title: MKK7 mediates miR-493-dependent suppression of liver metastasis of colon cancer cells.
abstract: 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.
authors.affiliation: Division of Cancer Development System, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sakai
authors.forename: Ai
authors.initials: A
authors.lastname: Sato
authors.forename: Yuki
authors.initials: Y
authors.lastname: Aihara
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ikarashi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Midorikawa
authors.forename: Michael
authors.initials: M
authors.lastname: Kracht
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagama
authors.forename: Koji
authors.initials: K
authors.lastname: Okamoto
mesh_terms: D020413:3' Untranslated Regions; D001665:Binding Sites; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary / Q000628:therapy; D048688:MAP Kinase Kinase 7 / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1
chemical_list: D020413:3' Untranslated Regions; C555448:MIRN493 microRNA, human; D035683:MicroRNAs; D017526:Receptor, IGF Type 1; D048688:MAP Kinase Kinase 7; C482569:MAP2K7 protein, human
keywords: Colon cancer; JNK; MKK7; metastasis; miR-493