title: Mature miR-17-5p and passenger miR-17-3p induce hepatocellular carcinoma by targeting PTEN, GalNT7 and vimentin in different signal pathways.
abstract: To study the physiological role of a single microRNA (miRNA), we generated transgenic mice expressing the miRNA precursor miR-17 and found that the mature miR-17-5p and the passenger strand miR-17-3p were abundantly expressed. We showed that mature miR-17-5p and passenger strand miR-17-3p could synergistically induce the development of hepatocellular carcinoma. The mature miR-17-5p exerted this function by repressing the expression of PTEN. In contrast, the passenger strand miR-17-3p repressed expression of vimentin, an intermediate filament with the ability to modulate metabolism, and GalNT7, an enzyme that regulates metabolism of liver toxin galactosamine. Hepatocellular carcinoma cells, HepG2, transfected with miR-17 formed larger tumors with more blood vessels and less tumor cell death than mock-treated cells. Expression of miR-17 precursor modulated HepG2 proliferation, migration, survival, morphogenesis and colony formation and inhibited endothelial tube formation. Silencing of PTEN, vimentin or GalNT7 with their respective siRNAs enhanced proliferation and migration. Re-expressing these molecules reversed their roles in proliferation, migration and tumorigenesis. Further experiments indicated that these three molecules do not interact with each other, but appear to function in different signaling pathways. Our results demonstrated that a mature miRNA can function synergistically with its passenger strand leading to the same phenotype but by regulating different targets located in different signaling pathways. We anticipate that our assay will serve as a helpful model for studying miRNA regulation.
authors: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto M4N 3M5, Canada.
authors: Sze Wan
authors: SW
authors: Shan
authors: Ling
authors: L
authors: Fang
authors: Tatiana
authors: T
authors: Shatseva
authors: Zina Jeyapalan
authors: ZJ
authors: Rutnam
authors: Xiangling
authors: X
authors: Yang
authors: William
authors: W
authors: Du
authors: Wei-Yang
authors: WY
authors: Lu
authors: Jim W
authors: JW
authors: Xuan
authors: Zhaoqun
authors: Z
authors: Deng
authors: Burton B
authors: BB
authors: Yang
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D004794:Enzyme Repression / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019076:Transgenes / Q000235:genetics; D014410:Tumor Stem Cell Assay; D014746:Vimentin / Q000235:genetics / Q000378:metabolism*; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D035683:MicroRNAs; D017350:N-Acetylgalactosaminyltransferases; D051059:PTEN Phosphohydrolase; D014746:Vimentin; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C524941:MIRN17 microRNA, human; C585052:GalNT7 protein, mouse
keywords: GalNT7; Hepatocellular carcinoma; MicroRNA; Pten; Vimentin