title: A suppressive role of ionizing radiation-responsive miR-29c in the development of liver carcinoma via targeting WIP1.
abstract: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide, and it has been linked to radiation exposure. As a well-defined oncogene, wild-type p53-induced phosphatase 1 (WIP1) plays an inhibitory role in several tumor suppressor pathways, including p53. WIP1 is amplified and overexpressed in many malignancies, including HCC. However, the underlying mechanisms remain largely unknown. Here, we show that low-dose ionizing radiation (IR) induces miR-29c expression in female mouse liver, while inhibiting its expression in HepG2, a human hepatocellular carcinoma cell line which is used as a model system in this study. miR-29c expression is downregulated in human hepatocellular carcinoma cells, which is inversely correlated with WIP1 expression. miR-29c attenuates luciferase activity of a reporter harboring the 3'UTR binding motif of WIP1 mRNA. Ectopic expression of miR-29c significantly represses cell proliferation and induces apoptosis and G1 arrest in HepG2. In contrast, the knockdown of miR-29c greatly enhances HepG2 cell proliferation and suppresses apoptosis. The biological effects of miR-29c may be mediated by its target WIP1 which regulates p53 activity via dephosphorylation at Ser-15. Finally, fluorescence in situ hybridization (FISH) and immunohistochemical analyses indicate that miR-29c is downregulated in 50.6% of liver carcinoma tissues examined, whereas WIP1 is upregulated in 45.4% of these tissues. The expression of miR-29c inversely correlates with that of WIP1 in HCC. Our results suggest that the IR-responsive miR-29c may function as a tumor suppressor that plays a crucial role in the development of liver carcinoma via targeting WIP1, therefore possibly representing a target molecule for therapeutic intervention for this disease.
authors.affiliation: Department of Biological Sciences, University of Lethbridge, Lethbridge, Canada.|Department of Biochemistry, Qiqihar Medical University, Qiqihar, P.R. China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Biological Sciences, University of Lethbridge, Lethbridge, Canada.|Department of Biochemistry, Qiqihar Medical University, Qiqihar, P.R. China.
authors.forename: Dongping
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Biological Sciences, University of Lethbridge, Lethbridge, Canada.
authors.forename: Corinne
authors.initials: C
authors.lastname: Sidler
authors.affiliation: Department of Biological Sciences, University of Lethbridge, Lethbridge, Canada.
authors.forename: Rocio
authors.initials: R
authors.lastname: Rodriguez-Juarez
authors.affiliation: Department of Biological Sciences, University of Lethbridge, Lethbridge, Canada.
authors.forename: Natasha
authors.initials: N
authors.lastname: Singh
authors.affiliation: Department of Biological Sciences, University of Lethbridge, Lethbridge, Canada.
authors.forename: Mieke
authors.initials: M
authors.lastname: Heyns
authors.affiliation: Department of Biological Sciences, University of Lethbridge, Lethbridge, Canada.
authors.forename: Yaroslav
authors.initials: Y
authors.lastname: Ilnytskyy
authors.affiliation: The Dana Farber/Harvard Comprehensive Cancer Center, Boston, Massachusetts, USA.
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.affiliation: Department of Biological Sciences, University of Lethbridge, Lethbridge, Canada.
authors.forename: Olga
authors.initials: O
authors.lastname: Kovalchuk
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics / Q000473:pathology; D048708:Cell Growth Processes / Q000235:genetics / Q000528:radiation effects; D015536:Down-Regulation; D005260:Female; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009381:Neoplasms, Radiation-Induced / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D011897:Random Allocation
chemical_list: C547014:MIRN29 microRNA, mouse; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C
keywords: WIP1; hepatocellular carcinoma; ionizing radiation; miR-29c