635,P=0.006）.Conclusions DUSP6 is over expressed in tumor tissue compared to peritumor or normal liver tissue.Higher expression of DUSP6 in tumor tissue,than in peritumor tissue,is associated with the recurrence after curative resection of HCC,and the relative tumor DUSP6 expression has good power to predict the recurrence of HCC.