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Genetic alterations involved in initiation and progression of human cancer

基因改变参与人类癌症的发生和进展

基本信息

批准号：
07272204
负责人：
HORII Akira
金额：
$ 38.21万
依托单位：
Tohoku University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
1999
资助国家：
日本
起止时间：
1999 至无数据
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-07272204/
关键词：
tumor suppressor gene pancreatic cancer endometrial cancer lung cancer renal cell carcinoma neuroblastoma the DMBT1 gene the PTEN gene DNAミスマッチ修復異常 DUSP6遺伝子 H-cadherin遺伝子 BAX遺伝子 hMSII6遺伝子癌遺伝子 TGFBβレセプターII型 IGFIIレセレプター hMSH

项目摘要

1. Among regions of frequent chromosomal aberrations, loss of three chromosomal regions, 12q, 17p, and 18q, associated with poor prognosis in human pancreatic cancer. Ade noviral mediated delivery of the SMAD4 gene in pancreatic cancer cell lines with homozygous deletion of SMAD4 did not show any suppression of cell growth. We previously reported that loss of 18q is an early event in pancreatic carcinogenesis. There is a possibility that mutation of the SMAD4 gene is responsible for the initial step of pancreatic carcinogenesis as well as prognosis defining factor. However there is a possibility of unknown tumor suppressor gene on 18q that is distinct from SMAD4.2. We and others previously reported frequent somatic mutation of the PTEN gene in endometrial cancer. We attempted a trial of gene therapy by adenovirus mediated introduction of this gene in endometrial cancer cell lines with two-hit mutation of this gene. The trial was successful in vitro, and apoptosis was induced in tumor cells after introduction of normat copy of PTEN.However, the attempt was not successful in vivo. These results suggested that the PTEN gene is a good candidate for gene therapy in human endometrial cancer after appropriate improvement.3. In human lung cancer, frequent loss of 10q at the DMBT1 locus was found. Moreover, mutation as well as suppression of expression was found in this gene. There is a possibility that DMBT1 acts as the tumor suppressor gene in human lung carcinogenesis.4. In neuroblastoma, allelic loss was studied in 14q and identified a 500-kb region of common deletion on 14q32. A BAC contig harboring the deleted region was also constructed. On the other hand, a break point on 1p32 that occurred in a neuroblastoma patient with constitutional reciprocal translocation was also cloned. We are attempting to isolate the genes responsible for neuroblastoma.

1. 在染色体畸变频繁的区域中，12q、17p和18q这三个染色体区域的缺失与人类胰腺癌的不良预后相关。在SMAD4纯合缺失的胰腺癌细胞系中，腺病毒介导的SMAD4基因递送没有显示出任何细胞生长抑制。我们之前报道过 18q 缺失是胰腺癌发生的早期事件。 SMAD4 基因的突变可能是胰腺癌发生的第一步以及预后决定因素。然而，18q 上可能存在与 SMAD4.2 不同的未知抑癌基因。我们和其他人之前报道了子宫内膜癌中 PTEN 基因频繁发生的体细胞突变。我们尝试通过腺病毒介导将该基因引入具有该基因的二次突变的子宫内膜癌细胞系来进行基因治疗试验。该试验在体外取得了成功，并且在引入正常拷贝的PTEN后在肿瘤细胞中诱导了细胞凋亡。然而，该尝试在体内并不成功。这些结果表明PTEN基因经过适当改进后是人类子宫内膜癌基因治疗的良好候选基因。 3．在人类肺癌中，DMBT1 基因座经常出现 10q 缺失。此外，在该基因中发现了突变和表达抑制。 DMBT1可能作为抑癌基因参与人肺癌的发生。 4．在神经母细胞瘤中，研究了 14q 的等位基因缺失，并鉴定了 14q32 上 500 kb 的常见缺失区域。还构建了包含删除区域的 BAC 重叠群。另一方面，还克隆了患有先天性易位的神经母细胞瘤患者中发生的 1p32 断点。我们正在尝试分离导致神经母细胞瘤的基因。