Downregulation of miR-34a in breast tumors is not associated with either p53 mutations or promoter hypermethylation while it correlates with metastasis
Downregulation of miR-34a in breast tumors is not associated with either p53 mutations or promoter hypermethylation while it correlates with metastasis
复制标题
DOI：
10.1007/s12032-012-0413-7
复制
发表时间：
2013-03-01
期刊：
影响因子：
3.4
通讯作者：
Houshmand, Massoud
中科院分区：
文献类型：
--
作者：
Javeri, Arash;Ghaffarpour, Massoud;Houshmand, Massoud
MicroRNA-34家族具有抗增殖和凋亡作用。最近的研究表明，p53上调miR-34家族，导致几个关键癌基因的直接抑制。在包括乳腺癌在内的多种类型的恶性肿瘤中已经报道了miR-34 a的失活。miR-34 a在p53介导的细胞周期阻滞和凋亡中的关键作用引起了关注miR-34 a失调在癌发生中的特定作用的研究。虽然在乳腺癌中经常描述存在p53突变，但大多数乳腺肿瘤在p53编码序列或蛋白质表达中没有显示出任何变化。因此，阐明p53通路的其他介质在乳腺癌中的可能参与是重要的。在这项研究中，研究了成熟miR-34 a在具有野生型p53的乳腺肿瘤中的表达，以发现miR-34 a表达失调与乳腺癌之间的任何相关性。在约40%的野生型p53样本中，miR-34 a显著下调。在miR-34 a下调的肿瘤样本中，既没有检测到miR-34 a启动子的超甲基化，也没有检测到p53结合位点的遗传变异。这项研究提供了证据表明，很大一部分乳腺肿瘤的miR-34 a表达可能会受到影响，而与p53无关。此外，miR-34 a的下调与转移显著相关，而miR-34 a的上调与非转移性疾病之间存在显著相关性，表明miR-34 a对更具侵袭性的疾病具有保护作用。miR-34 a状态的知识可以提供关于乳腺肿瘤性质的额外有用信息，特别是当p53检测未显示任何畸变时。
MicroRNA-34 family has anti-proliferative and apoptotic roles. Recent studies have shown that p53 upregulates miR-34 family leading to direct repression of several key oncogenes. Inactivation of miR-34a has been reported in multiple types of malignancies including breast cancer. The critical role of miR-34a in p53-mediated cell cycle arrest and apoptosis invokes studies focusing on the specific role of miR-34a dysregulation in carcinogenesis. While presence of p53 mutations has frequently been described in breast cancer, still most of the breast tumors do not show any variation in the p53 coding sequence or protein expression. Therefore, it is important to clarify possible involvement of other mediators of p53 pathway in breast cancer. In this study, expression of mature miR-34a in breast tumors with wild-type p53 was investigated in order to find any correlation between dysregulation of miR-34a expression and breast cancer. In about 40 % of the wild-type p53 samples, miR-34a was significantly downregulated. Neither hypermethylation of the miR-34a promoter nor genetic variations of the p53-binding site were detected in tumor samples with downregulated miR-34a. This study has provided evidence that miR-34a expression can be affected in a significant proportion of breast tumors independent of p53. Furthermore, downregulation of miR-34a was significantly associated with metastasis, while there was a significant correlation between upregulation of miR-34a and non-metastatic condition indicating a protective role for miR-34a against more invasive disease. Knowledge of miR-34a status may provide additional useful information regarding the nature of breast tumors, especially when p53 testing does not show any aberration.