title: MicroRNA-433 inhibits liver cancer cell migration by repressing the protein expression and function of cAMP response element-binding protein.
abstract: We show for the first time that potent microRNA-433 (miR-433) inhibition of expression of the cAMP response element-binding protein CREB1 represses hepatocellular carcinoma (HCC) cell migration. We identified a miR-433 seed match region in human and mouse CREB1 3'-UTRs. Overexpression of miR-433 markedly decreased human CREB1 3'-UTR reporter activity, and the inhibitory effect of miR-433 was alleviated upon mutation of its binding site. Ectopic expression of miR-433 reduced CREB1 protein levels in a variety of human and mouse cancer cells, including HeLa, Hepa1, Huh7, and HepG2. Human CREB1 protein levels in highly invasive MHCC97H cells were diminished by expression of miR-433 but were induced by miR-433 antagomir (anti-miR-433). The expression of mouse CREB1 protein negatively correlated with miR-433 levels in nuclear receptor Shp(-/-) liver tissues and liver tumors compared with wild-type mice. miR-433 exhibited a significant repression of MHCC97H cell migration, which was reversed by anti-miR-433. Overexpressing miR-433 inhibited focus formation dramatically, demonstrating that miR-433 may exert a tumor suppressor function. Knockdown of CREB1 by siRNAs impeded MHCC97H cell migration and invasion and antagonized the effect of anti-miR-433. Interestingly, CREB1 siRNA decreased MHCC97H cell proliferation, which was not influenced by anti-miR-433. Overexpressing CREB1 decreased the inhibitory activity of miR-433. The CpG islands surrounding miR-433 were hypermethylated, and the DNA methylation agent 5'-aza-2'-deoxycytidine, but not the histone deacetylase inhibitor trichostatin A, drastically stimulated the expression of miR-433 and miR-127 in HCC cells. The latter is clustered with miR-433. The results reveal a critical role of miR-433 in mediating HCC cell migration via CREB1.
authors: From the Departments of Medicine and Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, and.
authors: Zhihong
authors: Z
authors: Yang
authors: Hiroyuki
authors: H
authors: Tsuchiya
authors: Yuxia
authors: Y
authors: Zhang
authors: M Elizabeth
authors: ME
authors: Hartnett
authors: Li
authors: L
authors: Wang
mesh_terms: D000107:Acetylation; D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: C115163:CREB1 protein, human; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C548883:MIRN433 microRNA, human; D035683:MicroRNAs; C533108:Mirn433 microRNA, mouse; D034741:RNA, Small Interfering
keywords: Cell Migration; HCC; Liver Cancer; MicroRNA; Post-translational Modification; Translation Regulation
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