低氧诱导因子-1α对 NCI-H446 人小细胞肺癌细胞基因表达谱的影响。

The effects of HIF-1alpha on gene expression profiles of NCI-H446 human small cell lung cancer cells.

机构信息

Department of Cardiothoracic Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, PR China.

出版信息

J Exp Clin Cancer Res. 2009 Dec 10;28(1):150. doi: 10.1186/1756-9966-28-150.

DOI:10.1186/1756-9966-28-150

PMID:20003295

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2797501/

Abstract

BACKGROUND

Gene targeted therapy refers to any therapy focused on one of the many biological features of the tumor. Such features are mediated by specific genes that are involved in tumor metastasis, recurrence, poor response to chemotherapy and others. Hypoxia is an important pathognomonic feature of many malignant tumors including SCLC (small cell lung cancer). HIF-1alpha, which is induced by hypoxia, is the most important regulatory factor of many specific genes that can influence the biological features of tumors.

METHODS

In this study, we tried to elucidate the changes in gene expression profiles of SCLC NCI-H446 cells mediated by HIF-1alpha. According to different treatments of cells, three experimental pairwise comparisons were designed: hypoxia group vs. control group, Ad5-HIF-1alpha group vs. Ad5 group, and Ad5-siHIF-1 alpha group Vs Ad5 group.

RESULTS

Results from the analysis of gene expression profiles indicated that there were 65 genes upregulated and 28 genes downregulated more than two-fold in all three experimental pairwise comparisons. These genes were involved in transport, signal-transduction, cell adhesion/motility, growth factor/cytokines, transcription, inflammatory response, metabolic process, in addition to others. SOCS1, IGFBP5, IL-6 and STAT3 were also upregulated at protein level. SOCS1 could significantly induce apoptosis and suppress growth of NCI-H446 cells but HIF-1alpha could induce growth and suppress apoptosis.

CONCLUSIONS

Through this research, we are trying to find novel functional genes that are mediated by HIF-1alpha and provide the theoretical basis for new therapeutic targets. HIF-1 alpha maybe upregulate the expression of SOCS1 through mediation of STAT3 and IL-6. In addition, SOCS1 could significantly induce apoptosis and suppress growth of NCI-H446 cells. This was contrary to HIF-1alpha and it indicated that there might be an antagonism effect between HIF-1alpha and SOCS1 on regulating growth and apoptosis of NCI-H446 cells.

摘要

背景

基因靶向治疗是指针对肿瘤众多生物学特征之一的任何治疗方法。这些特征是由特定基因介导的，这些基因参与肿瘤转移、复发、对化疗反应不良等。缺氧是包括小细胞肺癌（SCLC）在内的许多恶性肿瘤的重要特征。缺氧诱导的 HIF-1alpha 是许多特定基因的最重要调节因子，这些基因可以影响肿瘤的生物学特征。

方法

在本研究中，我们试图阐明 HIF-1alpha 介导的 SCLC NCI-H446 细胞基因表达谱的变化。根据细胞的不同处理，设计了三个实验性两两比较：缺氧组与对照组、Ad5-HIF-1alpha 组与 Ad5 组、Ad5-siHIF-1alpha 组与 Ad5 组。

结果

基因表达谱分析结果表明，三个实验性两两比较中，有 65 个基因上调，28 个基因下调超过两倍。这些基因参与了运输、信号转导、细胞黏附和运动、生长因子/细胞因子、转录、炎症反应、代谢过程等。SOCS1、IGFBP5、IL-6 和 STAT3 的蛋白水平也上调。SOCS1 可显著诱导 NCI-H446 细胞凋亡并抑制其生长，但 HIF-1alpha 可诱导其生长并抑制其凋亡。

结论

通过这项研究，我们试图找到由 HIF-1alpha 介导的新的功能基因，为新的治疗靶点提供理论依据。HIF-1alpha 可能通过 STAT3 和 IL-6 的介导而上调 SOCS1 的表达。此外，SOCS1 可显著诱导 NCI-H446 细胞凋亡并抑制其生长，这与 HIF-1alpha 相反，表明 HIF-1alpha 和 SOCS1 可能在调节 NCI-H446 细胞的生长和凋亡方面存在拮抗作用。