An integrative framework identifies alternative splicing events in colorectal cancer development
An integrative framework identifies alternative splicing events in colorectal cancer development
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DOI：
10.1016/j.molonc.2013.10.004
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发表时间：
2014-02-01
影响因子：
6.6
通讯作者：
Mandruzzato, Susanna
中科院分区：
文献类型：
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作者：
Bisognin, Andrea;Pizzini, Silvia;Mandruzzato, Susanna
选择性剪接（AS）是一种常见的机制，它从单个基因产生不同的RNA异构体，潜在地增加蛋白质的多样性。越来越多的证据表明，这种机制与癌症进展密切相关。本研究采用基因芯片技术对46例大肠癌患者的23例正常结肠黏膜、30例原发性大肠癌和27例肝转移标本进行了全转录组分析，以确定大肠癌进展中的AS事件。将外显子水平分析与AltAnalyze算法和转录水平估计（MMBGX概率方法）相结合，估计差异表达的基因和外显子，并重建AS事件。从正常结肠粘膜到原发性肿瘤的转变中AS基因的数量是最丰富的，但在接下来的转变中显著下降到肝转移。206个基因与结肠癌的发展和进展中可能的AS事件进行了鉴定，这些基因参与了与肿瘤生物学相关的过程和途径，如细胞-细胞和细胞-基质相互作用。在RNA和蛋白质水平验证了VCL、CALD 1、B3 GNT 6和CTHRC 1基因中的几个AS事件，这些基因在肿瘤发展过程中差异表达。总之，这些结果表明，癌症特异性AS在结直肠癌自然史的早期阶段很常见。(C)2013年欧洲生物化学学会联合会。Elsevier B. V.出版，保留所有权利。
Alternative splicing (AS) is a common mechanism which creates diverse RNA isoforms from a single gene, potentially increasing protein variety. Growing evidence suggests that this mechanism is closely related to cancer progression. In this study, whole transcriptome analysis was performed with GeneChip Human exon 1.0 ST Array from 80 samples comprising 23 normal colon mucosa, 30 primary colorectal cancer and 27 liver metastatic specimens from 46 patients, to identify AS events in colorectal cancer progression. Differentially expressed genes and exons were estimated and AS events were reconstructed by combining exon-level analyses with AltAnalyze algorithms and transcript-level estimations (MMBGX probabilistic method). The number of AS genes in the transition from normal colon mucosa to primary tumor was the most abundant, but fell considerably in the next transition to liver metastasis. 206 genes with probable AS events in colon cancer development and progression were identified, that are involved in processes and pathways relevant to tumor biology, as cell-cell and cell-matrix interactions. Several AS events in VCL, CALD1, B3GNT6 and CTHRC1 genes, differentially expressed during tumor development were validated, at RNA and at protein level. Taken together, these results demonstrate that cancer-specific AS is common in early phases of colorectal cancer natural history. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.