Alternative splicing in colon, bladder, and prostate cancer identified by exon array analysis
Alternative splicing in colon, bladder, and prostate cancer identified by exon array analysis
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DOI：
10.1074/mcp.m700590-mcp200
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发表时间：
2008-07-01
影响因子：
7
通讯作者：
Orntoft, Torben F.
中科院分区：
文献类型：
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作者：
Thorsen, Kasper;Sorensen, Karina D.;Orntoft, Torben F.
选择性剪接增强蛋白质组多样性并调节癌症相关蛋白。为了鉴定组织特异性和肿瘤特异性的选择性剪接，我们使用GeneChip Human Exon 1.0 ST阵列测量了来自结肠、膀胱和前列腺的102个不同阶段的正常和癌症组织样本的全基因组外显子表达。我们在结肠、膀胱和前列腺的正常组织样本中发现了2069个备选剪接事件，并选择了15个剪接事件进行RT-PCR验证，其中10个通过RT-PCR和测序成功验证。此外，分别在结肠、膀胱和前列腺中选择23、19和18个候选肿瘤特异性剪接改变，在81个独立的正常和肿瘤组织样本上进行RT-PCR验证。总共鉴定出7个具有肿瘤特异性剪接变异的基因（ACTN1、CALD1、COL6A3、LRRFIP2、PIK4CB、TPM1和VCL）。经过验证的肿瘤特异性剪接改变是高度一致的，可以清楚地分离正常和癌症样本，在某些情况下甚至可以区分不同的肿瘤分期。肿瘤特异性剪接改变的一个子集（ACTN1， CALD1和VCL）在所有三个器官中都被发现，可能代表了一般的癌症相关剪接事件。硅蛋白预测表明，鉴定出的癌症特异性剪接变异体编码的蛋白质具有潜在的功能改变，表明它们可能参与发病机制，因此代表了新的治疗靶点。总之，我们确定并验证了结肠、膀胱和前列腺正常组织样本之间的选择性剪接，以及结肠癌、膀胱和前列腺癌中可能具有诊断和预后意义的癌症特异性剪接事件。
Alternative splicing enhances proteome diversity and modulates cancer-associated proteins. To identify tissue- and tumor-specific alternative splicing, we used the GeneChip Human Exon 1.0 ST Array to measure whole-genome exon expression in 102 normal and cancer tissue samples of different stages from colon, urinary bladder, and prostate. We identified 2069 candidate alternative splicing events between normal tissue samples from colon, bladder, and prostate and selected 15 splicing events for RT-PCR validation, 10 of which were successfully validated by RT-PCR and sequencing. Furthermore 23, 19, and 18 candidate tumor-specific splicing alterations in colon, bladder, and prostate, respectively, were selected for RT-PCR validation on an independent set of 81 normal and tumor tissue samples. In total, seven genes with tumor-specific splice variants were identified (ACTN1, CALD1, COL6A3, LRRFIP2, PIK4CB, TPM1, and VCL). The validated tumor-specific splicing alterations were highly consistent, enabling clear separation of normal and cancer samples and in some cases even of different tumor stages. A subset of the tumor-specific splicing alterations (ACTN1, CALD1, and VCL) was found in all three organs and may represent general cancer-related splicing events. In silico protein predictions suggest that the identified cancers-pecific splice variants encode proteins with potentially altered functions, indicating that they may be involved in pathogenesis and hence represent novel therapeutic targets. In conclusion, we identified and validated alternative splicing between normal tissue samples from colon, bladder, and prostate in addition to cancer-specific splicing events in colon, bladder, and prostate cancer that may have diagnostic and prognostic implications.