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

Resistance to growth inhibitory effects of transforming growth factor (TGF)-beta is a frequent consequence of malignant transformation. On the other hand, serum concentrations of TGF-beta, plasminogen activator inhibitor type 1 (PAI-1), and vascular endothelial growth factor (VEGF) are elevated as tumor progresses. The molecular mechanism of autocrine TGF-beta signaling and its effects on PAI-1 and VEGF production in human hepatocellular carcinoma (HCC) is unknown. TGF-beta signaling involves TGF-beta type I receptor-mediated phosphorylation of serine residues within the conserved SSXS motif at the C-terminus of Smad2 and Smad3. To investigate the involvement of autocrine TGF-beta signal in cell growth, PAI-1 and VEGF production of HCC, we made stable transfectants of human HCC line (HuH-7 cells) to express a mutant Smad2(3S-A), in which serine residues of SSXS motif were changed to alanine. The transfectants demonstrated an impaired Smad2 signaling. Along with the resistance to growth inhibition by TGF-beta, forced expression of Smad2(3S-A) induced endogenous TGF-beta secretion. Moreover, this increased TGF-beta enhanced ligand-dependent signaling through the activated Smad3 and Smad4 complex, and transcriptional activities of PAI-1 and VEGF genes. In conclusion, distortion of autocrine TGF-beta signals in human HCC accelerates their malignant potential by enhancing cell growth as well as PAI-1 and VEGF production.
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PMID:Distortion of autocrine transforming growth factor beta signal accelerates malignant potential by enhancing cell growth as well as PAI-1 and VEGF production in human hepatocellular carcinoma cells. 1270 Jun 66

The transforming growth factor-beta (TGF-beta) and glucocorticoid signaling pathways interact both positively and negatively in regulating a variety of physiological and pathologic processes. We previously reported that liganded glucocorticoid receptor (GR) repressed TGF-beta induction of human plasminogen activator inhibitor-1 gene transcription by directly targeting the transcriptional activation function of Smad3. To identify the domain(s) in the glucocorticoid receptor involved in this repression, we have examined the ability of various GR truncation, deletion, and substitution mutants to repress TGF-beta transactivation in Hep3B human hepatoma cells that lack functional endogenous GR. Partial deletions in the ligand-binding domain (LBD), including the tau2 and tauc regions, greatly reduced or eliminated GR repression, whereas deletion of the N-terminal AF1 (tau1) domain and substitution mutations in the DNA-binding domain had little or no effect. Liganded androgen receptor repressed TGF-beta transactivation, whereas mineralocorticoid receptor did not, and studies with rat GR-mineralocorticoid receptor chimeras confirmed that the GR C-terminal domains were required for repression. RU486, a strong antagonist of transactivation by GR, partially reversed repression by wild type GR. Co-immunoprecipitation experiments in Hep3B cells indicated that physical interaction between GR and Smad3 is necessary but not sufficient for repression. Physical interaction required activation of Smad3 by TGF-beta but not dexamethasone binding to GR. Glutathione S-transferase pull-down assays demonstrated that several regions of the LBD could mediate GR-Smad3 physical interaction. We conclude that the LBD of GR, but not the DNA-binding domain or the N-terminal activation domain, is required for GR-mediated transrepression of TGF-beta transactivation.
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PMID:Identification of glucocorticoid receptor domains involved in transrepression of transforming growth factor-beta action. 1290 38

Mad proteins (Mad1, Mxi1, Mad3, Mad4, Mnt/Rox) are biochemical and biological antagonists of c-Myc oncoprotein. Mad-Max dimers repress the transcription of the same target genes activated by Myc-Max dimers. Despite the critical role of Max and Mad proteins as modulators of c-Myc functions, there are no comparative data on their regulation in vivo. We carried out a systematic analysis of c-myc, max, and mad family expression in a model of synchronized cell proliferation in vivo in adult tissues, that is, rat hepatocytes after partial hepatectomy. We confirmed the previously reported early peak of c-myc expression after hepatectomy but we show that it did not correlate with hepatocyte proliferation as it also occurred in sham-operated animals as a result of surgical stresses. A second peak of c-myc expression was observed later, at the time of the wave of DNA synthesis. No such expression was detected in sham-operated rat quiescent hepatocytes. max expression increased around 4-16 h after hepatectomy, before the peaks of c-myc and DNA synthesis. mxi1 and mad4 were slightly downregulated during liver regeneration. mnt/rox expression did not change. These expression patterns suggest a role of Myc-Max for efficient mitogenic response of hepatocytes. We also analyzed the effects of Myc and Max ectopic expression on the clonogenic growth of the rat hepatoma cells. Expression of c-Myc and Max increased clonogenic growth, whereas the reduction of c-Myc levels by an antisense vector decreased growth. The results suggest nonredundant roles for mad genes in hepatocyte proliferation and point to c-Myc as a putative target for anticancer therapy of liver cancer.
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PMID:Kinetics of myc-max-mad gene expression during hepatocyte proliferation in vivo: Differential regulation of mad family and stress-mediated induction of c-myc. 1475 Feb 13

Activin receptor-like kinase (ALK)7 is a type I serine/threonine kinase receptor of the transforming growth factor (TGF)-beta family of proteins that has similar properties to other type I receptors when activated. To see whether ALK7 can induce apoptosis as can some of the other ALK proteins, we infected the FaO rat hepatoma cell line with adenovirus expressing a constitutively active form of the ALK7. Cells infected with active ALK7 adenovirus showed an apoptotic-positive phenotype, as opposed to those that were infected with a control protein. DNA fragmentation assays and fluorescence-activated cell sorter analysis also indicated that ALK7 infection induced apoptosis in FaO cells. We also confirmed this finding in Hep3B human hepatoma cells by transiently transfecting the constitutively active form of ALK7, ALK7(T194D). Investigation into the downstream targets and mechanisms involved in ALK7-induced apoptosis revealed that the TGF-beta signaling intermediates, Smad2 and -3, were activated, as well as the MAPKs JNK and p38. In addition, caspase-3 and -9 were also activated, and cytochrome c release from the mitochondria was observed. Short interfering RNA-mediated inhibition of Smad3 markedly suppressed ALK7-induced caspase-3 activation. Treatment with protein synthesis inhibitors or the expression of the dominant-negative form of the stress-activated protein/extracellular signal-regulated kinase 1 abolished not only JNK activation but apoptosis as well. Taken together, these results suggest that ALK7 induces apoptosis through activation of the traditional TGF-beta pathway components, thus resulting in new gene transcription and JNK and p38 activation that initiates cross-talk with the cellular stress death pathway and ultimately leads to apoptosis.
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PMID:Activin receptor-like kinase-7 induces apoptosis through activation of MAPKs in a Smad3-dependent mechanism in hepatoma cells. 1510 18

Thyroid hormones regulate growth, development, differentiation, and metabolic processes by interacting with and activating thyroid hormone receptors and associated pathways. We investigated the triiodothyronine (T3) modulation of gene expression, in human hepatocellular carcinoma cell lines, via a PCR-based cDNA subtraction method. Here we present further data on one of the T3-upregulated genes, fibronectin (FN). We demonstrate that the induction of FN protein expression by T3 in TRalpha1 and TRbeta1 over-expressing cells was time and dose-dependent at the mRNA and protein levels. Blockade of protein synthesis by cycloheximide almost completely inhibited the concomitant induction of FN mRNA by T3, indicating that T3 indirectly regulates FN. Furthermore, nuclear-run on and FN promoter assay clearly can specifically increase the number of FN transcriptional demonstrated that the presence of T3 initiations. In addition, we further confirmed that the up-regulation of FN by T3 was mediated, at least in part, by transforming growth factor-beta (TGF-beta), because the induction of FN was blocked in a dose-dependent manner by the addition of TGF-beta neutralizing antibody. In an effort to elucidate the we demonstrated the involvement of the signaling pathways involved in the activation of FN by T3, mitogen activated protein kinase/c-Jun N-terminal kinase/p38 MAPK (MAPK/JNK/p38) pathway. Although T3 induces the expression of TGF-beta, neither wild-type nor dominant-negative Smad3 or Smad4 over-expression affected the activation of FN by T3. Thus, we demonstrate that T3 regulates FN gene expression indirectly at the transcriptional level, with the participation of the MAPK/JNK/p38 pathway and the TGF-beta signaling pathway but independent of Smad3/4.
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PMID:Regulation of fibronectin by thyroid hormone receptors. 1552

Hepatitis C virus (HCV) is a major risk factor for human hepatocellular carcinoma (HCC) but the mechanisms underlying HCV-induced carcinogenesis are still poorly understood. We have hypothesized that viral variants, selected during long-term infection, might contribute to cellular transformation. To address this issue, we have investigated the effect of natural HCV core variants isolated from liver tumors (T), or their non-tumor (NT) counterparts, on the tumor growth factor-beta (TGF-beta) pathway, a major regulator of cellular proliferation, differentiation and apoptosis. We have found a significant reduction in TGF-beta reporter gene activity with the expression of core sequences isolated from liver tumors. In contrast, moderate or no effects were observed with non-tumor mutants or a core reference sequence. The molecular mechanisms have been characterized and involved the inhibition, by tumor-derived cores, of the DNA-binding activity of the Smad3/4 transcription factors complex. This inhibition occurs through a direct interaction between the central domain (amino acids 59-126) of tumor-derived core and the MH1 DNA-binding domain of Smad3, thus preventing its binding to DNA. We have therefore identified a new cell-signaling pathway targeted by HCV core and inhibited by tumor-derived core sequences. These results suggest that during chronic infection, there is selection of viral variants that may promote cell transformation by providing, to clonally expanding cells, resistance to TGF-beta antiproliferative effects.
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PMID:Hepatitis C virus core variants isolated from liver tumor but not from adjacent non-tumor tissue interact with Smad3 and inhibit the TGF-beta pathway. 1600 7

Transforming growth factor-beta (TGF-beta) is implicated in the pathogenesis of liver disease. TGF-beta is involved both in liver regeneration and in the fibrotic and cirrhotic transformation with hepatitis viral infection. Hepatitis C virus (HCV) infection often leads to cirrhosis and hepatocellular carcinoma. HCV nonstructural 5A (NS5A) protein is a multifunctional protein that modulates cytokine-mediated signal transduction pathways. To elucidate the molecular mechanism of HCV pathogenesis, we examined the effect of NS5A protein on TGF-beta-stimulated signaling cascades. We show that NS5A protein inhibited the TGF-beta-mediated signaling pathway in hepatoma cell lines as determined by reporter gene assay. To further investigate the role of NS5A, we examined the protein/protein interaction between NS5A and TGF-beta signal transducers. Both in vitro and in vivo binding data showed that NS5A protein directly interacted with TGF-beta receptor I (TbetaR-I) in hepatoma cell lines. This interaction was mapped to amino acids 148-238 of NS5A. We also found that NS5A protein co-localized with TbetaR-I in the cytoplasm of Huh7 cells and inhibited TGF-beta-mediated nuclear translocation of Smad2. Furthermore, we demonstrate that NS5A protein abrogated the phosphorylation of Smad2 and the heterodimerization of Smad3 and Smad4. To further explore the relevance to viral infection, we examined the effect of the HCV subgenomic replicon on the TGF-beta signaling pathway. We show that the HCV subgenomic replicon also inhibited TGF-beta-induced signaling cascades. These results indicate that HCV NS5A modulates TGF-beta signaling through interaction with TbetaR-I and that NS5A may be an important risk factor in HCV-associated liver pathogenesis.
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PMID:Modulation of the transforming growth factor-beta signal transduction pathway by hepatitis C virus nonstructural 5A protein. 1640 86

TGFbeta is a major regulator of extracellular matrix deposition and a potent inducer of type-1 plasminogen activator inhibitor (PAI-1) gene expression. We have reported that liganded glucocorticoid receptor (GR) represses TGFbeta transactivation of PAI-1 in Hep3B human hepatoma cells and that it interacts functionally and physically with the C-terminal activation domain of Smad3, a mediator of TGFbeta signaling. The ligand binding domain of GR is required for GR-mediated transrepression, but the GR DNA binding domain and activation function 1 domains are not. We report here that overexpression of steroid receptor coactivator-1 (SRC-1) and GR-interacting protein-1 (GRIP-1) enhanced repression by liganded GR, and by a GR mutant defective in repression. Surprisingly, SRC-1 and GRIP-1 also enhanced TGFbeta-induced activation from the TGFbeta-responsive sequence of the PAI-1 gene by a GR-independent mechanism. Coimmunoprecipitation and mammalian one-hybrid experiments demonstrated that SRC-1 and GRIP-1 interact physically with endogenous Smad3 and functionally with the C-terminal domain of Smad3 to directly enhance transcription. Thus, the GR coactivators, SRC-1 and GRIP-1, act as both corepressors of the glucocorticoid repression of PAI-1 gene transcription, and coactivators of TGFbeta-induced activation of the PAI-1 promoter.
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PMID:Role of steroid receptor coactivators in glucocorticoid and transforming growth factor beta regulation of plasminogen activator inhibitor gene expression. 1642 81

In order to investigate the inhibitory effects on the vascular endothelial growth factor (VEGF) expression and cell growth in hapatocellular carcinoma (HCC) by blocking HIF-1alpha and Smad3 binding site in the VEGF promoter, antisense oligodeoxynucleotides (ASODN) were designed to block HIF-1alpha and Smad3 binding site in the VEGF promoter. Different concentrations of ASODN and ODN were transfected into HCC cells respectively. The expression of VEGF mRNA and protein was detected by SABC, Western blot and RT-PCR techniques and the inhibitory effects on the expression of VEGF and cell growth of the HCC cells stimulated by the supernatants were determined by using MTT method. Immunohistochestry revealed that after co-inoculation of hepatocellular carcinoma cells with different concentrations of ODN and ASODN for 48 h, there was no significant difference in the expression of VEGF protein between ODN group and control group (P > 0.05), but there was significant difference between ASODN group and control group (P < 0.05). At a concentration of 10 micromol/L ASODN, the difference was very significant (P < 0.01). Western blot and RT-PCR revealed that, after treatment for 48 h at a concentration of 10 micromol/L. the integral gray levels and RNA odds were 59743.2 +/- 10412.5 and 0.783 +/- 0.032 in ODN group, and 38694.5 +/- 10925.1 and 0.468 +/- 0.015 in ASODN group, respectively, with the difference being very significant (P < 0.01). Antisense ODN could inhibit the growth of HCC cells in a concentration-dependent manner. It was concluded that anti-gene technique of aiming at HIF-1alpha action site in the VEGF promoter could suppress the VEGF expression and inhibit HCC cell growth, and it is promising that anti-gene technique works as a new gene therapeutic tool for anti-angiogenesis of HCC.
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PMID:Inhibition of the VEGF expression and cell growth in hepatocellular carcinoma by blocking HIF-1alpha and Smad3 binding site in VEGF promoter. 1671 28

In the liver, derangement of TGF-beta signaling is associated with an increased incidence of hepatocellular carcinoma (HCC), but the mechanism is not clear. We report here that forced expression of a major TGF-beta signaling transducer, Smad3, reduces susceptibility to HCC in a chemically induced murine model. This protection is conferred by Smad3's ability to promote apoptosis by repressing Bcl-2 transcription in vivo through a GC-rich element in the Bcl-2 promoter. We also show that the proapoptotic activity of Smad3 requires both input from TGF-beta signaling and activation of p38 MAPK, which occurs selectively in the liver tumor cells. Thus, Smad3 enables the tumor suppression function of TGF-beta by serving as a physiological mediator of TGF-beta-induced apoptosis.
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PMID:Smad3 reduces susceptibility to hepatocarcinoma by sensitizing hepatocytes to apoptosis through downregulation of Bcl-2. 1676 64


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