Multiple microRNAs induced by Cdx1 suppress Cdx2 in human colorectal tumour cells

作者：Tagawa Takanobu; Haraguchi Takeshi; Hiramatsu Hiroaki; Kobayashi Kazuyoshi; Sakurai Kouhei; Inada Ken Ichi; Iba Hideo^*

来源：Biochemical Journal, 2012, 447: 449-455.

DOI：10.1042/BJ20120434

• caudal-type homeobox gene 1 (CDX1)
• caudal-type homeobox gene 2 (CDX2)
• hsa-miR-9
• hsa-miR-16
• hsa-miR-22
• microRNA (miRNA)

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 Cdx 1 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.

• 出版日期2012-11-1
• 单位河北医科大学