MKK7 mediates miR-493-dependent suppression of liver metastasis of colon cancer cells.
Bottom Line: MKK7 was expressed in six out of seven colon cancer cell lines examined but not in non-transformed colon epithelial cells, and its expression was required for the activating phosphorylation of JNK.RNA interference-mediated inhibition of MKK7 resulted in marked suppression of liver metastasis of colon cancer cells.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.