Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-6 (IL-6) is a multifunctional cytokine playing roles in the immune system, hematopoiesis, and acute phase reactions. IL-6 also regulates the growth of various types of human malignant tumors. Here we demonstrate that IL-6-induced gene expression was suppressed by a specific heat-shock protein 90 (Hsp90) inhibitor, geldanamycin (GA) in human hepatoma Hep3B cells. GA also suppressed the IL-6-induced activation of signal transducer and activator of transcription 3 (STAT3) in a human embryonic kidney carcinoma 293T cells. This inhibitory effect of GA on STAT3 activation was reversed by overexpression of Hsp90. Furthermore, Hsp90 directly bound to STAT3 via its N-terminal region, which interacted with GA. We provide evidence that the action of GA on IL-6 functions was due to the inhibition of direct physical interactions between STAT3 and Hsp90, which represents a novel role of Hsp90 in the IL-6 signaling pathways.
 ...
PMID:Involvement of heat-shock protein 90 in the interleukin-6-mediated signaling pathway through STAT3. 1255 50

Signal transducer and activator of transcription 3 (Stat3) dimerization is commonly thought to be triggered by its tyrosine phosphorylation in response to interleukin-6 (IL-6) or other cytokines. Accumulating evidence from in vitro studies, however, suggests that cytoplasmic Stat3 may be associated with high-molecular-mass protein complexes and/or dimerize prior to its activation. To directly study Stat3 dimerization and subcellular localization upon cytokine stimulation, we used live-cell fluorescence spectroscopy and imaging microscopy combined with fluorescence resonance energy transfer (FRET). Stat3 fusion proteins with spectral variants of green fluorescent protein (GFP), cyan fluorescent protein (CFP) and yellow fluorescent protein (YFP) were constructed and expressed in human hepatoma cells (HepG2) and human embryonic kidney cells (HEK-293). Like wild-type Stat3, the fusion proteins redistributed from a preferentially cytoplasmic to nuclear localization upon IL-6 stimulation and supported IL-6-dependent target gene expression. FRET studies in cells co-expressing Stat3-CFP and Stat3-YFP demonstrated that Stat3 dimers exist in the absence of tyrosine phosphorylation. IL-6 induced a 2-fold increase of this basal FRET signal, indicating that tyrosine phosphorylation either increases the dimer/monomer ratio of Stat3 or induces a conformational change of the dimer yielding a higher FRET efficiency. Studies using a mutated Stat3 with a non-functional src-homology 2 (SH2) domain showed that the SH2 domain is essential for dimer formation of phosphorylated as well as non-phosphorylated Stat3. Furthermore, our data show that visualization of normalized FRET signals allow insights into the spatiotemporal dynamics of Stat3 signal transduction.
 ...
PMID:Analysis of Stat3 (signal transducer and activator of transcription 3) dimerization by fluorescence resonance energy transfer in living cells. 1297 72

Signal transducer and activator of transcription 3 (STAT3) is a recently characterized transcription factor which is essential to liver regeneration. We have previously reported that hepatic stimulator substance (HSS), a novel growth-promoting substance, phosphorylated the epidermal growth factor (EGF) receptors and activated downstream Ras-MAP kinase (extracellular signal-regulated kinases, ERK1/2) cascade. However, whether HSS signal is related to STAT3 pathway remains unclear. The present study is aiming to explore the regulatory effect of activation of ERK1/2 evoked by HSS on STAT3 phosphorylation and STAT3 signaling. Human hepatoma cell line HepG2 was stably transfected with HSS cDNA and HSS expression was measured by Northern blot. The results showed that the transfection of HSS into HepG2 resulted in remarkable increase in cellular proliferation as compared with the non-transfected cells, and it was further proved that the cellular proliferation in the HSS-transfected cells was related to ERK1/2 activation. Treatment of the cells with 50 mM of PD98059, an ERK1/2 specific upstream inhibitor, resulted in ERK1/2 inactivation completely. Inhibition of ERK1/2 allowed the tyrosine of STAT3 to be phosphorylated in a dose-dependent manner to PD98059. Furthermore, transient transfection of STAT3 mutant (STAT3S727A) into HSS-bearing cells could remarkably reverse the inhibitory effect of ERK1/2 on STAT3 phosphorylation. Based upon these results, it is concluded that ERK1/2 negatively modulates STAT3 phosphorylation and this function is dependent on residual serine-727 (S727) of STAT3.
 ...
PMID:ERK1/2 contributes negative regulation to STAT3 activity in HSS-transfected HepG2 cells. 1511 15

Adiponectin, a major adipose cytokine, plays a crucial role in the inhibition of metabolic syndrome by acting on such cell types as muscle cells and hepatocytes. Furthermore, evidence suggests that adiponectin may influence cancer pathogenesis. Adiponectin occurs in non-proteolytic (full-length adiponectin: f-adiponectin) and proteolytic (globular adiponectin: g-adiponectin) forms in various oligomeric states. Different forms of adiponectin show distinct biological effects through differential activation of downstream signaling pathways. Here we identify c-Jun NH(2)-terminal kinase (JNK), and signal transducer and activator of transcription 3 (STAT3) as common downstream effectors of f- and g-adiponectin. f- and g-adiponectin both stimulate JNK activation in prostate cancer DU145, PC-3, and LNCaP-FGC cells, hepatocellular carcinoma HepG2 cells, and C2C12 myoblasts. Furthermore, both f- and g-adiponectin drastically suppress constitutive STAT3 activation in DU145 and HepG2 cells. These suggest that JNK and STAT3 may constitute a universal signaling pathway to mediate adiponectin's pathophysiological effects on metabolic syndrome and cancer.
 ...
PMID:Adiponectin activates c-Jun NH2-terminal kinase and inhibits signal transducer and activator of transcription 3. 1593 15

Signal transducer and activator of transcription 3 (STAT3), which mediates biological actions in many physiological processes, is activated by cytokines and growth factors, and has been reported to be constitutively activated in numerous cancer cells. In this study, we examined whether low molecular weight-dual specificity phosphatase two (LMW-DSP2) is involved in the regulation of the interleukin 6 (IL-6)/leukemia inhibitory factor (LIF)/STAT3-mediated signaling pathway. IL-6/LIF-induced LMW-DSP2 expression in murine testicular or hepatoma cell lines, while LMW-DSP2 overexpression in 293T cells suppressed IL-6-induced phosphorylation and activation of STAT3. Furthermore, LMW-DSP2 suppressed the expression of IL-6-induced endogenous genes. In contrast, small-interfering RNA-mediated reduction of LMW-DSP2 expression enhanced IL-6-induced STAT3-dependent transcription. In fact, LMW-DSP2 interacted with STAT3 in vivo and endogenous LMW-DSP2 bound to STAT3 in murine testicular GC-1 cells. These results strongly suggest that LMW-DSP2 acts as a negative regulator of the IL-6/LIF/STAT3-mediated signaling pathway.
 ...
PMID:Regulation of STAT3-mediated signaling by LMW-DSP2. 1663 63

In this study, we have investigated the underlying molecular mechanism for the potent proapoptotic effect of luteolin on human hepatoma cells both in vitro and in vivo, focusing on the signal transducer and activator of transcription 3 (STAT3)/Fas signaling. A clear apoptosis was found in the luteolin-treated HLF hepatoma cells in a time- and dosage-dependent manner. In concert with the caspase-8 activation by luteolin, an enhanced expression in functional Fas/CD95 was identified. Consistent with the increased Fas/CD95 expression, a drastic decrease in the Tyr(705) phosphorylation of STAT3, a known negative regulator of Fas/CD95 transcription, was found within 20 minutes in the luteolin-treated cells, leading to down-regulation in the target gene products of STAT3, such as cyclin D1, survivin, Bcl-xL, and vascular endothelial growth factor. Of interest, the rapid down-regulation in STAT3 was consistent with an accelerated ubiquitin-dependent degradation in the Tyr(705)-phosphorylated STAT3, but not the Ser(727)-phosphorylated one, another regulator of STAT3 activity. The expression level of Ser(727)-phosphorylated STAT3 was gradually decreased by the luteolin treatment, followed by a fast and clear down-regulation in the active forms of CDK5, which can phosphorylate STAT3 at Ser(727). An overexpression in STAT3 led to resistance to luteolin, suggesting that STAT3 was a critical target of luteolin. In nude mice with xenografted tumors using HAK-1B hepatoma cells, luteolin significantly inhibited the growth of the tumors in a dosage-dependent manner. These data suggested that luteolin targeted STAT3 through dual pathways-the ubiquitin-dependent degradation in Tyr(705)-phosphorylated STAT3 and the gradual down-regulation in Ser(727)-phosphorylated STAT3 through inactivation of CDK5, thereby triggering apoptosis via up-regulation in Fas/CD95.
 ...
PMID:Luteolin promotes degradation in signal transducer and activator of transcription 3 in human hepatoma cells: an implication for the antitumor potential of flavonoids. 1665 38

In murine models of Crohn's disease, rheumatoid arthritis and colon cancer, IL-6 (interleukin-6) signalling via the sIL-6R (soluble IL-6 receptor; termed IL-6 trans-signalling) has been shown to promote the pathology associated with these conditions. These detrimental activities can, however, be selectively blocked by soluble forms of the gp130 (glycoprotein 130) receptor. Although sgp130 (soluble gp130) therefore represents a viable therapeutic modality for the treatment of these conditions, the mass manufacture of such biologics is often expensive. The advent of molecular farming has, however, provided an extremely cost-effective strategy for the engineering of recombinant proteins. Here, we describe the expression and production of a biologically active sgp130 variant that is expressed in transgenic tobacco plants as an ELP (elastin-like peptide)-fusion protein (mini-gp130-ELP). Mini-gp130-ELP consists of the first three domains of gp130 (Ig-like domain and cytokine binding module) fused to 100 repeats of ELP. Expression of mini-gp130-ELP did not affect the growth rate or morphology of the transgenic plants, and purification was achieved using inverse transition cycling. This approach led to an overall yield of 141 microg of purified protein per g of fresh leaf weight. The purified mini-gp130-ELP specifically inhibited sIL-6R-mediated trans-signalling as measured by binding to the IL-6-sIL-6R complex and through its ability to block sIL-6R-mediated activation of STAT3 (signal transducer and activator of transcription 3) phosphorylation and proliferation in human hepatoma cells and murine pre-B-cells. Consequently, the present study validates the potential application of molecular farming in transgenic tobacco plants as a strategy for the expression and purification of therapeutically advantageous biologics such as sgp130.
 ...
PMID:Functional expression of a biologically active fragment of soluble gp130 as an ELP-fusion protein in transgenic plants: purification via inverse transition cycling. 1671 47

Des-gamma-carboxyl prothrombin (DCP) is a well recognized tumor marker for hepatocellular carcinoma. Previously, we have demonstrated that DCP stimulates cell proliferation in hepatocellular carcinoma cell lines through Met-Janus kinase 1 signal transducer and activator of transcription 3 signaling pathway. In the present study, we demonstrated that DCP induces both cell proliferation and migration in human umbilical vein endothelial cells. DCP was found to bind with the kinase insert domain receptor (KDR), alternatively referred to as vascular endothelial growth factor receptor-2. Furthermore, DCP induced autophosphorylation of KDR and its downstream effector phospholipase C-gamma and mitogen-activated protein kinase (MAPK). To support these results, we showed that DCP-induced cell proliferation and cell migration were inhibited by KDR short interfering RNA, KDR kinase inhibitor, or MAPK inhibitor. In conclusion, these results indicate that DCP is a novel type of vascular endothelial growth factor that possesses potent mitogenic and migrative activities.
 ...
PMID:Des-gamma-carboxyl prothrombin-promoted vascular endothelial cell proliferation and migration. 1725 2

Auranofin (AF) is a sulphur-containing gold compound. Because of its anti-inflammatory and immunosuppressive activities, AF has been widely used for the therapeutic treatment of rheumatoid arthritis. However, little is known about its mechanism of action. To elucidate the molecular mechanism underlying the anti-inflammatory effect of AF, we studied the effects of AF on cellular responses to interleukin-6 (IL-6). In HepG2 human hepatoma cells, AF markedly inhibited IL-6-induced phosphorylation of janus kinase 1 (JAK1) and signal transducer and activator of transcription 3 (STAT3) and STAT3 translocation into the nucleus. Consistent with this, AF diminished IL-6-induced production of the acute-phase proteins, haptoglobin, fibrinogen, C3 complement and alpha(1)-acid glycoprotein, and gene expression of vascular endothelial growth factor, all of whose transcriptional activities are regulated by STAT3. The inhibitory activity of AF on STAT3 phosphorylation was also demonstrated in primary cells, i.e. fibroblast-like synoviocytes from rheumatoid arthritis patients, human umbilical vein endothelial cells and rat astrocytes. Auranofin-mediated inhibition of STAT3 phosphorylation was recovered by pretreatment with antioxidants containing thiol groups. These findings suggest that the anti-inflammatory action of AF is associated with a blockade of JAK1/STAT3 signalling. Thiol-group-reactive proteins may be involved in AF-induced suppression of JAK1/STAT3 phosphorylation.
 ...
PMID:Auranofin blocks interleukin-6 signalling by inhibiting phosphorylation of JAK1 and STAT3. 1764 97

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in various cancers and plays a crucial role in oncogensis, including the activation of genes encoding apoptosis inhibitors and cell-cycle regulators. We investigated the biological significance of the Janus kinase (Jak)-STAT pathway in human hepatocellular carcinoma (HCC). Constitutive activation of STAT3 was seen in 49.4% of human HCC specimens and in HCC cell lines. Jak inhibitor AG490 inhibited activation of STAT3 and markedly reduced cell viability without significant apoptosis. AG490 also induced S phase cell-cycle arrest with down-regulation of cyclin D1, A, E and up-regulation of p21, p27, phospho-Chk2. AG490 also inhibited caspase inhibitory proteins, such as XIAP and survivin, and augmented TRAIL-induced apoptosis. Our study suggests that the Jak-STAT pathway plays an important role in cell-cycle progression and resistance to apoptosis. Inhibition of the Jak-STAT pathway may thus be a therapeutic target for HCC.
 ...
PMID:Jak inhibitor induces S phase cell-cycle arrest and augments TRAIL-induced apoptosis in human hepatocellular carcinoma cells. 1790 24


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>