摘要
应用全基因组cDNA表达芯片杂交技术,筛查了OCT4多潜能转录因子阳性(OCT4+)的肺腺癌干细胞及其OCT4表达沉默(OCT4-KD)细胞中的差异表达基因。发现与OCT4+细胞比较,OCT4-KD细胞有2 138个基因显示差异表达,其中1 554个基因表达上调,584个基因表达下调。这些差异表达基因涉及细胞周期、细胞增殖、细胞凋亡以及细胞迁移等功能,参与肿瘤通路、EGFR信号通路和低氧/p53信号通路等多个信号转导通路。选择差异表达最显著的基因进行分析,显示其中20个基因特异性表达在OCT4+细胞,而47个基因仅在OCT4-KD细胞中表达,该组基因可以作为肺腺癌中OCT4+细胞可资鉴别的特征性基因。此外,研究还发现在肺腺癌干细胞中,OCT4表达受HIF1α调控,应用RNA干扰技术选择性灭活HIF1α基因引起OCT4表达转阴和细胞表型分化,而采用棘霉素干预HIF1α的转录活性也明显下调了OCT4表达。实验结果揭示,肺腺癌干细胞中存在HIF1-OCT4调控轴,此发现为发展OCT4靶向治疗新技术提供了研究思路。
An analysis of cDNA microarray database was performed to search for the differentially expressed genes between the OCT4 pluripotent transcription factor-positive lung adenocarcinoma stem cells （OCT4＋ cells） and their OCT4 knockdown （OCT4-KD） cells. In comparison with OCT4＋ cells, OCT4-KD cells were found to exhibit differential expression in 2 138 genes, among which 1 554 genes were up-regulated and 584 genes down- regulated. These genes were involved in several cell functions such as cell cycle, proliferation, apoptosis and migration. They were also participated in some signaling pathways especially pathways in cancer, EGFR signaling pathway and hypoxia/p53 pathway. Analysis with the top differentially expressed genes revealed that 20 genes were specifically expressed in OCT4＋ cells, while 47 genes were exclusively existed in OCT4-KD cells. This signaturerepresents a unique type of genes that enable to identify the OCT4＋ cells in human lung adenocarcinoma. Moreover, our studies demonstrated that OCT4 expression in lung adenocarcinoma stem cells was regulated by HIF1α. With RNA interference technique, we showed that targeted inactivation of HIF1α in OCT4＋ cells was able to shut down OCT4 expression and thereby, to induce their phenotypic differentiation. Moreover, interference of HIF 1 transcriptional activity with echinomycin also significantly reduced the expression of OCT4. Collectively these data pointed out the presence of HIF1α-OCT4 axis in lung adenocarcinoma stem cells. This finding provided a new avenue for development of OCT4-based targeting approaches to treat this tumor.
出处
《中国细胞生物学学报》
CAS
CSCD
北大核心
2013年第7期928-936,共9页
Chinese Journal of Cell Biology
基金
国家自然科学基金(批准号:30872952
81101770)
上海市卫生局科研基金(批准号:20114184)资助的课题~~
关键词
肺腺癌
肿瘤干细胞
OCT4
lung adenocarcinoma
cancer stem cell
OCT4
