Curing of pancreatic cancer by DUSPG/MKP-3

为阐明DUSP 6/MKP-3在胰腺癌发生、发展中的作用，本研究进行了以下研究：1.应用20 K基因芯片技术对外源性过表达DUSP 6的胰腺癌细胞进行基因表达谱分析，共发现81个上调基因和78个下调基因。上调的基因包括5组基因（8个在转运中，7个在受体活性中，6个在细胞增殖中，4个在转录调节中，4个在信号转导中）以及34个具有其他功能的基因和18个具有未知功能的基因。下调的基因包括3类（细胞周期和有丝分裂相关基因17个、DNA复制相关基因7个、受体信号通路相关基因5个）、28个其他功能基因和21个未知功能基因。 ...更多信息 通过将携带DUSP 6的腺病毒载体注射到裸鼠中的人胰腺癌细胞的接种肿瘤中，使用DUSPG的体内基因治疗显示，几种肿瘤的体积显著减小，但总体疗效没有统计学显著差异。癌细胞和原发癌组织的分化程度不同，这与原发癌组织的低分化表型显著相关。希斯顿修饰在DUSPG的去除中也起重要作用。5.研究了浸润性导管癌和导管内乳头状黏液性肿瘤（IPMN）胰腺组织中DUSPG的去除情况。DUSP 6在胰腺上皮内瘤样病变中表达较好，但在浸润性癌中表达缺失，表明DUSP 6的缺失与浸润性表型密切相关。一小部分的IPMN显示废除，这表明其与IPMN的启动。少

To elucidate roles of DUSP6/MKP-3 in development and progression of pancreatic cancer, following investigations were carried out in this research.1.Expressional profiling of pancreatic cancer cells exogenously overexpressing DUSP6 by using microarray containing 20K genes uncovered 81 upregulated genes and 78 downregulated genes. The upregulated genes comprised five groups of genes (eight in transport seven in receptor activity, six in cell proliferation, four in regulation of transcription, and four in signal transduction) as well as 34 genes with other functions and 18 with unknown function. The downregulated genes comprised three groups of genes (17 in cell cycle and mitosis, seven in DNA replication, and five in receptor signaling pathway) as well as 28 genes with other functions and 21 with unknown function.2.Analysis of proteins pertaining to apoptosis in cells exogenously overexpressing DUSPG uncovered alterations of BH3-domain proteins and modification of Caspases.3.Experimental … More in vivo gene therapy employing DUSPG by means of injection of the adenovirus vector harboring DUSP6 into inoculated tumors of human pancreatic cancer cells in nude mice revealed remarkable reductions of volumes of several tumors but no statistically significant difference in efficacy overall.4.Analysis of candidate gene-expression controlling regions of DUSP6 uncovered hypermethylation of CpG islands in intron 1 of DUSP6 in DUSP6-abrogated cancer cells and primary cancer tissues, which was significantly associated with the poorly differentiated phenotype of the latter. Histon modification was found to play an important role in the abrogation as well.5.Abrogation of DUSPG in precursor lesions in pancreatic tissues with invasive ductal carcinoma or intraductal papillary-mucinous neoplasm (IPMN) was investigated. DUSP6 was fairly expressed in pancreatic intraepithelial neoplasia but lost in invasive carcinoma, indicating strong association of the abrogation with invasive phenotype. A small fraction of IPMN revealed the abrogation, suggesting its association with initiation of IPMN. Less