Journal
CANCER SCIENCE
Volume 105, Issue 4, Pages 425-430Publisher
WILEY-BLACKWELL
DOI: 10.1111/cas.12380
Keywords
Colon cancer; JNK; metastasis; miR-493; MKK7
Categories
Funding
- Ministry of Health, Labor and Welfare of Japan
- National Institute of Biomedical Innovation (NiBio)
- Japan Society for the Promotion of Science
- National Cancer Center [25-A-2, 25-B-6]
- Grants-in-Aid for Scientific Research [23591972] Funding Source: KAKEN
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The prognosis of advanced colon cancer patients is profoundly affected by the presence or absence of liver metastasis. miR-493 functions as a potent suppressor of liver metastasis, and low-level miR-493 expression in human primary colon cancer is associated with an elevated incidence of liver metastasis. We previously showed that IGF1R is a target gene of miR-493, and that the inhibition of IGF1R partly explains how miR-493 suppresses liver metastasis. 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. 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. A significant decrease of metastasized cells by the MKK7 knockdown was observed, even at early stages of the metastatic settlement, in accordance with a time course of the miR-493-mediated inhibition of the metastasis. Immunohistochemical examination in human primary colon tumors revealed that the occurrence of liver metastasis is associated with elevated levels of MKK7. Thus, MKK7 is a major functional target of miR-493, and its suppression thwarts liver metastasis of colon cancer cells.
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