Mechanism of abnormality in p27^<K1P1> expression in human lung cancer and its therapeutic application

人肺癌p27^<K1P1>表达异常机制及其治疗应用

• 批准号: 11670159
• 负责人: MASUDA Akira
• 金额: $ 1.79万
• 依托单位: Aichi Cancer Center Research Institute
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670159/
• 关键词: Lung Cancer; p27^<K1P1>; Small Cell Lung Cancer; Cell Cycle; Apoptosis

A previous study of ours unexpectedly found that in contrast to frequent reduction in non-small cell lung cancer (NSCLC) in association with poor prognosis, high expression of the p27^<K1P1> cyclin-dependent kinase (CDK) inhibitor was retained in virtually all small cell lung cancers (SCLCs), which represent the most aggressive form of lung cancer. This observation suggested the possibility that highly expressed p27^<K1P1> in SCLC may be non-functional, possibly due to multiple genetic defects in this tumor type. Biochemical analyses, however, revealed that p27^<K1P1> in SCLC is functional aas a CDK inhibitor, clearly showing induction apparently associated with G1/G0 arrest and efficient inhibition of cyclin-CDK kinase activities. Interestingly, we could show that induction of p27^<K1P1> confers on SCLC cells the ability to survive under culture conditions unfavorable for cell growth such as a lack of nutrients and hypoxia. Subsequent transfection experiments with p27^<K1P1> supported this notion. These obsevations suggest that high expression of p27^<K1P1> in vivo may favor the survival of SCLC by preventing apoptosis in a microenvironment unfavorable for cell proliferation.

我们之前的一项研究出人意料地发现，与预后不良的非小细胞肺癌(NSCLC)的频繁减少相反，p27；；K1P1和GT；细胞周期蛋白依赖激酶(CDK)抑制物在几乎所有小细胞肺癌(SCLC)中都保持高表达，小细胞肺癌是最具侵袭性的肺癌形式。这一观察结果提示，在小细胞肺癌中高表达的p27^&lt；K1P1&gt；可能是由于该肿瘤类型中的多个基因缺陷所致。然而，生化分析表明，SCLC中的p27^-lt；K1P1&gt；是一种CDK抑制剂，明显地表明诱导明显与G1/G0停滞和有效地抑制Cyclin-CDK激酶活性有关。有趣的是，我们可以证明诱导p27^&lt；K1P1&gt；赋予SCLC细胞在不利于细胞生长的培养条件下存活的能力，例如缺乏营养和低氧。随后用p27^&lt；K1P1&gt；进行的转基因实验支持了这一观点。这些观察结果提示，体内高表达p27^&lt；K1P1和gt；可能通过在不利于细胞增殖的微环境中阻止细胞凋亡，从而有利于小细胞肺癌的生存。

项目成果

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