Necdin, a negative growth regulator, is a novel STAT3 target gene down-regulated in human cancer.
Necdin, a negative growth regulator, is a novel STAT3 target gene down-regulated in human cancer.
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DOI：
10.1371/journal.pone.0024923
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Cress WD
中科院分区：
文献类型：
--
作者：
Haviland R;Eschrich S;Bloom G;Ma Y;Minton S;Jove R;Cress WD
涉及STAT 3的细胞因子和生长因子信号通路在许多人类原发性肿瘤中经常被组成性激活，并且因其在控制细胞生长和细胞周期进程中发挥的转录作用而闻名。然而，STAT3对整个基因组的转录控制的范围仍然是一个重要的问题。我们预测这种持续的STAT3信号传导影响各种各样的细胞功能，其中许多功能仍有待表征。我们采取了广泛的方法来确定新的STAT3调节基因，通过微阵列检测全基因组基因表达谱的变化，使用表达组成型激活的STAT3的细胞。使用计算分析，我们能够定义含有激活的STAT3的细胞的基因表达谱，并识别具有广泛生物学功能的候选靶基因。在这些基因中，我们确定了Necdin，一种负性生长调节因子，作为一种新的STAT3靶基因，当STAT3是组成性活性时，其表达在mRNA和蛋白水平上下调。这种抑制是STAT3依赖性的，因为使用siRNA抑制STAT3恢复Necdin表达。在Necdin启动子中鉴定了STAT3 DNA结合位点，EMSA和染色质免疫沉淀证实了STAT3与该区域的结合。Necdin的表达在黑色素瘤和耐药卵巢癌细胞系中被下调。Necdin表达的进一步分析表明在人黑素瘤、前列腺癌和乳腺癌细胞系中以STAT3依赖性方式抑制。这些结果表明，STAT3协调参与多种代谢和生物合成途径的基因的表达，整合导致全局转录变化和肿瘤发生的信号。STAT3可以通过上调参与促进生长和增殖的基因的转录，但也可以通过下调相同细胞过程的负调节因子如Necdin的表达来发挥其致癌作用。
Cytokine and growth factor signaling pathways involving STAT3 are frequently constitutively activated in many human primary tumors, and are known for the transcriptional role they play in controlling cell growth and cell cycle progression. However, the extent of STAT3's reach on transcriptional control of the genome as a whole remains an important question. We predicted that this persistent STAT3 signaling affects a wide variety of cellular functions, many of which still remain to be characterized. We took a broad approach to identify novel STAT3 regulated genes by examining changes in the genome-wide gene expression profile by microarray, using cells expressing constitutively-activated STAT3. Using computational analysis, we were able to define the gene expression profiles of cells containing activated STAT3 and identify candidate target genes with a wide range of biological functions. Among these genes we identified Necdin, a negative growth regulator, as a novel STAT3 target gene, whose expression is down-regulated at the mRNA and protein levels when STAT3 is constitutively active. This repression is STAT3 dependent, since inhibition of STAT3 using siRNA restores Necdin expression. A STAT3 DNA-binding site was identified in the Necdin promoter and both EMSA and chromatin immunoprecipitation confirm binding of STAT3 to this region. Necdin expression has previously been shown to be down-regulated in a melanoma and a drug-resistant ovarian cancer cell line. Further analysis of Necdin expression demonstrated repression in a STAT3-dependent manner in human melanoma, prostate and breast cancer cell lines. These results suggest that STAT3 coordinates expression of genes involved in multiple metabolic and biosynthetic pathways, integrating signals that lead to global transcriptional changes and oncogenesis. STAT3 may exert its oncogenic effect by up-regulating transcription of genes involved in promoting growth and proliferation, but also by down-regulating expression of negative regulators of the same cellular processes, such as Necdin.