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Yang, Y M,Lee, W H,Lee, C G,An, J,Kim, E-S,Kim, S H,Lee, S-K,Lee, C H,Dhanasekaran, D N,Moon, A,Hwang, S,Lee, S J,Park, J-W,Kim, K M,Kim, S G Macmillan Publishers Limited 2015 Oncogene Vol.34 No.22
Hepatocellular carcinoma (HCC) has a poor prognosis owing to aggressive phenotype. Gα<SUB>12</SUB> gep oncogene product couples to G-protein-coupled receptors, whose ligand levels are frequently increased in tumor microenvironments. Here, we report Gα<SUB>12</SUB> overexpression in human HCC and the resultant induction of zinc-finger E-box-binding homeobox 1 (ZEB1) as mediated by microRNA deregulation. Gα<SUB>12</SUB> expression was higher in HCC than surrounding non-tumorous tissue. Transfection of Huh7 cell with an activated mutant of Gα<SUB>12</SUB> (Gα<SUB>12</SUB>QL) 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 Gα<SUB>12</SUB> gene knockout. An integrative network of miRNAs and mRNA changes enabled us to predict ZEB1 as a key molecule governed by Gα<SUB>12</SUB>. Decreases of miR-200a/b, -192 and -215 by Gα<SUB>12</SUB> caused ZEB1 induction. The ability of Gα<SUB>12</SUB> 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. Gα<SUB>12</SUB>QL 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 Gα<SUB>12</SUB>QL to increase tumor cell migration/invasion. In xenograft studies, sustained knockdown of Gα<SUB>12</SUB> 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 Gα<SUB>12</SUB> level, a correlation existed in the comparison of relative changes of Gα<SUB>12</SUB> and ZEB1. In conclusion, Gα<SUB>12</SUB> 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 Gα<SUB>12</SUB> upregulation in liver tumor progression, implicating Gα<SUB>12</SUB> as an attractive therapeutic target.
Lee, S J,Yang, J W,Cho, I J,Kim, W D,Cho, M K,Lee, C H,Kim, S G Macmillan Publishers Limited 2009 Oncogene Vol.28 No.9
Transforming growth factor-β1 (TGFβ1) plays a role in neoplastic transformation and transdifferentiation. Gα<SUB>12</SUB> and Gα<SUB>13</SUB>, referred to as the gep oncogenes, stimulate mitogenic pathways. Nonetheless, no information is available regarding their roles in the regulation of the TGFβ1 gene and the molecules linking them to gene transcription. Knockdown or knockout experiments using murine embryonic fibroblasts and hepatic stellate cells indicated that a Gα<SUB>12</SUB> and Gα<SUB>13</SUB> deficiency reduced constitutive, auto-stimulatory or thrombin-inducible TGFβ1 gene expression. In contrast, transfection of activated mutants of Gα<SUB>12</SUB> and Gα<SUB>13</SUB> enabled the knockout cells to promote TGFβ1 induction. A promoter deletion analysis suggested that activating protein 1 (AP-1) plays a role in TGFβ1 gene transactivation, which was corroborated by the observation that a deficiency of the G-proteins decreased the AP-1 activity, whereas their activation enhanced it. Moreover, mutation of the AP-1-binding site abrogated the ability of Gα<SUB>12</SUB> and Gα<SUB>13</SUB> to induce the TGFβ1 gene. Transfection of a dominant-negative mutant of Rho or Rac, but not Cdc42, prevented gene transactivation and decreased AP-1 activity downstream of Gα<SUB>12</SUB> and Gα<SUB>13</SUB>. In summary, Gα<SUB>12</SUB> and Gα<SUB>13</SUB> regulate the expression of the TGFβ1 gene through an increase in Rho/Rac-dependent AP-1 activity, implying that the G-protein-coupled receptor (GPCR)-Gα<SUB>12</SUB> pathway is involved in the TGFβ1-mediated transdifferentiation process.Oncogene (2009) 28, 1230–1240; doi:10.1038/onc.2008.488; published online 19 January 2009
Kim, H.H.,Matthijnssens, J.,Kim, H.J.,Kwon, H.J.,Park, J.G.,Son, K.Y.,Ryu, E.H.,Kim, D.S.,Lee, W.S.,Kang, M.I.,Yang, D.K.,Hyun, B.H.,Park, S.I.,Park, S.J.,Cho, K.O. Elsevier Science 2012 INFECTION GENETICS AND EVOLUTION Vol.12 No.7
Group A rotaviruses (RVAs) are agents causing severe gastroenteritis in infants and young animals. G9 RVA strains are believed to have originated from pigs. However, this genotype has emerged as the fifth major human RVA genotype worldwide. To better understand the relationship between human and porcine RVA strains, complete RVA genome data are needed. For human RVA strains, the number of complete genome data have grown exponentially. However, there is still a lack of complete genome data on porcine RVA strains. Recently, G9 RVA strains have been identified as the third most important genotype in diarrheic pigs in South Korea in combinations with P[7] and P[23]. This study is the first report on complete genome analyses of 1 G9P[7] and 3 G9P[23] porcine RVA strains, resulting in the following genotype constellation: G9-P[7]/P[23]-I5-R1-C1-M1-A8-N1-T1-E1-H1. By comparisons of these genotype constellations, it was revealed that the Korean G9P[7] and G9P[23] RVA strains possessed a typical porcine RVA backbone, similar to other known porcine RVA strains. However, detailed phylogenetic analyses revealed the presence of intra-genotype reassortments among porcine RVA strains in South Korea. Thus, our data provide genetic information of G9 RVA strains increasingly detected in both humans and pigs, and will help to establish the role of pigs as a source or reservoir for novel human RVA strains.
Yin, Q.Q.,Chang, J.,Zuo, R.Y.,Chen, L.Y.,Chen, Q.X.,Wei, X.Y.,Guan, Q.F.,Sun, J.W.,Zheng, Q.H.,Yang, X.,Ren, G.Z. Asian Australasian Association of Animal Productio 2010 Animal Bioscience Vol.23 No.2
In order to improve the availability of phytase and probiotics together, a phytase gene from Aspergillus ficuum has been expressed in Lactobacillus. In this study, the transformed Lactobacillus with phytase gene was fed to pigs to determine its effect on pig production, feed conversion and gut microbes. Forty eight, 60-day-old, castrated pigs (Duroc${\times}$Landrace${\times}$Pietrain) were assigned to 6 groups, 8 pigs for each group. Group 1 was the control, group 2 was added with chlortetracycline (500 mg/kg), group 3 was added with the transformed Lactobacillus (500 mg/kg) with 20% (w/w) of calcium monohydrogen phosphate (CMP, $CaHPO_{4}$) removed, group 4 was added with the natural Lactobacillus (500 mg/kg) with 20% (w/w) of CMP removed, group 5 was added with the transformed Lactobacillus (500 mg/kg) with 40% (w/w) of CMP removed, group 6 was added with phytase (500 mg/kg) with 40% (w/w) of CMP removed. The results showed: i) the average daily gain (ADG) was improved in groups 2, 3 and 4 (p<0.05); ii) the diarrhea rates in the groups added with Lactobacillus were lower than in the other groups (p<0.05), in which the transformed Lactobacillus had more effect on reducing digestive disease; iii) the transformed Lactobacillus was most effective in improving the digestibilities of crude protein (CP), calcium (Ca), phosphorus (P), compared with the other groups (p<0.05); iv) Lactobacillus could increase lactic acid bacterium number and ammonia concentrations, and decrease pH values and E. coli number in pig feces (p<0.05); v) the phytase activity in the feces of pigs fed with the transformed Lactobacillus was 133.32 U/g, which was higher than in group 4 (9.58 U/g, p<0.05), and was almost the same as group 6 (135.94 U/g); vi) the transformed Lactobacillus could increase serum concentrations of IgA, triglyceride, and glutamic oxaloacetic transaminase activity (p<0.05), and had no significant effect on other serum indexes (p>0.05).