Department of Molecular Oncology, Institute for Cancer Research & K.G.Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, P.O.Box 4953 Nydalen, -0424, Oslo, NO, Norway.
Center for Cancer Biomedicine, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
Mol Cancer. 2017 Jul 6;16(1):116. doi: 10.1186/s12943-017-0691-y.
Colorectal cancer (CRC) cell lines are widely used pre-clinical model systems. Comprehensive insights into their molecular characteristics may improve model selection for biomedical studies.
We have performed DNA, RNA and protein profiling of 34 cell lines, including (i) targeted deep sequencing (n = 612 genes) to detect single nucleotide variants and insertions/deletions; (ii) high resolution DNA copy number profiling; (iii) gene expression profiling at exon resolution; (iv) small RNA expression profiling by deep sequencing; and (v) protein expression analysis (n = 297 proteins) by reverse phase protein microarrays.
The cell lines were stratified according to the key molecular subtypes of CRC and data were integrated at two or more levels by computational analyses. We confirm that the frequencies and patterns of DNA aberrations are associated with genomic instability phenotypes and that the cell lines recapitulate the genomic profiles of primary carcinomas. Intrinsic expression subgroups are distinct from genomic subtypes, but consistent at the gene-, microRNA- and protein-level and dominated by two distinct clusters; colon-like cell lines characterized by expression of gastro-intestinal differentiation markers and undifferentiated cell lines showing upregulation of epithelial-mesenchymal transition and TGFβ signatures. This sample split was concordant with the gene expression-based consensus molecular subtypes of primary tumors. Approximately ¼ of the genes had consistent regulation at the DNA copy number and gene expression level, while expression of gene-protein pairs in general was strongly correlated. Consistent high-level DNA copy number amplification and outlier gene- and protein- expression was found for several oncogenes in individual cell lines, including MYC and ERBB2.
This study expands the view of CRC cell lines as accurate molecular models of primary carcinomas, and we present integrated multi-level molecular data of 34 widely used cell lines in easily accessible formats, providing a resource for preclinical studies in CRC.
结直肠癌（CRC）细胞系是广泛使用的临床前模型系统。全面了解其分子特征可以提高生物医学研究中模型选择的准确性。
我们对 34 种细胞系进行了 DNA、RNA 和蛋白质谱分析，包括：（i）靶向深度测序（n=612 个基因）以检测单核苷酸变异和插入/缺失；（ii）高分辨率 DNA 拷贝数谱分析；（iii）外显子分辨率的基因表达谱分析；（iv）通过深度测序进行小 RNA 表达谱分析；（v）通过反相蛋白微阵列进行蛋白质表达分析（n=297 种蛋白质）。
根据 CRC 的关键分子亚型对细胞系进行分层，并通过计算分析在两个或更多水平上整合数据。我们证实，DNA 异常的频率和模式与基因组不稳定性表型相关，并且细胞系再现了原发性癌的基因组图谱。内在表达亚群与基因组亚型不同，但在基因、microRNA 和蛋白质水平上一致，并以两个不同的簇为主；具有胃肠道分化标志物表达的结肠样细胞系和上皮-间充质转化和 TGFβ特征上调的未分化细胞系。这种样本分割与原发性肿瘤的基于基因表达的共识分子亚型一致。大约有 1/4 的基因在 DNA 拷贝数和基因表达水平上具有一致的调节，而基因-蛋白质对的表达通常具有很强的相关性。在个别细胞系中，包括 MYC 和 ERBB2 在内的几个癌基因中发现了一致的高水平 DNA 拷贝数扩增和异常基因和蛋白质表达。
本研究扩展了结直肠癌细胞系作为原发性癌准确分子模型的观点，我们提供了 34 种广泛使用的细胞系的综合多层次分子数据，以易于访问的格式呈现，为 CRC 的临床前研究提供了资源。
Zotero 插件
