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

点击翻译按钮获取中文摘要

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.