Identification of putative immunologic targets for colon cancer prevention based on conserved gene upregulation from preinvasive to malignant lesions.
Identification of putative immunologic targets for colon cancer prevention based on conserved gene upregulation from preinvasive to malignant lesions.
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DOI：
10.1158/1940-6207.capr-12-0484
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发表时间：
2013-07
期刊：
影响因子：
--
通讯作者：
Disis ML
中科院分区：
文献类型：
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作者：
Broussard EK;Kim R;Wiley JC;Marquez JP;Annis JE;Pritchard D;Disis ML
侵袭前腺瘤（AD）进展为癌所需的时间长度、结直肠癌（CRC）的免疫原性以及高危人群的识别使得开发和测试用于预防CRC的预防性疫苗成为可能。我们假设，在AD中相对于正常组织上调的基因，其在CRC中保持增加的表达，将编码适合作为免疫预防的假定靶点的蛋白质。我们评估了现有的AD和CRC微阵列数据集，并确定了160个在AD和CRC中相对于正常结肠组织上调2倍的基因。基于文献综述，我们进一步鉴定了23个在结肠AD和CRC中表现出蛋白质过表达的基因。与对照相比，在AD和CRC细胞系中沉默最高度上调的基因CDH3、CLDN1、KRT23和MMP 7导致活力（p<0.0001）和增殖（p<0.0001）显著降低，并且细胞凋亡增加（对于CDH3、KRT23，p<0.05）。结果在代表微卫星不稳定性（MSI）、CpG岛甲基化因子（CIMP）和染色体不稳定性（CIN）表型的细胞系中重复，表明表达这些蛋白质的细胞的免疫消除可能影响所有CRC表型的进展。为了确定这些蛋白质是否是免疫原，我们询问了来自早期CRC患者和对照的血清，发现与对照相比，病例中CDH3（p=0.006）、KRT 23（p=0.0007）和MMP 7（p<0.0001）血清IgG显著升高。这些数据证明了鉴定CRC的生物学相关推定免疫学靶标的高通量方法，并鉴定了3种适合疫苗开发的候选物。
The length of time required for pre-invasive adenoma (AD) to progress to carcinoma, the immunogenicity of colorectal cancer (CRC), and the identification of high risk populations make development and testing of a prophylactic vaccine for the prevention of CRC possible. We hypothesized that genes upregulated in AD relative to normal tissue, which maintained increased expression in CRC, would encode proteins suitable as putative targets for immunoprevention. We evaluated existing AD and CRC microarray datasets and identified 160 genes that were 2-fold up-regulated in both AD and CRC relative to normal colon tissue. We further identified 23 genes that demonstrated protein over-expression in colon AD and CRC based on literature review. Silencing the most highly up-regulated genes, CDH3, CLDN1, KRT23, and MMP7, in AD and CRC cell lines resulted in a significant decrease in viability (p<0.0001) and proliferation (p<0.0001) as compared to controls and an increase in cellular apoptosis (p<0.05 for CDH3, KRT23). Results were duplicated across cell lines representing microsatellite instability (MSI), CpG island methylator (CIMP) and chromosomal instability (CIN) phenotypes suggesting immunologic elimination of cells expressing these proteins could impact the progression of all CRC phenotypes. To determine whether these proteins were immunogens, we interrogated sera from early stage CRC patients and controls and found significantly elevated CDH3 (p=0.006), KRT23 (p=0.0007), and MMP7 (p<0.0001) serum IgG in cases as compared to controls. These data demonstrate a high throughput approach to the identification of biologically relevant putative immunologic targets for CRC and identified 3 candidates suitable for vaccine development.