title: 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.
abstract: 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 Apc(Min/+) 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 Apc(Min/+) mice. This unique cascade, in turn, may prevent overproduction of a subset of tumor suppressive miRNAs by repressing their own modulators, p68/p72.
authors.affiliation: Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Aichi, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takaoka
authors.forename: Yuko
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Hitoki
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ouchi
authors.forename: Shanlou
authors.initials: S
authors.lastname: Qiao
authors.forename: Miki
authors.initials: M
authors.lastname: Nagahara
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Ichihara
authors.forename: Jiing-Dwan
authors.initials: JD
authors.lastname: Lee
authors.forename: Koichi
authors.initials: K
authors.lastname: Adachi
authors.forename: Michinari
authors.initials: M
authors.lastname: Hamaguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwamoto
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D023061:Gene Order; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D008954:Models, Biological; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism
chemical_list: C542359:MIRN143 microRNA, human; C543499:MIRN145a microRNA, mouse; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D051176:beta Catenin; D048054:Mitogen-Activated Protein Kinase 7; D053487:DEAD-box RNA Helicases