Identification of a metastasis signature and the DLX4 homeobox protein as a regulator of metastasis by combined transcriptome approach
Identification of a metastasis signature and the DLX4 homeobox protein as a regulator of metastasis by combined transcriptome approach
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DOI：
10.1038/sj.onc.1210242
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发表时间：
2007-07-01
期刊：
影响因子：
8
通讯作者：
Takahashi, T.
中科院分区：
文献类型：
--
作者：
Tomida, S.;Yanagisawa, K.;Takahashi, T.
尽管广泛转移是人类肺癌相关死亡的主要原因，但其潜在机制仍不清楚。我们对高度转移性肺癌细胞系 NCI-H460-LNM35 (LNM35) 及其亲代克隆 NCI-H460-N15 (N15) 的表达谱进行全基因组比较，结果鉴定出由 45 个基因组成的癌症转移特征。通过基因本体分析，我们的研究还深入了解了这种 45 个基因的转移特征如何有助于获得转移潜力。通过将签名应用于人类癌症病例的数据集，我们可以证明与预后不良的子集病例的显着关联，不仅对于肺癌的两个数据集，而且对于乳腺癌。此外，我们还发现，DLX4同源盒基因被确定为在LNM35中显着下调的基因，并且与肺癌患者的良好预后显着相关，其强制表达可显着抑制体外运动和侵袭以及通过血行和淋巴途径的体内转移。总而言之，这些发现表明，我们的组合转录组分析是寻找基因的有效方法，该基因在人类癌症病例的预后预测方面具有临床用途，并且在研究与转移相关的癌症生物学方面具有明确的功能相关性。
Although widespread metastasis is the major cause of human lung cancer-related deaths, its underlying mechanism remains largely unclear. Our genome-wide comparison of the expression profiles of a highly metastatic lung cancer cell line, NCI-H460-LNM35 (LNM35), and its parental clone, NCI-H460-N15 (N15), resulted in the identification of a cancer metastasis signature composed of 45 genes. Through gene ontology analysis, our study also provided insights into how this 45-gene metastasis signature may contribute to the acquisition of metastatic potential. By applying the signature to datasets of human cancer cases, we could demonstrate significant associations with a subset of cases with poor prognosis not only for the two datasets of cancers of the lung but also for cancers of the breast. Furthermore, we were able to show that enforced expression of the DLX4 homeobox gene, which was identified as a gene with significant downregulation in LNM35 as well as with significant association with favorable prognosis for lung cancer patients, markedly inhibited in vitro motility and invasion as well as in vivo metastasis via both hematogenous and lymphogenous routes. Taken together, these findings indicate that our combined transcriptome analysis is an efficient approach in the search for genes possessing both clinical usefulness in terms of prognostic prediction in human cancer cases and clear functional relevance for studying cancer biology in relation to metastasis.