p38α limits the contribution of MAP17 to cancer progression in breast tumors
p38α limits the contribution of MAP17 to cancer progression in breast tumors
复制标题
DOI：
10.1038/onc.2011.619
复制
发表时间：
2012-10-01
期刊：
影响因子：
8
通讯作者：
Carnero, A.
中科院分区：
文献类型：
--
作者：
Guijarro, M. V.;Vergel, M.;Carnero, A.
MAP 17是一种小的、17-kDa的、非糖基化的膜蛋白，其在一定百分比的癌中过表达。在目前的工作中，我们分析了MAP 17表达在乳腺癌进展过程中的作用。我们发现MAP 17在60%的人乳腺肿瘤中表达，而在正常或良性肿瘤中不表达。MAP 17水平随着乳腺肿瘤分期而增加，并且与乳腺肿瘤进展密切相关。与亲本细胞相比，在表达MAP 17的细胞中观察到活性氧（ROS）水平的显著增加。这种增加被癌细胞的致瘤能力的增加而不是永生的非肿瘤乳腺上皮细胞进一步证实，这提供了一个选择性的优势，一旦肿瘤发生已经开始。特异性MAP 17 shRNA在表达蛋白质的肿瘤细胞中的表达降低了它们的致瘤能力，这表明这种作用依赖于MAP 17蛋白质的表达。我们的数据表明，ROS作为第二信使的功能，增强肿瘤的特性，这是在非肿瘤细胞抑制。我们已经发现p38 α激活介导了这种反应。MAP 17触发ROS依赖性衰老样反应，该反应在p38 a活化不存在的情况下被消除。此外，在人乳腺肿瘤中，MAP 17活化与p38 a磷酸化的缺乏相关。因此，MAP 17在晚期乳腺肿瘤中过表达，其中致癌活性依赖于p38不敏感性来诱导细胞内ROS。Oncogene（2012）31，4447-4459; doi：10.1038/onc.2011.619; 2012年1月23日在线发表
MAP17 is a small, 17-kDa, non-glycosylated membrane protein that is overexpressed in a percentage of carcinomas. In the present work, we have analyzed the role of MAP17 expression during mammary cancer progression. We have found that MAP17 is expressed in 60% human mammary tumors while it is not expressed in normal or benign neoplasias. MAP17 levels increased with breast tumor stage and were strongly correlated with mammary tumoral progression. A significant increase in the levels of reactive oxygen species (ROS) was observed in MAP17-expressing cells, as compared with parental cells. This increase was further paralleled by an increase in the tumorigenic capacity of carcinoma cells but not in immortal non-tumoral breast epithelial cells, which provides a selective advantage once tumorigenesis has begun. Expression of specific MAP17 shRNA in protein-expressing tumor cells reduced their tumorigenic capabilities, which suggests that this effect is dependent upon MAP17 protein expression. Our data show that ROS functions as a second messenger that enhances tumoral properties, which are inhibited in non-tumoral cells. We have found that p38 alpha activation mediates this response. MAP17 triggers a ROS-dependent, senescence-like response that is abolished in the absence of p38a activation. Furthermore, in human breast tumors, MAP17 activation is correlated with a lack of phosphorylation of p38a. Therefore, MAP17 is overexpressed in late-stage breast tumors, in which oncogenic activity relies on p38 insensitivity to induce intracellular ROS. Oncogene (2012) 31, 4447-4459; doi: 10.1038/onc.2011.619; published online 23 January 2012