Esteban Sergio, Moya Patricia, Fernandez-Suarez Antonio, Vidaurreta Marta, González-Peramato Pilar, Sánchez-Carbayo Marta
Tumor Markers Group, 308A, Molecular Pathology Program, Spanish National Cancer Center, Melchor Fernandez Almagro 3, 28029, Madrid, Spain.
Tumour Biol. 2012 Apr;33(2):337-46. doi: 10.1007/s13277-012-0320-8. Epub 2012 Jan 18.
Myopodin is an actin-binding protein believed to play a tumor suppressor role in several solid neoplasias. We evaluated the potential differential myopodin methylation and expression and their clinical relevance in colon cancer. The epigenetic silencing of myopodin by hypermethylation was tested in colon cancer cells (n = 5) before and after azacitidine treatment. Myopodin methylation status was evaluated by methylation-specific PCR in colon cancer cells and colorectal tissues (n = 210) grouped in a training set (n = 62) and two independent validation series (n = 100 and n = 48) collected at independent clinical settings. Myopodin expression patterns were analyzed by immunohistochemistry on tissue arrays. Myopodin hypermethylation correlated with gene and protein expression loss, being increased in vitro by azacitidine. Myopodin was frequently methylated in colon cancer cells (four out of five). Methylation rates were 90.3%, 70.0%, and 47.8% in the training and validation sets, respectively. Myopodin methylation rendered a diagnostic accuracy of 83.9% (p < 0.0005). Cytoplasmic myopodin expression was significantly higher in non-neoplastic biopsies compared to colon tumors (p < 0.0005). Loss of myopodin expression correlated with increasing tumor stage (p = 0.011), methylation (p = 0.005), and poor overall survival (p = 0.003). In the first validation set (n = 100), myopodin methylation predicted disease-free (p = 0.046) and overall survival (p = 0.031). In the second validation cohort, myopodin methylation and protein expression patterns predicted disease-specific (p = 0.012 and p = 0.001, respectively) and overall survival (p = 0.009 and p = 0.043, respectively). Thus, myopodin was revealed to be epigenetically modified in colon cancer. The diagnostic and prognostic clinical utility of myopodin methylation and expression patterns suggest considering their assessment for the clinical management of colon cancer patients.
肌动蛋白结合蛋白被认为在多种实体瘤中发挥肿瘤抑制作用。我们评估了结肠癌中肌动蛋白结合蛋白甲基化和表达的潜在差异及其临床相关性。在阿扎胞苷治疗前后，对结肠癌细胞（n = 5）中肌动蛋白结合蛋白因高甲基化导致的表观遗传沉默进行了检测。通过甲基化特异性PCR评估结肠癌细胞和结直肠组织（n = 210）中的肌动蛋白结合蛋白甲基化状态，这些样本分为一个训练集（n = 62）和两个独立的验证系列（n = 100和n = 48），它们是在独立的临床环境中收集的。通过组织芯片免疫组化分析肌动蛋白结合蛋白的表达模式。肌动蛋白结合蛋白高甲基化与基因和蛋白表达缺失相关，在体外阿扎胞苷可使其增加。结肠癌细胞中肌动蛋白结合蛋白经常发生甲基化（五分之四）。训练集和验证集的甲基化率分别为90.3%、70.0%和47.8%。肌动蛋白结合蛋白甲基化的诊断准确率为83.9%（p < 0.0005）。与结肠肿瘤相比，非肿瘤活检组织中细胞质肌动蛋白结合蛋白的表达显著更高（p < 0.0005）。肌动蛋白结合蛋白表达缺失与肿瘤分期增加（p = 0.011）、甲基化（p = 0.005）和总体生存率差（p = 0.003）相关。在第一个验证集（n = 100）中，肌动蛋白结合蛋白甲基化可预测无病生存期（p = 0.046）和总体生存率（p = 0.031）。在第二个验证队列中，肌动蛋白结合蛋白甲基化和蛋白表达模式可预测疾病特异性生存率（分别为p = 0.012和p = 0.001）和总体生存率（分别为p = 0.009和p = 0.043）。因此，研究发现结肠癌中肌动蛋白结合蛋白存在表观遗传修饰。肌动蛋白结合蛋白甲基化和表达模式的诊断及预后临床效用表明，在结肠癌患者的临床管理中应考虑对其进行评估。
