Open AccessMKK 7 mediates miR‐493‐dependent suppression of liver metastasis of colon cancer cells
Author(s) -
Sakai Hiroaki,
Sato Ai,
Aihara Yuki,
Ikarashi Yoshinori,
Midorikawa Yutaka,
Kracht Michael,
Nakagama Hitoshi,
Okamoto Koji
Publication year - 2014
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12380
Subject(s) - metastasis , gene knockdown , cancer research , metastasis suppressor , metastasis suppressor gene , colorectal cancer , kinase , protein kinase a , medicine , cancer , biology , cell culture , microbiology and biotechnology , genetics
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 IGF 1R is a target gene of miR‐493, and that the inhibition of IGF 1R 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 MKK 7 , a mitogen‐activated protein kinase kinase, as a novel target of miR‐493. miR‐493 inhibits MKK 7 expression by targeting the binding site at the 3′‐ UTR of the mkk7 gene. MKK 7 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 MKK 7 resulted in marked suppression of liver metastasis of colon cancer cells. A significant decrease of metastasized cells by the MKK 7 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 MKK 7. Thus, MKK 7 is a major functional target of miR‐493, and its suppression thwarts liver metastasis of colon cancer cells.