Bianchini Michele, Levy Estrella, Zucchini Cinzia, Pinski Victor, Macagno Carlos, De Sanctis Paola, Valvassori Luisa, Carinci Paolo, Mordoh José
Centro de Investigaciones Oncológicas, CIO-FUCA, Buenos Aires, Argentina.
Int J Oncol. 2006 Jul;29(1):83-94.
The causative molecular pathways underlying the pathogenesis of colorectal cancer (CRC) need to be better characterized. The purpose of our study was to better understand the genetic mechanism of oncogenesis for human colorectal cancer and to identify new potential tumor markers of use in clinical practice. We used cDNA microarrays to compare gene expression profiles of colorectal biopsies from 25 CRC patients and 13 normal mucosa from adjacent non-cancerous tissues. Findings were validated by real-time PCR; in addition, western blotting and immunochemistry analysis were carried out as further confirmation of differential expression at a protein level. Comparing cancerous tissues with normal colonic mucosa we identified 584 known genes differentially expressed to a significant degree (p<0.001). Many of the transcripts that were more abundant in tumors than in non-neoplastic tissues appear to reflect important events for colon carcinogenesis. For example, a significant number of these genes serve as apoptotic inhibitors (e.g. BFAR, BIRC1, BIRC6). Furthermore, we observed the simultaneous up-regulation of HLA-E and the down-regulation of beta2-microglobulin; these genes strongly support a potential tumor escape strategy from immune surveillance in colon cancer tissues. Our study provides new gene candidates in the pathogenesis of human CRC disease. From our results we hypothesize that CRC cells escape immune surveillance through a specific gene expression alteration; moreover, over-expression of several survival genes seems to confer a more anti-apoptotic phenotype. These genes are involved in pathways not previously implicated in CRC pathogenesis and they may provide new targets for therapy.
结直肠癌（CRC）发病机制背后的致病分子途径需要得到更充分的表征。我们研究的目的是更好地理解人类结直肠癌发生的遗传机制，并识别出可用于临床实践的新的潜在肿瘤标志物。我们使用cDNA微阵列比较了25例CRC患者的结直肠活检组织与13例相邻非癌组织正常黏膜的基因表达谱。研究结果通过实时PCR进行验证；此外，还进行了蛋白质印迹和免疫化学分析，以进一步确认蛋白质水平上的差异表达。将癌组织与正常结肠黏膜进行比较，我们鉴定出584个差异表达显著的已知基因（p<0.001）。许多在肿瘤中比在非肿瘤组织中表达更丰富的转录本似乎反映了结肠癌发生的重要事件。例如，这些基因中有相当一部分作为凋亡抑制剂（如BFAR、BIRC1、BIRC6）。此外，我们观察到HLA-E的同时上调和β2-微球蛋白的下调；这些基因有力地支持了结肠癌组织中潜在的免疫监视逃逸策略。我们的研究为人类CRC疾病的发病机制提供了新的基因候选物。根据我们的结果，我们推测CRC细胞通过特定的基因表达改变逃避免疫监视；此外，几种存活基因的过表达似乎赋予了更抗凋亡的表型。这些基因参与了以前未涉及CRC发病机制的途径，它们可能为治疗提供新的靶点。
