| First Author | Yang YM | Year | 2015 |
| Journal | Oncogene | Volume | 34 |
| Issue | 22 | Pages | 2910-21 |
| PubMed ID | 25065598 | Mgi Jnum | J:222537 |
| Mgi Id | MGI:5644794 | Doi | 10.1038/onc.2014.218 |
| Citation | Yang YM, et al. (2015) Galpha12 gep oncogene deregulation of p53-responsive microRNAs promotes epithelial-mesenchymal transition of hepatocellular carcinoma. Oncogene 34(22):2910-21 |
| abstractText | Hepatocellular carcinoma (HCC) has a poor prognosis owing to aggressive phenotype. Galpha12 gep oncogene product couples to G-protein-coupled receptors, whose ligand levels are frequently increased in tumor microenvironments. Here, we report Galpha12 overexpression in human HCC and the resultant induction of zinc-finger E-box-binding homeobox 1 (ZEB1) as mediated by microRNA deregulation. Galpha12 expression was higher in HCC than surrounding non-tumorous tissue. Transfection of Huh7 cell with an activated mutant of Galpha12 (Galpha12QL) deregulated microRNA (miRNA or miR)-200b/a/429, -194-2/192 and -194-1/215 clusters in the miRNome. cDNA microarray analyses disclosed the targets affected by Galpha12 gene knockout. An integrative network of miRNAs and mRNA changes enabled us to predict ZEB1 as a key molecule governed by Galpha12. Decreases of miR-200a/b, -192 and -215 by Galpha12 caused ZEB1 induction. The ability of Galpha12 to decrease p53 levels, as a result of activating protein-1 (AP-1)/c-Jun-mediated mouse double minute 2 homolog induction, contributed to transcriptional deregulation of the miRNAs. Galpha12QL induced ZEB1 and other epithelial-mesenchymal transition markers with fibroblastoid phenotype change. Consistently, transfection with miR-200b, -192 or -215 mimic prevented the ability of Galpha12QL to increase tumor cell migration/invasion. In xenograft studies, sustained knockdown of Galpha12 decreased the overall growth rate and average volume of tumors derived from SK-Hep1 cell (mesenchymal-typed). In HCC patients, miR-192, -215 and/or -200a were deregulated with microvascular invasion or growth advantage. In the HCC samples with higher Galpha12 level, a correlation existed in the comparison of relative changes of Galpha12 and ZEB1. In conclusion, Galpha12 overexpressed in HCC causes ZEB1 induction by deregulating p53-responsive miRNAs, which may facilitate epithelial-mesenchymal transition and growth of liver tumor. These findings highlight the significance of Galpha12 upregulation in liver tumor progression, implicating Galpha12 as an attractive therapeutic target. |
