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)

The HBx (X protein of hepatitis B virus) is a promiscuous transactivator implicated to play a key role in hepatocellular carcinoma. However, HBx-regulated molecular events leading to deregulation of cell cycle or establishment of a permissive environment for hepatocarcinogenesis are not fully understood. Our cell culture-based studies suggested that HBx had a profound effect on cell cycle progression even in the absence of serum. HBx presence led to an early and sustained level of cyclin-cdk2 complex during the cell cycle combined with increased protein kinase activity of cdk2 heralding an early proliferative signal. The increased cdk2 activity also led to an early proteasomal degradation of p27(Kip1) that could be reversed by HBx-specific RNA interference and blocked by a chemical inhibitor of cdk2 or the T187A mutant of p27. Further, our co-immunoprecipitation and in vitro binding studies with recombinant proteins suggested a direct interaction between HBx and the cyclin E/A-cdk2 complex. Interference with different signalling cascades known to be activated by HBx suggested a constitutive requirement of Src kinases for the association of HBx with these complexes. Notably, the HBx mutant that did not interact with cyclin E/A failed to destabilize p27(Kip1) or deregulate the cell cycle. Thus HBx appears to deregulate the cell cycle by interacting with the key cell cycle regulators independent of its well-established role in transactivation.
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PMID:HBx-dependent cell cycle deregulation involves interaction with cyclin E/A-cdk2 complex and destabilization of p27Kip1. 1693 21

Keratins (Ks) are the intermediate filament (IF) proteins of epithelial cells. Hepatocyte IFs are made solely of keratins 8 and 18 (K8/K18), the hallmark of all simple epithelia. While K8/K18 are essential for maintaining structural integrity, there is accumulating evidence indicating that they also exert non-mechanical functions. We have reported recently that K8/K18-free hepatocytes from K8-null mice are more sensitive to Fas-mediated apoptosis, in line with an increased Fas density at the cell surface and an altered c-Flip regulation of the anti-apoptotic ERK1/2 signaling pathway. In the present study, we show that K8-null hepatocytes attach more rapidly but spread more slowly on a fibronectin substratum and undergo a more efficient G1/S transition than wild-type hepatocytes. Moreover, plectin, an IF associated protein, receptor for activated C kinase 1 (RACK1), a plectin partner, and vinculin, a key component of focal adhesions, distribute differently in spreading K8-null hepatocytes. Cell seeding leads to no differential activation of ERK1/2 in WT versus K8-null hepatocytes, whereas a stronger Akt activation is detected in K8-null hepatocytes. Insulin stimulation also leads to a differential Akt activation, implying altered Akt signaling capacity as a result of the K8/K18 loss. In addition, a delayed autophosphorylation of FAK, a target for integrin beta1 signaling, was obtained in seeding K8-null hepatocytes. These alterations in cell cycle-related events in hepatocytes in primary culture are also found in a K8-knockdown H4-II-E-C3 rat hepatoma cell line. Besides, K8/K18-free cells are smaller and exhibit a reduced rate of protein synthesis. In addition, a distinctive cyclin interplay is observed in these K8/K18-free hepatic cells, namely a more efficient cyclin A-dependent G1/S phase transition. Furthermore, K8 re-expression in these cells, following transfer of a human K8 cDNA, restores proper cell size, spreading and growth. Together, these results suggest new interrelated signaling roles of K8/18 with plectin/RACK1 in the modulation of cell attachment/spreading, size/protein synthesis and G1/S transition.
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PMID:Keratins modulate hepatic cell adhesion, size and G1/S transition. 1711 11

Alpha-lipoic acid (alpha-LA) is an antioxidant used for the treatment of a variety of diseases, including liver cirrhosis, heavy metal poisoining, and diabetic polyneuropathy. In addition to its protective effect against oxidative stress, alpha-LA induces apoptosis in different cancer cells types. However, whether alpha-LA acid induces apoptosis of hepatoma cells is unknown. Herein, we investigated whether alpha-LA induces apoptosis in two different hepatoma cell lines FaO and HepG2. The results showed that alpha-LA inhibits the growth of both cell lines as indicated by the reduction in cell number, the reduced expression of cyclin A and the increased levels of the cyclin/CDKs inhibitors, p27(Kip1) and p21(Cip1). Cell cycle arrest was associated with cell loss, and DNA laddering indicative of apoptosis. Apoptosis was preceded by increased generation of reactive oxygen species, and associated with p53 activation, increased expression of Bax, release of cytochrome c from mitochondria, caspases activation, decreased levels of survivin, induction of pro-apoptotic signaling (i.e JNK) and inhibition of anti-apoptotic signaling (i.e. PKB/Akt) pathways. In conclusion, this study provides evidence that alpha-LA induces apoptosis in hepatoma cells, describes a possible sequence of molecular events underlying its lethal effect, and suggests that it may prove useful in liver cancer therapy.
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PMID:Increased ROS generation and p53 activation in alpha-lipoic acid-induced apoptosis of hepatoma cells. 1713 95

Scutellaria barbata, a Traditional Chinese Medicine native in southern China, has been widely used for treating liver diseases. In this study, the anti-proliferative effect of Pheophorbide a (Pa), an active component from S. barbata, was examined on a multi-drug resistant (MDR) human hepatoma cell line R-HepG2. Our study showed that Pa could significantly inhibit the growth of R-HepG2 cells with an IC50 value at 25.0 microM after 48 hours treatment. When compared with the parental HepG2 cells, Pa showed weak resistance to R-HepG2. Efflux of Pa out of R-HepG2 cells was not observed as its cellular uptake level showed no significant difference comparing with HepG2 cells. Interestingly, significant reduction of P-glycoprotein expression on Pa-treated R-HepG2 cells was found at both transcriptional and translational levels, leading to reduction of P-glycoprotein activity. In addition, mechanistic study elucidated that Pa induced cell cycle arrest at G2/M phase and inhibited the expressions of G2/M phase cell cycle regulatory proteins, cyclin-A1 and cdc2 in a dose-dependent manner.
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PMID:Pheophorbide a, an active component in Scutellaria barbata, reverses P-glycoprotein-mediated multidrug resistance on a human hepatoma cell line R-HepG2. 1745 45

Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates diverse cell functions including proliferation and differentiation. Within the liver IL-6 signaling plays a central role during normal hepatic growth and regeneration yet can inhibit the proliferation of hepatocellular carcinoma (HCC) cells. The aim of the current study was to identify underlying mechanisms whereby IL-6 induces cell-cycle arrest in HCC cells. These studies demonstrate that IL-6 inhibits cell-cycle progression at the G(0)/G(1) interface through inhibition of cyclin-dependent kinase (cdk) 2 and cdk4 activity in the absence of changes in total cyclin (A, D1, D3, and E) or cdk (cdk2, 4, and cdc2 p34) expression. Inhibition of signal transduction pathways associated with IL-6 receptor activation demonstrates that IL-6-dependent inhibition of G(0)-G(1) progression occurs via Janus tyrosine kinase-signal transducers and activators of transcription-3 (Jak-STAT3)-dependent induction of p21(waf1/cip1) and is independent of ERK-MAPK signaling. These data demonstrate that, while IL-6 plays a central role in hepatocyte priming and proliferation in vivo, the pronounced inhibition of proliferation observed in HCC cells occurs due to IL-6-STAT3-dependent regulation of cdk2/cdk4 activity and p21(waf1/cip1) expression.
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PMID:Interleukin-6 mediates G(0)/G(1) growth arrest in hepatocellular carcinoma through a STAT 3-dependent pathway. 1757 77

Tamoxifen is a widely used anti-estrogenic drug for chemotherapy and, more recently, for the chemoprevention of breast cancer. Despite the indisputable benefits of tamoxifen in preventing the occurrence and re-occurrence of breast cancer, the use of tamoxifen has been shown to induce non-alcoholic steatohepatitis, which is a life-threatening fatty liver disease with a risk of progression to cirrhosis and hepatocellular carcinoma. In recent years, the high-throughput microarray technology for large-scale analysis of gene expression has become a powerful tool for increasing the understanding of the molecular mechanisms of carcinogenesis and for identifying new biomarkers with diagnostic and predictive values. In the present study, we used the high-throughput microarray technology to determine the gene expression profiles in the liver during early stages of tamoxifen-induced rat hepatocarcinogenesis. Female Fisher 344 rats were fed a 420 ppm tamoxifen containing diet for 12 or 24 weeks, and gene expression profiles were determined in liver of control and tamoxifen-exposed rats. The results indicate that early stages of tamoxifen-induced liver carcinogenesis are characterized by alterations in several major cellular pathways, specifically those involved in the tamoxifen metabolism, lipid metabolism, cell cycle signaling, and apoptosis/cell proliferation control. One of the most prominent changes during early stages of tamoxifen-induced hepatocarcinogenesis is dysregulation of signaling pathways in cell cycle progression from the G(1) to S phase, evidenced by the progressive and sustained increase in expression of the Pdgfc, Calb3, Ets1, and Ccnd1 genes accompanied by the elevated level of the PI3K, p-PI3K, Akt1/2, Akt3, and cyclin B, D1, and D3 proteins. The early appearance of these alterations suggests their importance in the mechanism of neoplastic cell transformation induced by tamoxifen.
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PMID:Gene expression profiling reveals underlying molecular mechanisms of the early stages of tamoxifen-induced rat hepatocarcinogenesis. 1770 60

Natural products derived from plants provide a rich source for development of new anticancer drugs. Dulxanthone A was found to be an active cytotoxic component in Garcinia cowa by bioactivity-directed isolation. Studies to elucidate the cytotoxic mechanisms of dulxanthone A showed that dulxanthone A consistently induced S phase arrest and apoptosis in the most sensitive cell line HepG2. Furthermore, p53 was dramatically up-regulated, leading to altered expression of downstream proteins upon dulxanthone A treatment. Cell cycle related proteins, such as cyclin A, cyclin B, cyclin E, cdc-2, p21 and p27 were down-regulated. Some apoptosis correlated proteins were also altered following the drug treatment. Bcl-2 family members PUMA was up-regulated while Bcl-2 and Bax were down-regulated. However, the expression ratio of Bax/Bcl-2 was increased. This resulted in the release of cytochrome C from the mitochondria to the cytosol. Concurrently, Apaf-1 was stimulated with p53 by dulxanthone A. In result, cytochrome C, Apaf-1 and procaspase-9 form an apoptosome, which in turn triggered the activation of caspase-9, caspase-3 and downstream caspase substrates. Lamin A/C and PARP were down-regulated or cleaved, respectively. Moreover, cell cycle arrest and apoptosis in HepG2 cells induced by dulxanthone A were markedly inhibited by siRNA knockdown of p53. In summary, dulxanthone A is an active cytotoxic component of G. cowa. It induces cell cycle arrest at lower concentrations and triggers apoptosis at higher concentrations via up-regulation of p53 through the intrinsic mitochondrial pathway in HepG2 cells. Dulxanthone A is therefore likely a promising preventive and/or therapeutic agent against Hepatoma.
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PMID:Dulxanthone A induces cell cycle arrest and apoptosis via up-regulation of p53 through mitochondrial pathway in HepG2 cells. 1784 33

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, with no effective treatment for most individuals who succumb to this neoplasm. We report that treatment of primary HCC cells with the mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase 1/2 inhibitor AZD6244 (ARRY-142886) plus doxorubicin led to synergistic growth inhibition and apoptosis. In vivo administration of AZD6244, doxorubicin, or the combination of AZD6244 and doxorubicin in mice bearing 5-1318 HCC xenografts resulted in approximately 52% +/- 15%, 12% +/- 9%, and 76% +/- 7% growth inhibition, respectively. AZD6244-inhibited tumor growth was associated with increased apoptosis, inactivation of ERK1/2, inhibition of cell proliferation, and down-regulation of cell cycle regulators, including cyclin D1, cdc-2, cyclin-dependent kinases 2 and 4, cyclin B1, and c-Myc. The AZD6244-doxorubicin combined protocol not only promoted apoptosis but also induced a synergistic effect not seen in single-agent-treated tumors, including increased expression of the p130 RB tumor suppressor gene. Our study provides a strong rationale for clinical investigation of combination therapy with the mitogen-activated protein/ERK kinase 1/2 inhibitor AZD6244 and doxorubicin in patients with HCC.
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PMID:AZD6244 and doxorubicin induce growth suppression and apoptosis in mouse models of hepatocellular carcinoma. 1787 44

Hepatocellular carcinoma (HCC) is a frequent neoplasia which still misses a therapeutical gold standard. Recently, new acquisitions in cancerogenesis process evidenced the genetic and epigenetic alterations of genes involved in the different metabolic pathways of liver cancer suggesting that antibodies, small molecules, demethylating agents, etc. specifically acting against molecular target can be utilized alone or in combination in clinical practice. The main altered targets are: cell membrane receptors, in particular tyrosine kinase receptors, factors involved in cell signalling, specifically Wnt/beta-catenin, Ras/Raf/MEK/ERK and PI3K/Akt/mTOR pathways, proteins linked to cell cycle regulation pathway (i.e. p53, p16/INK4, cyclin/cdk complex) or in invasiveness (EMT, TGFbeta) and proteins involved in DNA metabolism. Genetic or epigenetic changes in these molecules have been used in preclinical settings and, some of them also in clinical trials of phase II and III. This scenario opens new avenues for the prevention and the treatment of HCC. In the present review the main metabolic pathways and molecular alterations have been described together with recent advances in molecular and gene therapy.
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PMID:Molecular pathways and related target therapies in liver carcinoma. 1804 79

The initiation of endoplasmic reticulum (ER) stress has been suggested to play potential roles in hepatocarcinogenesis. However, many obstacles remain as to whether ER stress plays a role in carcinogenesis or tumoricide. This study sought to identify the signals that can serve as anticancer effectors in cells in response to ER stress. Tunicamycin (an N-glycosylation inhibitor) inhibited cell proliferation with IC(50) values of 0.19 and 0.62 microg/ml in hepatoma (Hep) 3B and HepG2 cells, respectively. It induced G1 arrest of the cell cycle in both cell lines. The anticancer mechanism of tunicamycin was investigated in Hep3B cells. Tunicamycin induced a rapid decline of cyclin D1 and cyclin A expression and an early increase of glucose-related protein (GRP) 78 and growth arrest and DNA damage-inducible transcription factor (GADD) 153 levels. Cyclin A was the most sensitive regulator to tunicamycin-triggered degradation mechanism. The association of p27(Kip1) with cyclin D1/cyclin-dependent kinase (Cdk) 4 was also increased by tunicamycin. The inhibition of GADD153 expression by transfection of GADD153 antisense did not modify tunicamycin-induced G1 arrest and cyclin/Cdk expressions. The knockdown of GRP78 expression by the siRNA transfection technique moderately increased tunicamycin-induced apoptosis but not the antiproliferative effect by sulforhodamine B assay. We suggest that tunicamycin induces G1 arrest through down-regulation of cyclins and Cdks, in which cyclin A is more susceptible to ER stress-triggered degradation mechanism in Hep3B cells. The increased association of p27(Kip1) with cyclin D1/Cdk4 may also contribute to tunicamycin-induced cell-cycle arrest. GADD153 and GRP78 play a minor role in tunicamycin-mediated antiproliferative effect, although GRP78 moderately inhibits apoptosis in Hep3B cells. These data provide evidence that cell-cycle regulators are susceptible factors in hepatocellular carcinoma (HCC) responsive to ER stress.
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PMID:Elucidation of susceptible factors to endoplasmic reticulum stress-mediated anticancer activity in human hepatocellular carcinoma. 1822 3


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