Reseearch on Genetic Alterations in the Development and Progression of Human Pancreatic Cancer

人类胰腺癌发生发展中的基因改变研究

基本信息

批准号：
12470043
负责人：
HORII Akira
金额：
$ 10.5万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470043/
关键词：
Pancreatic Cancer SMAD4 18q BAI1 Gene Therapy 1p36-p35 RIZ MSI BAI1遺伝子膵がん遺伝子変異 12q 17p 1p RIZ

项目摘要

Six frequently lost regions in pancreatic cancer were analyzed for association between poor prognosis and LOH ; in three regions (12q, 17p, and 18q) significant association. Among these, 18q harbors SMAD4, one of the key genes in pancreatic carcinogenesis. IPMT is recognized as one of the premalignant lesions of pancreatic ductal cells, and frequent loss of 18q at the SMAD4 locus has been observed. However, SMAD4 did not alter and its protein product expressed. Introduction of SMAD4 did not affect cell growth in vitro, irrespective of SMAD4 status. On the other hand, introduction of chromosome 18 significantly suppressed cell growth in vitro in both cells with and without inactivation of SMAD4. These observations strongly suggest the existence of novel tumor suppressor gene, near but distinct from SMAD4, that plays an important role in the early stage of pancreatic tumorigenesis. On 12q, we found the DUSP6 gene, the protein product of which works as an ERK specific phosphatase. Expression of this gene was frequently suppressed in pancreatic cancer, and adenovirus mediated introduction caused apoptosis in pancreatic cancer cells. BAI1 is one of the important protein that upregulated by p53. It works as angiogenesis inhibitor and expresses specifically in brain. We introduced BAI1 in pancreatic cancer cells using adenovirus vector and observed growth suppression in vivo by means of suppressed angiogenesis; there is a possibility of gene therapy utilizing tumor dormancy. 1p36-p35 is one of the hot spots for LOH in a variety of human cancers. We constructed a 35-Mb BAC-based contig in this region. The RIZ gene encoding the RB interacting zinc finger protein was in this region and mutation analysis revealed the frequent frameshift mutation at the microsatellite in the coding region of the gene in MSI-H tumors of the colorectum, stomach, and endometrium as well as pancreas. RIZ may be one of the candidates for mutation in MSI-H pancreatic cancers.

分析了胰腺癌中六个经常丢失的区域，以了解不良预后与 LOH 之间的关联；在三个区域（12q、17p 和 18q）显着相关。其中，18q含有SMAD4，这是胰腺癌发生的关键基因之一。 IPMT被认为是胰腺导管细胞的癌前病变之一，并且已观察到SMAD4基因座处的18q频繁丢失。然而，SMAD4 并没有改变，并且其蛋白质产物得以表达。无论 SMAD4 状态如何，引入 SMAD4 都不影响体外细胞生长。另一方面，在 SMAD4 失活和未失活的细胞中，18 号染色体的引入显着抑制了体外细胞生长。这些观察结果强烈表明存在一种新型抑癌基因，该基因与 SMAD4 接近但不同，在胰腺肿瘤发生的早期阶段发挥着重要作用。在12q上，我们发现了DUSP6基因，其蛋白质产物作为ERK特异性磷酸酶。该基因的表达在胰腺癌中经常受到抑制，腺病毒介导的引入导致胰腺癌细胞凋亡。 BAI1是p53上调的重要蛋白之一。它作为血管生成抑制剂发挥作用，并在大脑中特异性表达。我们使用腺病毒载体将 BAI1 引入胰腺癌细胞中，并通过抑制血管生成观察体内生长抑制；利用肿瘤休眠进行基因治疗是有可能的。 1p36-p35是多种人类癌症中LOH的热点之一。我们在该区域构建了一个 35 Mb 的基于 BAC 的重叠群。编码RB相互作用锌指蛋白的RIZ基因位于该区域，突变分析显示，在结直肠、胃、子宫内膜以及胰腺的MSI-H肿瘤中，该基因编码区的微卫星频繁发生移码突变。 RIZ可能是MSI-H胰腺癌突变的候选者之一。