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。在频繁染色体畸变的区域中，与人类胰腺癌的预后不良有关的三个染色体区域的损失为12q，17p和18q。 Ade Noviral介导的Smad4基因在胰腺癌细胞系中具有SMAD4的纯合缺失的递送没有显示任何对细胞生长的抑制。我们先前报道说，损失18Q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定义因子的第一步。但是，在18Q上有未知的肿瘤抑制基因可能与Smad4.2不同。我们和其他人以前报道了子宫内膜癌中PTEN基因的体细胞突变。我们尝试通过腺病毒介导的该基因在子宫内膜癌细胞系中引入该基因的基因疗法试验，该基因具有两次打击该基因的突变。该试验在体外成功，在引入PTEN的Normat副本后，肿瘤细胞诱导了凋亡。这些结果表明，PTEN基因是适当改善后人子宫内膜癌基因治疗的良好候选者。3。在人类肺癌中，发现DMBT1基因座经常丢失10q。此外，在该基因中发现了突变以及表达的抑制。 DMBT1可能充当人类肺癌发生中的肿瘤抑制基因4。在神经母细胞瘤中，在14q中研究了等位基因损失，并在14q32上确定了500 kb的公共缺失区域。还构建了带有已删除区域的BAC重点。另一方面，还克隆了具有宪法相互易位的神经母细胞瘤患者中发生的132上的断裂点。我们正在尝试分离负责神经母细胞瘤的基因。