【作者】 杨博；

【导师】 谭云山； 纪元；

【作者基本信息】 复旦大学 ， 病理学与病理生理学， 2010， 硕士

【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。更多还原

【Abstract】 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.更多还原