Institute of Genomic Medicine, Wenzhou Medical College, 268 Xueyuan Road, Wenzhou, Zhejiang 325000, People's Republic of China.
Carcinogenesis. 2012 Mar;33(3):519-28. doi: 10.1093/carcin/bgr304. Epub 2011 Dec 22.
MicroRNA-34a (miR-34a), a transcriptional target of p53, is a well-known tumor suppressor gene. Here, we identified Fra-1 as a new target of miR-34a and demonstrated that miR-34a inhibits Fra-1 expression at both protein and messenger RNA levels. In addition, we found that p53 indirectly regulates Fra-1 expression via a miR-34a-dependant manner in colon cancer cells. Overexpression of miR-34a strongly inhibited colon cancer cell migration and invasion, which can be partially rescued by forced expression of the Fra-1 transcript lacking the 3'-untranslated region. The expression of matrix metalloproteinase (MMP)-1 and MMP-9, two enzymes involved in cell migration and invasion, was decreased in miR-34a-transfected cells, and this can be rescued by Fra-1 overexpression. Moreover, we found that miR-34a was downregulated in 25 of 40 (62.5%) colon cancer tissues, as compared with the adjacent normal colon tissues and that the expression of miR-34a was correlated with the DNA-binding activity of p53. Unexpectedly, the DNA-binding activity of p53 was not inversely correlated with Fra-1 expression, and a significant statistical inverse correlation between miR-34a and Fra-1 expression was only observed in 14 of 40 (35%) colon cancer tissues. Taken together, our in vitro data suggest that p53 regulates Fra-1 expression, and eventually cell migration/invasion, via a miR-34a-dependent manner. However, in vivo data indicate that the p53-miR-34a pathway is not the major regulator of Fra-1 expression in human colon cancer tissues.
微小 RNA-34a（miR-34a）是 p53 的转录靶标，是一种众所周知的肿瘤抑制基因。在这里，我们鉴定 Fra-1 是 miR-34a 的一个新靶标，并证明 miR-34a 在蛋白质和信使 RNA 水平上抑制 Fra-1 的表达。此外，我们发现 p53 通过 miR-34a 依赖性方式间接调节结肠癌细胞中 Fra-1 的表达。miR-34a 的过表达强烈抑制结肠癌细胞的迁移和侵袭，而 Fra-1 转录本的 3'-非翻译区缺失的强制表达可部分挽救这种抑制作用。参与细胞迁移和侵袭的两种酶基质金属蛋白酶（MMP）-1 和 MMP-9 的表达在 miR-34a 转染的细胞中降低，而 Fra-1 的过表达可以挽救这种情况。此外，我们发现与相邻的正常结肠组织相比，在 40 个结肠癌组织中的 25 个（62.5%）中下调了 miR-34a 的表达，并且 miR-34a 的表达与 p53 的 DNA 结合活性相关。出乎意料的是，p53 的 DNA 结合活性与 Fra-1 的表达没有呈负相关，并且仅在 40 个结肠癌组织中的 14 个（35%）中观察到 miR-34a 和 Fra-1 表达之间存在显著的统计学负相关。总之，我们的体外数据表明 p53 通过 miR-34a 依赖性方式调节 Fra-1 的表达，进而调节细胞的迁移/侵袭。然而，体内数据表明，p53-miR-34a 途径不是人结肠癌组织中 Fra-1 表达的主要调节因子。
