title: 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.
authors.affiliation: Institute of Genomic Medicine, Wenzhou Medical College, 268 Xueyuan Road, Wenzhou, Zhejiang 325000, People's Republic of China.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wu
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.forename: Lu
authors.initials: L
authors.lastname: Lv
authors.forename: Yong-Feng
authors.initials: YF
authors.lastname: Ren
authors.forename: Xue-Jiao
authors.initials: XJ
authors.lastname: Zhang
authors.forename: Yong-Feng
authors.initials: YF
authors.lastname: Xue
authors.forename: Guiling
authors.initials: G
authors.lastname: Li
authors.forename: Xincheng
authors.initials: X
authors.lastname: Lu
authors.forename: ZhongSheng
authors.initials: Z
authors.lastname: Sun
authors.forename: Kai-Fu
authors.initials: KF
authors.lastname: Tang
mesh_terms: D020413:3' Untranslated Regions; D045744:Cell Line, Tumor; D002465:Cell Movement; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D057809:HEK293 Cells; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000099169:Fos-Related Antigen 1
chemical_list: D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; D020781:Matrix Metalloproteinase 1; D020780:Matrix Metalloproteinase 9; D035683:MicroRNAs; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D000099169:Fos-Related Antigen 1; C522425:MIRN34 microRNA, human