Comparative analysis of gene regulatory networks of highly metastatic breast cancer cells established by orthotopic transplantation and intra-circulation injection
Comparative analysis of gene regulatory networks of highly metastatic breast cancer cells established by orthotopic transplantation and intra-circulation injection
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DOI：
10.3892/ijo.2016.3809
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发表时间：
2017-02-01
影响因子：
5.2
通讯作者：
Semba, Kentaro
中科院分区：
文献类型：
--
作者：
Nakayama, Jun;Ito, Emi;Semba, Kentaro
已经研究了乳腺癌中的转移标记基因，将通过循环内注射建立的高转移性癌细胞系的转录组学谱与其亲本细胞系的转录组学谱进行比较。然而，这种方法不适合分析转移的初始步骤，包括侵入局部组织和循环系统。为了表征早期转移的分子机制，我们通过两种动物移植模型建立了转移到肺的高转移性MDA-MB-231细胞系：原位移植方法，其模拟转移的所有步骤，或循环内注射方法。然后，我们进行了数据挖掘和网络分析的基因表达谱的转移细胞系建立的每种移植方法。7个转移细胞系的转录组分析揭示了新的肺转移标记基因，包括已知的转移促进基因和标记基因。在OXconc（原位异种移植物浓度）特征中，富集了“趋化性”和“细胞粘附”术语。在TVIconc（尾静脉注射浓度）特征中，“抗原识别”和“细胞粘附”被富集。此外，转移标记基因的网络分析突出了基因调控网络中的枢纽基因。我们的研究结果表明，高转移细胞系的表达谱之间的原位移植和循环内注射方法是不同的。这也表明一些转移标记基因在以前的研究中被遗漏了。利用原位移植的方法对转移基因进行表征将有助于理解转移的多步骤机制。OXconc中的特征基因可能有潜力成为预后标志物。
Metastasis signature genes in breast cancer have been studied comparing transcriptomic profiles of highly metastatic cancer cell lines established by intra-circulation injection with that of their parental cell line. However, this method is not suitable to analyze the initial steps of metastasis including invasion into local tissues and the circulatory system. To characterize the molecular mechanisms of early metastasis, we established highly metastatic MDA-MB-231 cell lines that metastasized to lung by the two animal transplantation models: the orthotopic transplantation method, which mimics all steps of metastasis, or intra-circulation injection method. We then performed data-mining and network analysis of gene expression profiles of metastatic cell lines established by each transplantation method. Transcriptome analysis of seven metastatic cell lines revealed novel lung metastasis signature genes, including known metastasis promoting genes and signature genes. In the OXconc (orthotopic xenograft concentration) signature, 'chemotaxis' and 'cell adhesion' terms were enriched. In the TVIconc (tail vein injection concentration) signature, 'antigen recognition' and 'cell adhesion' were enriched. Furthermore, network analysis of the metastasis signature genes highlighted hub genes in the gene regulatory network. Our findings show that expression profiles of highly metastatic cell lines were different between the orthotopic transplantation and intra-circulation injection method. It also indicates that some metastatic signature genes have been missed in previous studies. Characterization of metastasis genes using the orthotopic transplantation method will be helpful in understanding the multi-step mechanisms of metastasis. Signature genes in OXconc may have the potential to become prognostic markers.