Molecular evidence of field cancerization initiated by diabetes in colon cancer patients
Molecular evidence of field cancerization initiated by diabetes in colon cancer patients
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DOI：
10.1002/1878-0261.12438
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发表时间：
2019-04-01
影响因子：
6.6
通讯作者：
Garcia-Foncillas, Jesus
中科院分区：
文献类型：
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作者：
Del Puerto-Nevado, Laura;Minguez, Pablo;Garcia-Foncillas, Jesus
2型糖尿病（T2 DM）作为结肠癌（CC）的风险因素的潜在参与先前已被报道。虽然一些临床研究显示糖尿病患者的CC发病率较高，存活率较低，但其他研究报告没有相关性。我们自己的经验表明，一旦肿瘤存在，糖尿病似乎不会使预后恶化。尽管存在争议，但目前还没有广谱分子研究深入研究T2 DM相关机制在结肠癌发生中的影响。在这里，我们提出了一个转录组和蛋白质组分析配对的肿瘤和正常结肠粘膜样本在一个队列的42例CC患者，其中23例有T2 DM。我们使用基因集富集和网络方法来提取糖尿病患者的相关通路，将其引用到现有知识中，并使用体外技术对其进行测试。通过我们的转录组学方法，我们发现了一个意想不到的重叠的途径在糖尿病患者中过度代表相比，非糖尿病患者，在肿瘤和正常粘膜，包括糖尿病相关的代谢和信号传导过程。蛋白质组学方法强调了糖尿病患者中仅在正常粘膜中发现的几种癌症相关信号通路，而不是肿瘤。转录组和蛋白质组分析的整合表明，与结肠癌发生相关的关键途径的失调，其聚集在肿瘤起始轴TEAD/YAP-TAZ上，作为该过程的潜在起始物。体外研究证实，在高糖条件下，非肿瘤结肠细胞中该途径上调。总之，2型糖尿病与发生恶变的组织附近的正常结肠粘膜中癌症相关过程的失调有关。这些数据支持在糖尿病患者中，正常结肠粘膜中的局部微环境可能是驱动场癌变促进癌变的因素。我们的研究结果为研究糖尿病和结肠癌之间的联系建立了一个新的框架，包括TEAD/YAP-TAZ复合物作为潜在驱动因素的新作用。
The potential involvement of type 2 diabetes mellitus (T2DM) as a risk factor for colon cancer (CC) has been previously reported. While several clinical studies show a higher incidence of CC and a lower survival rate in diabetics, others report no association. Our own experience indicates that diabetes does not seem to worsen the prognosis once the tumor is present. Despite this controversy, there are no wide-spectrum molecular studies that delve into the impact of T2DM-related mechanisms in colon carcinogenesis. Here, we present a transcriptomic and proteomic profiling of paired tumor and normal colon mucosa samples in a cohort of 42 CC patients, 23 of which have T2DM. We used gene set enrichment and network approaches to extract relevant pathways in diabetics, referenced them to current knowledge, and tested them using in vitro techniques. Through our transcriptomics approach, we identified an unexpected overlap of pathways overrepresented in diabetics compared to nondiabetics, in both tumor and normal mucosa, including diabetes-related metabolic and signaling processes. Proteomic approaches highlighted several cancer-related signaling routes in diabetics found only in normal mucosa, not in tumors. An integration of the transcriptome and proteome analyses suggested the deregulation of key pathways related to colon carcinogenesis which converged on tumor initiation axis TEAD/YAP-TAZ as a potential initiator of the process. In vitro studies confirmed upregulation of this pathway in nontumor colon cells under high-glucose conditions. In conclusion, T2DM associates with deregulation of cancer-related processes in normal colon mucosa adjacent to tissue which has undergone a malignant transformation. These data support that in diabetic patients, the local microenvironment in normal colon mucosa may be a factor driving field cancerization promoting carcinogenesis. Our results set a new framework to study links between diabetes and colon cancer, including a new role of the TEAD/YAP-TAZ complex as a potential driver.