Forced expression of miR-143 represses ERK5/c-Myc and p68/p72 signaling in concert with miR-145 in gut tumors of Apc(Min) mice.
Forced expression of miR-143 represses ERK5/c-Myc and p68/p72 signaling in concert with miR-145 in gut tumors of Apc(Min) mice.
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DOI：
10.1371/journal.pone.0042137
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Iwamoto T
中科院分区：
文献类型：
--
作者：
Takaoka Y;Shimizu Y;Hasegawa H;Ouchi Y;Qiao S;Nagahara M;Ichihara M;Lee JD;Adachi K;Hamaguchi M;Iwamoto T
最近，miR-143和miR-145已被证明属于microRNA的子集，其表达由肿瘤抑制因子p53和DEAD盒RNA解旋酶亚基p68/p72的复合物控制。虽然越来越多的研究已经承认，这两种miRNA作为肿瘤抑制因子的功能，并类似地调节，它们对肿瘤发生的协调作用的证据已经很少提出。在此，我们建立了在CAG调控单元控制下表达miR-143的转基因小鼠。当与ApcMin/+小鼠杂交时，小肠肿瘤的发展显着减弱。在转基因小肠肿瘤中，内源性miR-145也被增强，c-Myc和p68/p72的表达被抑制，这两者都被报道为肠道肿瘤发展的关键，对应于ERK 5的下调。我们证明了miR-143和miR-145的组合抑制了人结肠癌细胞中c-Myc的表达，而miR-145延迟了p72的表达。此外，我们发现miR-145通过其3′非翻译区调节p72表达的可能性，以及c-Myc下调参与p68抑制和miR-145诱导。这些发现表明，miR-143的强制表达可能与内源性miR-145相互作用，抑制ERK 5/c-Myc和p68/p72/β-catenin信号传导，并阻碍ApcMin/+小鼠中小肠肿瘤的发展。反过来，这种独特的级联反应可以通过抑制它们自己的调节剂p68/p72来防止肿瘤抑制性miRNA子集的过度产生。
Recently, miR-143 and miR-145 have been shown to belong to a subset of microRNAs whose expression is controlled by a complex of a tumor suppressor p53 and DEAD-box RNA helicase subunits p68/p72. While accumulating studies have acknowledged that both miRNAs function as tumor suppressors and are similarly regulated, evidence of their coordinated action against tumorigenesis has been poorly presented. Herein, we establish transgenic mice that express miR-143 under the control of the CAG regulatory unit. When crossbred with ApcMin/+ mice, the development of tumors in the small intestines is significantly attenuated. In the transgenic small intestine tumors, the endogenous miR-145 is also enhanced and the expression of c-Myc and p68/p72, both of which have been reported to be pivotal for gut tumor development, is suppressed, corresponding to the downregulation of ERK5. We demonstrate that the combination of miR-143 and miR-145 inhibits the expression of c-Myc in human colon cancer cells, whereas miR-145 retards that of p72. Moreover, we show the possibilities that miR-145 modulates p72 expression through its 3′ untranslated region and that c-Myc downregulation is involved in both p68 suppression and miR-145 induction. These findings suggest that forced expression of miR-143, probably interacting with endogenous miR-145, inhibits ERK5/c-Myc and p68/p72/β-catenin signaling and hampers small intestine tumor development in ApcMin/+ mice. This unique cascade, in turn, may prevent overproduction of a subset of tumor suppressive miRNAs by repressing their own modulators, p68/p72.
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DOI：
10.1146/annurev.pathol.4.110807.092222
发表时间：
2009
期刊：
Annual review of pathology
影响因子：
--
作者：
Lee YS;Dutta A
通讯作者：
Dutta A
影响因子：
64.8
作者：
Cordes KR;Sheehy NT;White MP;Berry EC;Morton SU;Muth AN;Lee TH;Miano JM;Ivey KN;Srivastava D
通讯作者：
Srivastava D
影响因子：
11.4
作者：
Kato, Y;Kravchenko, VV;Lee, JD
通讯作者：
Lee, JD
影响因子：
64.8
作者：
Lee, Y;Ahn, C;Kim, VN
通讯作者：
Kim, VN
影响因子：
4.8
作者：
Esau, C;Kang, XL;Griffey, R
通讯作者：
Griffey, R