Curing of pancreatic cancer by DUSPG/MKP-3

DUSPG/MKP-3 治疗胰腺癌

• 批准号: 15590295
• 负责人: FURUKAWA Toru
• 金额: $ 2.18万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590295/
• 关键词: DUSP6; MKP-3; MAPK; pancreatic cancer; microarray; molecular targeting; PanIN; IPMN; hypermethylation; gene therapy; 膵臓がん; マイクロアレイ; 遺伝子発現; アポトーシス; アデノウィルス

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

为了阐明DUSP6/MKP-3在胰腺癌发生发展中的作用，本研究开展了以下研究：1.利用含有20K基因的芯片对外源性高表达DUSP6的胰腺癌细胞进行表达谱分析，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组与运输有关，7组与受体活性有关，6组与细胞增殖有关，4组与转录调控有关，4组与信号转导有关)以及34个其他功能基因和18个未知功能基因。下调的基因包括三组基因(17个与细胞周期和有丝分裂有关，7个与DNA复制有关，5个与受体信号通路有关)，以及28个其他功能基因和21个功能未知的基因。2.对外源过表达的细胞中与凋亡相关的蛋白质进行分析，发现BH3结构域蛋白的变化和Caspase的修饰。3.实验性…通过将携带DUSP6的腺病毒载体注射到裸鼠移植的人胰腺癌细胞中进行更多的体内基因治疗，发现一些肿瘤的体积明显缩小，但总体疗效没有统计学意义上的差异。4.对DUSP6候选基因表达控制区的分析发现，在DUSP6去除的癌细胞和原发癌组织中，DUSP6内含子1的CpG岛发生了高甲基化，这与后者的低分化表型显著相关。5.研究了DUSPG在胰腺浸润性导管癌或导管内乳头粘液瘤(IPMN)癌前病变中的抑制作用。DUSP6在胰腺上皮内瘤变中高表达，在浸润性癌中缺失，提示DUSP6的缺失与胰腺癌的侵袭表型密切相关。一小部分IPMN显示了这种取消，表明它与IPMN的启动有关。较少

项目成果

Furukawa T, et al.: "Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer"American Journal Pathology. 162. 1807-1815 (2003)

Furukawa T 等人：“胰腺癌中涉及 DUSP6/MKP-3 的潜在肿瘤抑制途径”美国病理学杂志。

Furukawa T, et al.: "Molecular pathology of pancreatic cancer : In quest of tumor suppressor genes"Pancreas. 28. 253-256 (2004)

Furukawa T 等人：“胰腺癌的分子病理学：寻找肿瘤抑制基因”胰腺。

古川徹, 他: "膵癌と遺伝子異常"肝胆膵. 46. 719-725 (2003)

Toru Furukawa 等人：“胰腺癌和遗传异常”《肝胆胰》46. 719-725 (2003)

Molecular pathology of pancreatic cancer - In quest of tumor suppressor genes

• DOI: 10.1097/00006676-200404000-00007
• 发表时间: 2004-04-01
• 期刊: PANCREAS
• 影响因子: 2.9
• 作者: Furukawa, T;Horii, A
• 通讯作者: Horii, A

上皮内腫瘍性病変PanIN分類の問題点Three-tiered system vs.two-tiered sysytem, 膵上皮内癌フォーラム(跡見裕 監修、高折恭一 編集)

原位肿瘤病变PanIN分类中的问题三层系统与两层系统，胰腺原位癌论坛（由Yutaka Atomi监督，由Kyoichi Takaori编辑）

• 发表时间: 2005
• 作者: Hayashi K.;Joko H.;Koirala T.R.;Onoda S;Jin S.J.;Munemasa M.;Ohara N.;Oda W.;Tanaka T.;Oka T.;Kondo E.;Yoshino T;Takahashi K.;Yamada M.;Akagi T.;杉原 洋行;Tobioka H et al.;古川徹
• 通讯作者: 古川徹