Article

MicroRNA-34a inhibits migration and invasion of colon cancer cells via targeting to Fra-1.

Institute of Genomic Medicine, Wenzhou Medical College, 268 Xueyuan Road, Wenzhou, Zhejiang 325000, People's Republic of China.
Carcinogenesis (impact factor: 5.7). 12/2011; 33(3):519-28. DOI:10.1093/carcin/bgr304
Source: PubMed

ABSTRACT 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.

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Keywords

3'-untranslated region
 
adjacent normal colon tissues
 
cell migration
 
cell migration/invasion
 
colon cancer cells
 
DNA-binding activity
 
Fra-1 expression
 
Fra-1 overexpression
 
human colon cancer tissues
 
major regulator
 
matrix metalloproteinase
 
messenger RNA levels
 
miR-34a inhibits Fra-1 expression
 
miR-34a-dependent manner
 
miR-34a-transfected cells
 
new target
 
p53 regulates Fra-1 expression
 
significant statistical inverse correlation
 
transcriptional target
 
well-known tumor suppressor gene