Khalili Mitra, Vasei Mohammad, Khalili Davood, Alimoghaddam Kamran, Sadeghizadeh Majid, Mowla Seyed Javad
Department of Medical Genetics and Molecular Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.
J Gastrointest Cancer. 2015 Sep;46(3):251-8. doi: 10.1007/s12029-015-9695-2.
Many cell signaling pathways essential for normal stem cell development are involved in cancer initiation and progression. In the present study, motivated by a possible contribution of reprogramming process in induction of cancer, we compared the expression level of main genes involved in iPS generation, i.e., miR-302, miR-145, SOX2, c-MYC, and P21, in a series of tumor and non-tumor tissues of stomach.
A total number of 34 tumors and their matched non-tumor (as control) gastric surgical specimens were obtained. The expression of the candidate genes was evaluated by using real-time PCR and immunohistochemistry (IHC) techniques.
Our data revealed a significant downregulation of miR-302b, P21, and miR-145 genes in intestinal and SOX2 gene in diffuse type of tumor samples. SOX2, but not the other genes, showed a significant downregulation in both proximal (cardia and fundus) and distal (body and antrum) sites of stomach. Based on receiver-operating characteristic (ROC) analyses, the highest total area under the curve (AUC) was found for SOX2 (AUC = 82 %, P < 0.001). Interestingly, all tumor samples revealed a negative signal for c-MYC expression, while non-tumor samples represented an intense cytoplasmic staining.
Despite the fact that some hESC-specific genes are upregulated in tumors, our data revealed a significant downregulation of all candidate genes, except for c-MYC, in tumor samples of stomach. Moreover, ROC data demonstrated that SOX2 gene expression index is a better potential biomarker of gastric cancer, compared to other tested genes. SOX2 expression has a good sensitivity and specificity to discriminate correctly between tumor/non-tumor and also high/low grades of tumor malignancy. It seems downregulation of miR-302b, miR-145, and P21 could contribute to gastric tumor initiation and progression.
许多对正常干细胞发育至关重要的细胞信号通路都参与了癌症的发生和发展。在本研究中，受重编程过程在癌症诱导中可能作用的启发，我们比较了一系列胃肿瘤和非肿瘤组织中参与诱导多能干细胞（iPS）生成的主要基因，即miR-302、miR-145、SOX2、c-MYC和P21的表达水平。
共获取了34例肿瘤及其匹配的非肿瘤（作为对照）胃手术标本。通过实时聚合酶链反应（PCR）和免疫组织化学（IHC）技术评估候选基因的表达。
我们的数据显示，在弥漫型肿瘤样本中，miR-302b、P21和miR-145基因显著下调，在肠型肿瘤样本中SOX2基因显著下调。SOX2基因在胃的近端（贲门和胃底）和远端（胃体和胃窦）部位均显著下调，而其他基因则无此现象。基于受试者工作特征（ROC）分析，发现SOX2基因的曲线下总面积（AUC）最高（AUC = 82%，P < 0.001）。有趣的是，所有肿瘤样本的c-MYC表达均为阴性信号，而非肿瘤样本则表现为强烈的细胞质染色。
尽管一些人胚胎干细胞（hESC）特异性基因在肿瘤中上调，但我们的数据显示，在胃肿瘤样本中，除c-MYC外，所有候选基因均显著下调。此外，ROC数据表明，与其他测试基因相比，SOX2基因表达指数是胃癌更好的潜在生物标志物。SOX2表达在正确区分肿瘤/非肿瘤以及肿瘤恶性程度的高/低分级方面具有良好的敏感性和特异性。miR-302b、miR-145和P21的下调似乎可能促进胃肿瘤的发生和发展。
