Oncostatin M Inhibits Proliferation of Rat Oval Cells, OC15-5, Inducing Differentiation into Hepatocytes

Okaya, Atsuhito; Kitanaka, Junichi; Kitanaka, Nobue; Satake, Makoto; Kim, Yuna; Terada, Kunihiko; Sugiyama, Toshihiro; Takemura, Masashi; Fujimoto, Jiro; Terada, Nobuyuki; Miyajima, Atsushi; Tsujimura, Tohru

doi:10.1016/s0002-9440(10)62292-4

Cited by 45 publications

(31 citation statements)

References 30 publications

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“…To construct a vector expressing siRNA for NS siRNA and hTERT siRNA, the annealed oligonucleotides gatcccgTTCTCCGAACGTGTCACGTttcaagagaACG TGACACG TTCGGAGAAttttttccaaaagctt and 5'ggatcccgGCATTCCTGCT-CAAGCT aagagaTCAGCTTGAGCAGGAATGCttttttccaaaagctt) (target sequences in capital letters) were subcloned into the pRNAT-U6.1/Neo vector 11,12 (GenScript, Scotch Plains, NJ). This vector carries a neomycin resistance gene for establishing stable cell lines and a coral green fluorescent protein (cGFP) marker under CMV promoter control to track transfection efficiency.…”

Section: Methodsmentioning

confidence: 99%

hTERT-targeted RNA interference inhibits tumorigenicity and motility of HCT116 cells

Shen¹,

Zhang²,

Zhang³

et al. 2008

Cancer Biology & Therapy

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Telomerase is proposed as an anticancer target. Increasing evidence suggests that telomerase is involved in functions independent of telomere-extension activity. In this study, we designed a small interfering RNA (siRNA) targeting human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase. Using transient and persistent transfection of hTERT siRNA into telomerase-positive human colon carcinoma HCT116 cells, we demonstrated that hTERT siRNA suppresses hTERT expression and leads to inhibition of telomerase activity and HCT116 cell growth and in vivo tumorigenicity in nude mice. Further analysis indicated that depletion of hTERT reduces cell adhesion, migration, and invasion prior to inhibition of cell proliferation. Downregulation of hTERT also decreased the expression levels of adhesion-and motility-related proteins, in particular c-Met and integrins. The lack of detectable changes in telomere length showed that downregulation of hTERT in the present system had no significant effect on telomere-extension activity. Taken together, our results highlight the therapeutic potential of a novel hTERT siRNA and suggest that hTERT is involved in the regulation of cell motility in a telomere-independent manner.

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Section: Methodsmentioning

confidence: 99%

hTERT-targeted RNA interference inhibits tumorigenicity and motility of HCT116 cells

Shen¹,

Zhang²,

Zhang³

et al. 2008

Cancer Biology & Therapy

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“…To study the possibility of manipulating cellular phenotype, which will be helpful in many situations, we transduced P2-P6 fetal liver cells with GFP lentivirus vector using Alb, TTR and PGK promoters and cultured cells for up to 2 weeks in the presence or absence of fetal bovine serum (FBS), hHGF and oncostatin M (OSM) to regulate cell growth and differentiation (Schwartz et al, 2002;Shahdadfar et al, 2005;Okaya et al, 2005). Control cells cultured with FBS again showed flattened morphologies, although culture with OSM or without serum produced less spindle-like and more rounded morphology (Fig.…”

Section: Reversible Elements In Mesoendodermal Phenotype Switchmentioning

confidence: 99%

Phenotype reversion in fetal human liver epithelial cells identifies the role of an intermediate meso-endodermal stage before hepatic maturation

Inada

Follenzi

Cheng

et al. 2008

Journal of Cell Science

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Understanding the biological potential of fetal stem/progenitor cells will help define mechanisms in liver development and homeostasis. We isolated epithelial fetal human liver cells and established phenotype-specific changes in gene expression during continuous culture conditions. Fetal human liver epithelial cells displayed stem cell properties with multilineage gene expression, extensive proliferation and generation of mesenchymal lineage cells, although the initial epithelial phenotype was rapidly supplanted by meso-endodermal phenotype in culture. This meso-endodermal phenotype was genetically regulated through cytokine signaling, including transforming growth factor β, bone morphogenetic protein, fibroblast growth factor and other signaling pathways. Reactivation of HNF3α (FOXA1) transcription factor, a driver of hepatic specification in the primitive endoderm, indicated that the meso-endodermal phenotype represented an earlier developmental stage of cells. We found that fetal liver epithelial cells formed mature hepatocytes in vivo, including after genetic manipulation using lentiviral vectors, offering convenient assays for analysis of further cell differentiation and fate. Taken together, these studies demonstrate plasticity in fetal liver epithelial stem cells, offer paradigms for defining mechanisms regulating lineage switching in stem cells, and provide potential avenues for regulating cell phenotypes for applications of stem cells, such as for cell therapy.

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“…To examine the effect of OSM cDNA introduction on the physiological condition of rats, we injected HVJ-OSM, prepared from pEF-BOS with rat OSM cDNA 22 by HVJ Envelope Vector kit (GenomONE-Neo; Ishihara Industry Corp., Osaka, Japan) according to the manufacturer's protocol, or the HVJ envelope complex without rat OSM cDNA (hereafter called HVJ-Vector) into rats (n ϭ 12) weekly for 3 weeks. On the next day of the last injection, rats were sacrificed, blood was taken from the right ventricle of hearts, and sera were prepared and stored at Ϫ80°C until analysis.…”

Section: Rats and Treatmentsmentioning

confidence: 99%

“…22 In this study, we examined whether the introduction of this OSM cDNA enhances liver regeneration and suppresses fibrogenesis in rats administrated with dimethylnitrosamine (DMN). Repeated injection of HVJ envelope complex 23 with rat OSM cDNA (hereafter called HVJ-OSM) into the spleen reduced centrilobular necrosis and inflammatory cell infiltration, induced hepatocyte proliferation, and suppressed hepatocyte apoptosis.…”

mentioning

confidence: 99%

Oncostatin M Gene Therapy Attenuates Liver Damage Induced by Dimethylnitrosamine in Rats

Hamada

Sato

Hirano

et al. 2007

The American Journal of Pathology

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To assess the usefulness of oncostatin M (osm) gene therapy in liver regeneration, we examined whether the introduction of OSM cDNA enhances the regeneration of livers damaged by dimethylnitrosamine (DMN) in rats. Repeated injection of OSM cDNA enclosed in hemagglutinating virus of Japan envelope into the spleen resulted in the exclusive expression of OSM protein in Kupffer cells of the liver, which was accompanied by increases in body weight, liver weight, and serum albumin levels and the reduction of serum liver injury parameters (bilirubin, aspartate aminotransferase, and alanine aminotransferase) and a serum fibrosis parameter (hyaluronic acid). Histological examination showed that osm gene therapy reduced centrilobular necrosis and inflammatory cell infiltration and augmented hepatocyte proliferation. The apoptosis of hepatocytes and fibrosis were suppressed by osm gene therapy. Time-course studies on osm gene therapy before or after DMN treatment showed that this therapy was effective not only in enhancing regeneration of hepatocytes damaged by DMN but in preventing hepatic cytotoxicity caused by subsequent treatment with DMN. These results indicate that OSM is a key mediator for proliferation and anti-apoptosis of hepatocytes and suggest that osm gene therapy is useful , as preventive and curative means , for the treatment of patients with liver damage. The liver has a remarkable ability to respond to injuries inflicted by various causes, such as partial hepatectomy, toxic exposure, and virus infection.1,2 Hepatocytes, which are liver parenchymal cells and normally in the quiescent G 0 phase, re-enter the cell cycle after injury to restore its mass, architecture, and function. In this process, a number of growth factors and cytokines have been reported to be involved. [3][4][5][6][7][8][9] For example, hepatocyte growth factor (HGF) functions as a potent mitogen for hepatocytes, 10 and the administration of HGF has been shown to ameliorate hepatic injury in animal models of fulminant hepatic failure. [11][12][13] It has also been shown that the introduction of hgf gene into rat cirrhotic livers using liposome with the hemagglutinating virus of Japan (HVJ) inhibits fibrogenesis and hepatocyte apoptosis, leading to the complete resolution of fibrosis and improvement of survival rate.14 Oncostatin M (OSM) is a member of the interleukin (IL)-6 cytokine family that includes IL-6, IL-11, leukemia inhibitory factor, ciliary neurotrophic factor, cardiotrophin-1, and novel neutrophin-1/B-cell-stimulating factor-3. [15][16][17][18] Mouse OSM receptor is composed of the gp130 subunit, common to all of the IL-6 family cytokines, and an OSM-specific subunit (hereafter called OSM-specific receptor; OSM-R).19 Binding of OSM to its receptor complex activates Janus tyrosine kinases (Jak1, Jak2, and Tyk2), which in turn activates downstream signaling pathways, including SHP-2 tyrosine phosphatase and signal transducer and activator of transcription protein 3 (STAT3). Recently, OSM has been shown to induce maturation of mou...

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Oncostatin M Inhibits Proliferation of Rat Oval Cells, OC15-5, Inducing Differentiation into Hepatocytes

Cited by 45 publications

References 30 publications

hTERT-targeted RNA interference inhibits tumorigenicity and motility of HCT116 cells

hTERT-targeted RNA interference inhibits tumorigenicity and motility of HCT116 cells

Phenotype reversion in fetal human liver epithelial cells identifies the role of an intermediate meso-endodermal stage before hepatic maturation

Oncostatin M Gene Therapy Attenuates Liver Damage Induced by Dimethylnitrosamine in Rats

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