Acyclic retinoid targets platelet-derived growth factor signaling in the prevention of hepatic fibrosis and hepatocellular carcinoma development
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE29302 | GEO | 2012/08/19
SECONDARY ACCESSION(S): PRJNA138633
REPOSITORIES: GEO
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Project description:Gene expression profiling in non tumor lesion in the liver of patients prior to administering peretinoin was unrelated to the clinical outcome, however, gene expression profiling 8 weeks after starting peretinoin therapy significantly predicted the recurrence of HCC Peretinoin, a member of the acyclic retinoid family, is expected to be an effective chemo preventive drug for HCC.The patients had undergone curative surgical resection or radiofrequency ablation (RFA). They received 300 mg/day or 600 mg/day of peretinoin for 8 weeks and were followed up for 88 weeks with 600 mg/day of peretinoin. Hepatic gene expression profiling obtained from non tumor lesion of these patients prior to administering peretinoin and 8 weeks after starting peretinoin treatment
2012-08-19 | E-GEOD-29302 | biostudies-arrayexpress
Project description:The high rates of hepatocellular carcinoma (HCC) recurrence after initially successful curative therapy emphasize ongoing unmet needs to prevent or reduce HCC recurrence. Retinoid acid (RA), a metabolite of vitamin A and its related analogues (termed retinoids) has been suggested as a promising chemotherapeutic agent in cancer treatment. The synthetic oral retinoid peretinoin is the only agent for the secondary chemoprevention of HCC after curative therapy that is currently well applied into clinical development. Here we present an updated summary of the molecular pathogenesis of HCC and of preclinical and clinical findings with peretinoin, including its clinical characteristics, safety and tolerability profile and future perspectives for clinical use.
| S-EPMC7827668 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is a highly lethal cancer that has a high rate of recurrence, in part because of cancer stem cell (CSC)-dependent field cancerization. Acyclic retinoid (ACR) is a synthetic vitamin A-like compound capable of preventing the recurrence of HCC. Here, we performed a genome-wide transcriptome screen and showed that ACR selectively suppressed the expression of MYCN, a member of the MYC family of basic helix-loop-helix-zipper transcription factors, in HCC cell cultures, animal models, and liver biopsies obtained from HCC patients. MYCN expression in human HCC was correlated positively with both CSC and Wnt/?-catenin signaling markers but negatively with mature hepatocyte markers. Functional analysis showed repressed cell-cycle progression, proliferation, and colony formation, activated caspase-8, and induced cell death in HCC cells following silencing of MYCN expression. High-content single-cell imaging analysis and flow cytometric analysis identified a MYCN+ CSC subpopulation in the heterogeneous HCC cell cultures and showed that these cells were selectively killed by ACR. Particularly, EpCAM+ cells isolated using a cell-sorting system showed increased MYCN expression and sensitivity to ACR compared with EpCAM- cells. In a long-term (>10 y) follow-up study of 102 patients with HCC, MYCN was expressed at higher levels in the HCC tumor region than in nontumor regions, and there was a positive correlation between MYCN expression and recurrence of de novo HCC but not metastatic HCC after curative treatment. In summary, these results suggest that MYCN serves as a prognostic biomarker and therapeutic target of ACR for liver CSCs in de novo HCC.
| S-EPMC5949003 | biostudies-literature
Project description:To better understand the molecular basis of the anticancer effects of acyclic retinoid (ACR), a genome-wide screening was applied to identify novel targets of ACR in human hepatocellular carcinoma (HCC) cells JHH7. Gene expression profiles of JHH7 were measured at 0h, 1h and 4 hours after treatment with1 μM All-trans retinoic acid (AtRA) or 10 μM ACR. Hierarchical clustering with Ward’s method of 44,907 genes demonstrated diverse expression changes in HCC cells treated with ACR for 4h. A total of 973 differentially expressed genes in response to ACR by comparing with AtRA for 4h treatments were identified with a fold change more than 2. Then, network analysis was performed on the altered gene expression profiles using Ingenuity Pathways Analysis (IPA) program. The most highly populated networks were associated with the regulation of cell cycle and DNA replication, as ACR is well known to induce apoptosis and suppress cell proliferation in HCC cells. Moreover, networks related with amino acid metabolism, protein synthesis and lipid metabolism, such as the biological network entitled “Lipid Metabolism, Small Molecular Biochemistry, Vitamin and Mineral Metabolism” were also observed. Of interest, this network contains genes that play critical roles in controlling the development of tissues and organs such as the nuclear orphan receptor nuclear receptor subfamily 2, group F, member 2 (NR2F2), suggesting potential drug targets to prevent/treat HCC.
2015-08-08 | GSE71856 | GEO
Project description:Acyclic retinoid induction of HepG2 cells Keywords: other
2004-04-03 | GSE931 | GEO
Project description:To better understand the molecular basis of the anticancer effects of acyclic retinoid (ACR), a genome-wide screening was applied to identify novel targets of ACR in human hepatocellular carcinoma (HCC) cells JHH7. Gene expression profiles of JHH7 were measured at 0h, 1h and 4 hours after treatment with1 μM All-trans retinoic acid (AtRA) or 10 μM ACR. Hierarchical clustering with Ward’s method of 44,907 genes demonstrated diverse expression changes in HCC cells treated with ACR for 4h. A total of 973 differentially expressed genes in response to ACR by comparing with AtRA for 4h treatments were identified with a fold change more than 2. Then, network analysis was performed on the altered gene expression profiles using Ingenuity Pathways Analysis (IPA) program. The most highly populated networks were associated with the regulation of cell cycle and DNA replication, as ACR is well known to induce apoptosis and suppress cell proliferation in HCC cells. Moreover, networks related with amino acid metabolism, protein synthesis and lipid metabolism, such as the biological network entitled “Lipid Metabolism, Small Molecular Biochemistry, Vitamin and Mineral Metabolism” were also observed. Of interest, this network contains genes that play critical roles in controlling the development of tissues and organs such as the nuclear orphan receptor nuclear receptor subfamily 2, group F, member 2 (NR2F2), suggesting potential drug targets to prevent/treat HCC. Gene expression profiles of JHH7 were measured at 0h, 1h and 4 hours after treatment with 1μM AtRA or 10 μM ACR.
2015-08-08 | E-GEOD-71856 | biostudies-arrayexpress
Project description:Background/purposeAcyclic retinoid (ACR) is a promising chemopreventive agent for hepatocellular carcinoma (HCC) that selectively inhibits the growth of HCC cells (JHH7) but not normal hepatic cells (Hc). To better understand the molecular basis of the selective anti-cancer effect of ACR, we performed nuclear magnetic resonance (NMR)-based and capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS)-based metabolome analyses in JHH7 and Hc cells after treatment with ACR.Methodology/principal findingsNMR-based metabolomics revealed a distinct metabolomic profile of JHH7 cells at 18 h after ACR treatment but not at 4 h after ACR treatment. CE-TOFMS analysis identified 88 principal metabolites in JHH7 and Hc cells after 24 h of treatment with ethanol (EtOH) or ACR. The abundance of 71 of these metabolites was significantly different between EtOH-treated control JHH7 and Hc cells, and 49 of these metabolites were significantly down-regulated in the ACR-treated JHH7 cells compared to the EtOH-treated JHH7 cells. Of particular interest, the increase in adenosine-5'-triphosphate (ATP), the main cellular energy source, that was observed in the EtOH-treated control JHH7 cells was almost completely suppressed in the ACR-treated JHH7 cells; treatment with ACR restored ATP to the basal levels observed in both EtOH-control and ACR-treated Hc cells (0.72-fold compared to the EtOH control-treated JHH7 cells). Moreover, real-time PCR analyses revealed that ACR significantly increased the expression of pyruvate dehydrogenase kinases 4 (PDK4), a key regulator of ATP production, in JHH7 cells but not in Hc cells (3.06-fold and 1.20-fold compared to the EtOH control, respectively).Conclusions/significanceThe results of the present study suggest that ACR may suppress the enhanced energy metabolism of JHH7 cells but not Hc cells; this occurs at least in part via the cancer-selective enhancement of PDK4 expression. The cancer-selective metabolic pathways identified in this study will be important targets of the anti-cancer activity of ACR.
| S-EPMC3871542 | biostudies-literature
Project description:BackgroundHepatocellular carcinoma has a high mortality rate due to its rate of recurrence. Acyclic retinoid prevents recurrence of hepatocellular carcinoma in patients after surgical removal of their primary tumors by inducing apoptosis in hepatocellular carcinoma cells, although the molecular mechanisms of action are not understood.MethodsHuman hepatocellular carcinoma cells in culture, as well as nude mice transplanted with hepatocellular carcinoma cells and rats given with N-diethylnitrosamine were treated with acyclic retinoid. Changes in activated caspase 3 and transglutaminase 2 (TG2) levels, Sp1 cross-linking and its activities, expression of epidermal growth factor receptor, and apoptotic levels were measured.ResultsAcyclic retinoid simultaneously stimulated the activation of caspase 3, and the expression, nuclear localization and crosslinking activity of TG2, resulting in crosslinking and inactivation of the transcription factor, Sp1, thereby reducing expression of epidermal growth factor receptor and cell death in three hepatocellular carcinoma cell lines. These effects were partially restored by a caspase inhibitor, transfection of antisense TG2, restoration of functional Sp1, or an excess of epidermal growth factor. Nuclear expression of TG2 and crosslinked Sp1, as also activated caspase 3 were found in both hepatocellular carcinoma cells transplanted into nude mice and cancerous regions within the liver in N-diethylnitrosamine-induced hepatocarcinogenesis model in rats, following treatment of animals with acyclic retinoid.ConclusionsTreatment with acyclic retinoid produces a dual activation of caspase 3 and TG2 induced apoptosis of hepatocellular carcinoma cells via modification and inactivation of Sp1, resulting in reduced expression of epidermal growth factor receptor.
| S-EPMC3024303 | biostudies-literature
Project description:Acyclic retinoid induction of HepG2 cells
2010-06-09 | E-GEOD-931 | biostudies-arrayexpress
Project description:Nuclear accumulation of transglutaminase 2 (TG2) is an important step in TG2-dependent cell death. However, the underlying molecular mechanisms for nuclear translocation of TG2 are still poorly understood. In this study, we demonstrated that acyclic retinoid (ACR) induced nuclear accumulation of TG2 in JHH-7 cells, a hepatocellular carcinoma (HCC) leading to their apoptosis. We further demonstrated molecular mechanism in nuclear-cytoplasmic trafficking of TG2 and an effect of ACR on it. We identified a novel 14-amino acid nuclear localization signal (NLS) (466)AEKEETGMAMRIRV(479) in the 'C' domain and a leucine-rich nuclear export signal (NES) (657)LHMGLHKL(664) in the 'D' domain that allowed TG2 to shuttle between the nuclear and cytosolic milieu. Increased nuclear import of GAPDH myc-HIS fused with the identified NLS was observed, confirming its nuclear import ability. Leptomycin B, an inhibitor of exportin-1 as well as point mutation of all leucine residues to glutamine residues in the NES of TG2 demolished its nuclear export. TG2 formed a trimeric complex with importin-α and importin-β independently from transamidase activity which strongly suggested the involvement of a NLS-based translocation of TG2 to the nucleus. ACR accelerated the formation of the trimeric complex and that may be at least in part responsible for enhanced nuclear localization of TG2 in HCC cells treated with ACR.
| S-EPMC4720877 | biostudies-literature