Brush border Myosin Ia has tumor suppressor activity in the intestine
Brush border Myosin Ia has tumor suppressor activity in the intestine
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DOI：
10.1073/pnas.1108411109
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发表时间：
2012-01-31
影响因子：
11.1
通讯作者：
Arango, Diego
中科院分区：
文献类型：
--
作者：
Mazzolini, Rocco;Dopeso, Higinio;Arango, Diego
已知上皮结构和细胞极性/分化的丧失在肿瘤发生过程中是重要的。在这里，我们证明了刷状缘蛋白肌球蛋白Ia（MYO 1A）是重要的极化和分化的结肠癌细胞，并经常在大肠癌中失活的遗传和表观遗传机制。在32%（37/116）的结直肠肿瘤中观察到MYO 1A移码突变，分析了微卫星不稳定性，并在相当比例的结肠癌细胞系和原发性结直肠肿瘤中观察到启动子甲基化的证据。MYO 1A失活导致的极化/分化丧失与软琼脂和异种移植模型中较高的肿瘤生长相关。此外，与Myo 1a野生型动物相比，Myo 1a基因敲除小鼠中遗传和致癌物引发的肠道肿瘤的进展显著加速。此外，MYO 1A肿瘤表达被发现是结直肠癌患者的独立预后因素。MYO 1A肿瘤蛋白水平低的患者与MYO 1A肿瘤蛋白水平高的患者相比，无病生存期和总生存期显著缩短（logrank检验分别为P = 0.004和P = 0.009）。低MYO 1A患者的中位疾病复发时间为1年，而高MYO 1A患者组的中位疾病复发时间> 9年。这些结果将MYO 1A鉴定为结直肠癌中独特的肿瘤抑制基因，并证明参与细胞极性的结构刷状缘蛋白的丢失对肿瘤发展很重要。
The loss of the epithelial architecture and cell polarity/differentiation is known to be important during the tumorigenic process. Here we demonstrate that the brush border protein Myosin Ia (MYO1A) is important for polarization and differentiation of colon cancer cells and is frequently inactivated in colorectal tumors by genetic and epigenetic mechanisms. MYO1A frame-shift mutations were observed in 32% (37 of 116) of the colorectal tumors with microsatellite instability analyzed, and evidence of promoter methylation was observed in a significant proportion of colon cancer cell lines and primary colorectal tumors. The loss of polarization/differentiation resulting from MYO1A inactivation is associated with higher tumor growth in soft agar and in a xenograft model. In addition, the progression of genetically and carcinogen-initiated intestinal tumors was significantly accelerated in Myo1a knockout mice compared with Myo1a wild-type animals. Moreover, MYO1A tumor expression was found to be an independent prognostic factor for colorectal cancer patients. Patients with low MYO1A tumor protein levels had significantly shorter disease-free and overall survival compared with patients with high tumoral MYO1A (logrank test P = 0.004 and P = 0.009, respectively). The median time-to-disease recurrence in patients with low MYO1A was 1 y, compared with > 9 y in the group of patients with high MYO1A. These results identify MYO1A as a unique tumor-suppressor gene in colorectal cancer and demonstrate that the loss of structural brush border proteins involved in cell polarity are important for tumor development.