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

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.

Circulating microRNAs: New biomarkers in diagnosis, prognosis and treatment of cancer (Review)

“…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'-UTR. Moreover, they found that miRNA-34a was down-regulated in 25 of 40 (62.5%) colon cancer tissues, as compared to the adjacent normal colon tissues, and that the expression of miRNA-34a was correlated with the DNA binding activity of p53 (160,161). Cheng et al found that circulating miRNA-141 was significantly associated with stage IV colon cancer in a cohort of 102 plasma samples.…”

The analysis of microRNA-34 family expression in human cancer studies comparing cancer tissues with corresponding pericarcinous tissues

“…miR-34a was found present at highest levels in the brain, and miR-34b/c was most highly expressed in the lung (Bommer et al, 2007). The miR-34 family members share more than 80% homology and govern similar target genes (Hermeking, 2010), and they can act (Tazawa et al, 2007;Roy et al, 2012;Wu et al, 2012;Zhang et al, 2014;Akao et al, 2010;Toyota et al, 2008;Ma et al, 2013) as either tumor suppressors or oncogenes depending on the cellular environment in which they are expressed.…”

Epigenetics of Colorectal Cancer

“…MiR-192 and miR-215 are both effectors and regulators of p53 function to suppress colon carcinogenesis [ 160 ]. Another p53 related miRNA, miR-34a, has been shown to inhibit cell invasion in colon cancer cell lines by targeting FRA1 [ 161 ]. Cyclooxygenase 2 (COX-2) can be negatively regulated by miR-101 [ 162 ] and this may contribute to the initiation and progression of colon tumors.…”