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The functional role of a superoxide generating gene Nox1 in Ras oncogene-induced transformation and human tumor development

超氧化物生成基因 Nox1 在 Ras 癌基因诱导的转化和人类肿瘤发展中的功能作用

基本信息

批准号：
16590242
负责人：
KAMATA Tohru
金额：
$ 2.3万
依托单位：
Shinshu University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
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/en/grant/KAKENHI-PROJECT-16590242/
关键词：
Nox1 Ras reactive oxygen species redox signaling cancer pancreatic cancer melanoma Nox4 MAP Kinase 癌 RNAi MAPkinase 転移情報伝達

项目摘要

The aim of our study is to elucidate the functional role of reactive oxygen species (ROS) -generating Nox1 family genes in development of human cancers by utilizing Ras-transformation as a model system and lay a foundation for treatment and diagnosis of human cancers. We previously found that Ras oncogene upregulates Nox1 expression via Raf-MEK-MAPK pathway and Nox1 generated-ROS are required for oncogenic Ras transformation. This implicates an important role as a new limiting factor for Nox1 in oncogenesis. In the current study, we demonstrated that Nox4-generated ROS confer cell survival activity to pancreatic cancer cells through the AKT-ASK1 pathway and inhibit cell growth of melanoma cells by deregulating cell cycle. Furthermore, we identified ER proteins, PDI family proteins as potential downstream targets for Nox1-generated ROS whose Cys-SH residues are selectively oxidized by ROS. In the future study, we will further analyze what activity associated with these redox proteins is essential for Nox1-mediated cell transformation process. Our discovery accelerates the dissection of Nox-redox signaling pathway and provides a novel insight into its functional role in cancer development.

本研究的目的是通过Ras转化作为模型系统，阐明活性氧（ROS）生成Nox1家族基因在人类癌症发生过程中的功能作用，为人类癌症的治疗和诊断奠定基础。我们之前发现Ras致癌基因通过Raf-MEK-MAPK途径上调Nox1表达，并且Nox1产生的ROS是致癌Ras转化所必需的。这表明 Nox1 作为新的限制因素在肿瘤发生中发挥着重要作用。在当前的研究中，我们证明Nox4产生的ROS通过AKT-ASK1途径赋予胰腺癌细胞生存活性，并通过解除细胞周期的调节来抑制黑色素瘤细胞的生长。此外，我们确定了 ER 蛋白、PDI 家族蛋白作为 Nox1 生成的 ROS 的潜在下游靶标，其 Cys-SH 残基被 ROS 选择性氧化。在未来的研究中，我们将进一步分析与这些氧化还原蛋白相关的哪些活性对于Nox1介导的细胞转化过程至关重要。我们的发现加速了 Nox-氧化还原信号通路的剖析，并为其在癌症发展中的功能作用提供了新的见解。