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Gene targeting therapy for oral carcinoma using adrenomedullin antagonisit.

使用肾上腺髓质素拮抗剂治疗口腔癌的基因靶向治疗。

基本信息

批准号：
16390575
负责人：
SHINDOH Masanobu
金额：
$ 9.28万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390575/
关键词：
HIF-1 Adrenomedullin CRM1 口腔扁平上皮がんリンパ節転移

项目摘要

We have recently reported that intra-tumoral injection of adrenomedullin (AM) antagonist (AMA ; AM(22-52)) peptides significantly reduced the in vivo growth of a pancreatic cancer cell line in SCID mice. In this study, we examined the effects of intra-tumoral and intra-muscular transfers of naked DNA encoding. AMA on the in vivo growth of cancer cell lines. We demonstrated here that the intra-tumoral and intra-muscular transfers of naked DNA encoding AMA induced the regression of a pancreatic cancer cell line and a breast cancer cell line. We further demonstrated that CD31-positive cells completely disappeared from the tumor tissues treated with the intra-tumoral or intra-muscular transfer of naked DNA encoding AMA. These results suggest that the intra-tumoral or intra-muscular transfer of naked DNA encoding AMA might be a promising tool for treating cancersE4orf6 plays an important role in the transcription of cellular and viral mRNAs. We show that E4orf6 interacts with pp32/LAMP and exports pp32/LAMP from the nucleus to the cytoplasm with its binding partner, HuR, which binds to an AU-rich element (ARE) present within many protooncogene and cytokine mRNAs. We found that ARE-mRNAs, such as c-fos,c-myc and Cox-2, were exported to and stabilized in the cytoplasm of E4orf6-expressing cells.The oncodomain of E4orf6 was necessary for both binding to pp32/LAMP and defect for ARE-mRNA. Moreover, inhibition of CRM1-dependent export pathway failed to block the export of ARE-mRNAs mediated by E4orf6. Thus, E4orf6 interacts with pp32/LAMP to modulate the fate of ARE-mRNAs by altering the CRM1-dependent export pathway.

我们最近报道，肿瘤内注射肾上腺髓质素（AM）拮抗剂（AMA ; AM（22-52））肽显着降低胰腺癌细胞系在SCID小鼠体内的生长。在这项研究中，我们检查了裸DNA编码的肿瘤内和肌肉内转移的影响。AMA对癌细胞系的体内生长的影响。我们在这里证明了编码AMA的裸DNA的肿瘤内和肌肉内转移诱导胰腺癌细胞系和乳腺癌细胞系的消退。我们进一步证明，CD 31阳性细胞完全从肿瘤内或肌肉内转移编码AMA的裸DNA治疗的肿瘤组织中消失。这些结果表明，编码AMA的裸DNA的肿瘤内或肌肉内转移可能是一种有希望的治疗癌症的工具。E4 orf 6在细胞和病毒mRNA的转录中起重要作用。我们发现，E4 orf 6与pp 32/LAMP相互作用，并将pp 32/LAMP从细胞核输出到细胞质，其结合伴侣HuR与许多原癌基因和细胞因子mRNA中存在的富含AU的元件（ARE）结合。我们发现ARE-mRNA，如c-fos、c-myc和考克斯-2，在表达E4 orf 6的细胞中被输出并稳定在细胞质中，E4 orf 6的原癌域是与pp 32/LAMP结合和ARE-mRNA缺陷所必需的。此外，CRM 1依赖的输出途径的抑制未能阻断E4 orf 6介导的ARE-mRNA的输出。因此，E4 orf 6与pp 32/LAMP相互作用，通过改变CRM 1依赖性输出途径来调节ARE-mRNA的命运。