title: Quantitatively controlling expression of miR-17~92 determines colon tumor progression in a mouse tumor model.
abstract: The miRNA cluster miR-17~92 targets mRNAs involved in distinct pathways that either promote or inhibit tumor progression. However, the cellular and molecular mechanisms underlying miR-17~92 cluster-mediated protumorigenic or anti-tumorigenic effects have not been studied. Herein, we determined that inhibition of colon cancer progression is dictated by quantitatively controlling expression of the miR-17~92 cluster. miR-19 in the context of the miR-17~92 cluster at medium levels promoted tumor metastasis through induction of Wnt/β-catenin-mediated epithelial-mesenchymal transition by targeting to the tumor-suppressor gene, PTEN. However, higher levels of the miR-17~92 cluster switched from PTEN to oncogenes, including Ctnnb1 (β-catenin) via miR-18a, which resulted in inhibition of tumor growth and metastasis. However, overexpression of Ctnnb1in tumor cells with high-level miR-17~92 did not lead to an increase in the levels of β-catenin protein, suggesting that other factors regulated by higher levels of miR-17~92 might also contribute to inhibition of tumor growth and metastasis. Those unidentified factors may negatively regulate the production of β-catenin protein. Collectively, the data presented in this study revealed that higher levels of miR-17~92 were a critical negative regulator for activation of the Wnt/β-catenin pathway and could have a potential therapeutic application.
authors.affiliation: Louisville Veterans Administration Medical Center, Louisville, Kentucky; James Brown Cancer Center, University of Louisville, Louisville, Kentucky; Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky; Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, China. Electronic address: h0jian03@louisville.edu.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: James Brown Cancer Center, University of Louisville, Louisville, Kentucky.
authors.forename: Qilong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: James Brown Cancer Center, University of Louisville, Louisville, Kentucky.
authors.forename: Baomei
authors.initials: B
authors.lastname: Wang
authors.affiliation: James Brown Cancer Center, University of Louisville, Louisville, Kentucky.
authors.forename: Jingyao
authors.initials: J
authors.lastname: Mu
authors.affiliation: James Brown Cancer Center, University of Louisville, Louisville, Kentucky.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhuang
authors.affiliation: James Brown Cancer Center, University of Louisville, Louisville, Kentucky.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Zhang
authors.affiliation: James Brown Cancer Center, University of Louisville, Louisville, Kentucky.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.affiliation: James Brown Cancer Center, University of Louisville, Louisville, Kentucky.
authors.forename: Donald
authors.initials: D
authors.lastname: Miller
authors.affiliation: Louisville Veterans Administration Medical Center, Louisville, Kentucky; James Brown Cancer Center, University of Louisville, Louisville, Kentucky; Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky. Electronic address: h0zhan17@louisville.edu.
authors.forename: Huang-Ge
authors.initials: HG
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018390:Gene Targeting; D016678:Genome; D006801:Humans; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C575895:MIRN17-92 microRNA, mouse; C552691:MIRN18 microRNA, mouse; D035683:MicroRNAs; D051153:Wnt Proteins; D051176:beta Catenin