MKK7 mediates miR-493-dependent suppression of liver metastasis of colon cancer cells.
Bottom Line: However, major functional targets that mediate the antimetastatic activity of miR-493 remain elusive.Here, we extended our search for target genes and identified MKK7, a mitogen-activated protein kinase kinase, as a novel target of miR-493. miR-493 inhibits MKK7 expression by targeting the binding site at the 3'-UTR of the mkk7 gene.Immunohistochemical examination in human primary colon tumors revealed that the occurrence of liver metastasis is associated with elevated levels of MKK7.
Affiliation: Division of Cancer Development System, National Cancer Center Research Institute, Tokyo, Japan.Show MeSH
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Mentions: It was shown that miR-493 expression in HCT116 cells blocks settlement of the metastasized cells in the liver, at least in part, by inducing cell death at liver mesenchyme.(11) Hence, we examined whether the inhibition of liver metastasis is observed during the early phase of mesenchymal settlement of metastatic cells by MKK7 inhibition, as well as by miR-493 introduction. The GFP-expressing HCT116 cells were transfected with either the control or MKK7 siRNAs (Fig. 4a, upper panel), mixed with the RFP-positive cells and then used to generate metastatic foci in the liver, as we did in experiments shown in Figure 3. Two or 4 days after the splenic injection, the presence of the metastatic cells in liver mesenchyme was visualized by imaging (Fig. S2, right panel), and the GFP- and RFP-positive cells were counted to calculate the extent of the inhibition of metastasis. In accordance with the time course by miR-493 expression,(11) inhibition of MKK7 suppressed the settlement of metastatic foci by day 4 (Fig. 4a, lower panel). Thus, the inhibition of MKK7 blocks formation of metastatic foci during the early phase of the mesenchymal settlement.
Affiliation: Division of Cancer Development System, National Cancer Center Research Institute, Tokyo, Japan.