title: Multiple microRNAs induced by Cdx1 suppress Cdx2 in human colorectal tumour cells.
abstract: The mammalian transcriptional factors, Cdx1 and Cdx2 (Cdx is caudal-type homeobox) are paralogues and critical for the cellular differentiation of intestinal or colorectal epithelia. It has been reported previously that in Cdx1 transgenic or knockout mice, endogenous Cdx2 levels are inversely correlated with Cdx1 levels. Recently, we found that exogenous Cdx1 expression can suppress Cdx2 in a human colorectal tumour cell line, SW480, although the underlying molecular mechanisms were unclear. In the present study, we show that several microRNAs induced by exogenous Cdx1 expression directly bind to the CDX2 mRNA 3'UTR (untranslated region) to destabilize these transcripts, finally leading to their degradation. Using microarray analysis, we found that several miRNAs that were computationally predicted to target CDX2 mRNAs are up-regulated by exogenous Cdx1 expression in SW480 cells. Among these molecules, we identified miR-9, miR-16 and miR-22 as having the potential to suppress Cdx2 through the binding of the 3'UTR to its transcript. Importantly, simultaneous mutations of both the miR-9- and miR-16-binding sites in the CDX2 3'UTR were shown to be sufficient to block Cdx2 suppression. The results of the present study suggest a unique feature of miRNAs in which they contribute to homoeostasis by limiting the levels of transcription factors belonging to the same gene family.
authors: Division of Host-Parasite Interaction, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku Tokyo 108-8639, Japan.
authors: Takanobu
authors: T
authors: Tagawa
authors: Takeshi
authors: T
authors: Haraguchi
authors: Hiroaki
authors: H
authors: Hiramatsu
authors: Kazuyoshi
authors: K
authors: Kobayashi
authors: Kouhei
authors: K
authors: Sakurai
authors: Ken-Ichi
authors: K
authors: Inada
authors: Hideo
authors: H
authors: Iba
mesh_terms: D000071616:CDX2 Transcription Factor; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: C491273:CDX1 protein, human; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; C505362:MIRN16 microRNA, human; C548375:MIRN22 microRNA, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger