MKK7 mediates miR-493-dependent suppression of liver metastasis of colon cancer cells.
MKK7 mediates miR-493-dependent suppression of liver metastasis of colon cancer cells.
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DOI：
10.1111/cas.12380
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发表时间：
2014-04
期刊：
影响因子：
5.7
通讯作者：
Okamoto K
中科院分区：
文献类型：
--
作者：
Sakai H;Sato A;Aihara Y;Ikarashi Y;Midorikawa Y;Kracht M;Nakagama H;Okamoto K
晚期结肠癌患者的预后深受是否存在肝转移的影响。miR - 493是一种有效的肝转移抑制因子，人类原发性结肠癌中miR - 493的低水平表达与肝转移发生率升高相关。我们先前表明IGF1R是miR - 493的一个靶基因，并且IGF1R的抑制在一定程度上解释了miR - 493如何抑制肝转移。然而，介导miR - 493抗转移活性的主要功能靶点仍然难以捉摸。在此，我们扩大了对靶基因的搜索，并确定了一种有丝分裂原活化蛋白激酶激酶MKK7是miR - 493的一个新靶点。miR - 493通过靶向mkk7基因3′ - UTR的结合位点来抑制MKK7的表达。在所检测的7种结肠癌细胞系中，有6种表达MKK7，但在未转化的结肠上皮细胞中不表达，并且其表达是JNK激活磷酸化所必需的。RNA干扰介导的MKK7抑制导致结肠癌细胞肝转移显著受抑。根据miR - 493介导的转移抑制的时间进程，即使在转移定植的早期阶段，也观察到MKK7敲低后转移细胞显著减少。对人类原发性结肠肿瘤的免疫组化检查显示，肝转移的发生与MKK7水平升高相关。因此，MKK7是miR - 493的一个主要功能靶点，其抑制可阻止结肠癌细胞的肝转移。
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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影响因子：
168.9
作者：
Cunningham, David;Atkin, Wendy;Starling, Naureen
通讯作者：
Starling, Naureen
DOI：
10.4161/cc.7.16.6452
发表时间：
2008-08-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Lotterman CD;Kent OA;Mendell JT
通讯作者：
Mendell JT
影响因子：
6.2
作者：
Hess, KR;Varadhachary, GR;Abbruzzese, JL
通讯作者：
Abbruzzese, JL
影响因子：
11.1
作者：
Iorio, Marilena V.;Croce, Carlo M.
通讯作者：
Croce, Carlo M.
影响因子：
8.8
作者：
Dong, Y.;Wu, W. K. K.;Wu, C. W.;Sung, J. J. Y.;Yu, J.;Ng, S. S. M.
通讯作者：
Ng, S. S. M.