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)

This study investigated the effect of baicalein, silymarin, and their combination, on two human liver-derived cell lines, HepG2 (hepatocellular carcinoma) and Chang liver (non-tumor liver cells). It was found that 6.75 microg/ml baicalein or 100 microg/ml silymarin alone significantly inhibited the growth of HepG2. When baicalein was used in combination with silymarin on HepG2, an additive effect at 24 h and a synergistic effect at 48 h were observed. The viability at 48 h was 85.62% from 6.75 microg/ml baicalein treatment; but the viability reduced to 49.67%, 38.56%, and 19.61% when 25, 50, and 100 microg/ml silymarin respectively, was added to the treatment. By contrast, each treatment had little or no effect on Chang liver. Compared to treatment of baicalein or silymarin alone on HepG2, combination of both drugs synergistically increased the percentages of cells in G0/G1 phase and decreased those in S-phase, which were associated with up-regulation of Rb, p53, p21(Cip1) and p27(Kip1) and down-regulation of cyclin D1, cyclin E, CDK4 and phospho-Rb. The results indicate that the combination of baicalein and silymarin eradicates tumor cells efficiently, has minimal deleterious effects to the surrounding normal cells, and offers mechanistic insight for further exploitation of HCC treatment.
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PMID:Synergistic anti-cancer effect of baicalein and silymarin on human hepatoma HepG2 Cells. 1915 Mar 84

Hammerhead ribozymes (HRz), catalytic RNA molecules capable of inducing the site-specific cleavage of a phosphodiester bond within an RNA molecule, are typically introduced into target cells by specific constructs (such as viral vectors) able to drive their expression from defined expression cassettes (promoter). This strategy implies the presence of promoter-derived sequences bound to the hammerhead ribozyme structure, a fact which can unpredictably affect HRz cleavage efficiency and eventually the biological effect. We explored the effects of promoter-derived sequences on the cleavage kinetics of an HRz targeted against a relevant cell cycle regulator, i.e. cyclin E1, implicated in the pathogenesis of several human diseases including in-stent restenosis and hepatocellular carcinoma. Sequences derived form the most commonly used promoters (CMV, T7, Pol I and Pol III promoters) were added to the minimal HRz structure and their effects on the cleavage kinetic constants k(cat) and K(m) evaluated in vitro under single turn-over conditions, using a mathematical model we recently developed. The different promoter derived sequences variably affected HRz cleavage efficiency (k(cat)/K(m)) with those derived from the pol III and from a truncated form of T7 promoter (T7-S), impairing maximally and minimally k(cat)/K(m), respectively. Additionally, the extra sequences tend to increase K(m) and to reduce k(cat). The extent of this effect depends both on the secondary RNA structure and on the length of the added sequences. In conclusion, these data, together with further work in cultured cells, can lead to the selection of optimal expression cassettes thus contributing to improve HRz efficacy, bringing these molecules closer to practical applications.
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PMID:Effects of various promoter derived sequences on the cleavage kinetic of an hammerhead ribozyme directed against cyclin E1 mRNA. 1935 46

Wnt/beta-catenin signaling pathway and cell cycle play the key roles during the genesis and development of hepatocellular carcinoma (HCC). The cytoplasmic protein beta-catenin is a multifunctional protein and a central molecule in the Wnt signaling pathway. Cell cycle is regulated by a a series of regulatory factors. Current researches indicated that expression of cyclin D1 and c-myc decreased after silencing beta-catenin gene in HCC, but it is unclear if other cyclins are affected. To determine the relation, small interference RNA(siRNA) against beta-catenin was transfected into HCC cell line HepG(2), and cell cycle and cyclin A and cyclin E protein expression were detected. We demonstrated that cell cycle was arrested in G(0)/G(1) at 72 h after the transfection and with the time passing, the cell cycle began to transfer from G(0)/G(1) to G(2)/M through S and had a trend to revert at 96 h. In addition, beta-catenin protein expression was decreased at both 72 and 96 h, although the level was slightly higher at 96 h than that at 72 h. However, cyclin A and cyclin E protein expression increased at 72 h and decreased at 96 h. These findings suggest that silencing beta-catenin gene may induce the changes of cell cycle and cyclin A and cyclin E expression. Wnt/beta-catenin signaling pathway probably takes part in the genesis and development of HCC through regulating cell cycle and the expression of cyclin A and cyclin E.
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PMID:Wnt/beta-catenin signaling pathway may regulate cell cycle and expression of cyclin A and cyclin E protein in hepatocellular carcinoma cells. 1941 33

Many tumors are resistant to drug-induced cell-cycle arrest and apoptosis. We have reported that apoptosis can be restored in human multidrug-resistant (MDR) hepatocellular carcinoma cell lines by celecoxib. Here we show that P-glycoprotein (P-gp) mediates cell-cycle arrest and autophagy induced by celecoxib in human MDR overexpressing hepatocellular carcinoma cell line by down-regulation of the HGF/MET autocrine loop and Bcl-2 expression. Exposure of cells to a low concentration of celecoxib down-regulated the expression of mTOR and caused G1 arrest and autophagy, while higher concentration triggered apoptosis. Cell growth inhibition and autophagy were associated with up-regulation of the expression of TGFbeta1, p16(INK4b), p21(Cip1) and p27(Kip1) and down-regulation of cyclin D1, cyclin E, pRb and E2F. The role of P-glycoprotein expression in resistance of MDR cell clone to cell-cycle arrest, autophagy and apoptosis was shown in cells transfected with MDR1 small interfering RNA. These findings demonstrate that the constitutive expression of P-gp is involved in the HGF/MET autocrine loop that leads to increased expression of Bcl-2 and mTor, inhibition of eIF2alpha expression, resistance to autophagy/apoptosis and progression in the cell-cycle. Since mTor inhibitors have been proposed in treatment of "drug resistant" cancer, these data may help explain the reversing effect of mTor inhibitors.
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PMID:Down-regulation of the HGF/MET autocrine loop induced by celecoxib and mediated by P-gp in MDR-positive human hepatocellular carcinoma cell line. 1944 20

5'AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR) are two serine/threonine protein kinases responsible for cellular energy homeostasis and translational control, respectively. Evidence suggests that these two kniases are potential targets for cancer chemotherapy against hepatocellular carcinoma (HCC). Antroquinonol that is isolated from Antrodia camphorate, a well-known Traditional Chinese Medicine for treatment of liver diseases, displayed effective anticancer activity against both HBV DNA-positive and -negative HCC cell lines. The rank order of potency against HCCs is HepG2>HepG2.2.15>Mahlavu>PLC/PRF/5>SK-Hep1>Hep3B. Antroquinonol completely abolished cell-cycle progression released from double-thymidine-block synchronization and caused a subsequent apoptosis. The data were supported by down-regulation and reduced nuclear translocation of G1-regulator proteins, including cyclin D1, cyclin E, Cdk4 and Cdk2. Further analysis showed that the mRNA expressions of the G1-regulator proteins were not modified by antroquinonol, indicating an inhibition of translational but not transcriptional levels. Antroquinonol induced the assembly of tuberous sclerosis complex (TSC)-1/TSC2, leading to the blockade of cellular protein synthesis through inhibition of protein phosphorylation including mTOR (Ser(2448)), p70(S6K) (Thr(421)/Ser(424) and Thr(389)) and 4E-BP1 (Thr(37)/Thr(46) and Thr(70)). Furthermore, the AMPK activity was elevated by antroquinonol. Compound C, a selective AMPK inhibitor, significantly reversed antroquinonol-mediated effects suggesting the crucial role of AMPK. Besides, the loss of mitochondrial membrane potential and depletion of mitochondrial content indicated the mitochondrial stress caused by antroquinonol. In summary, the data suggest that antroquinonol displays anticancer activity against HCCs through AMPK activation and inhibition of mTOR translational pathway, leading to G1 arrest of the cell-cycle and subsequent cell apoptosis.
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PMID:Antroquinonol displays anticancer potential against human hepatocellular carcinoma cells: a crucial role of AMPK and mTOR pathways. 1972 12

The present study was carried out to evaluate the radioprotective efficacy of Podophyllum hexandrum fraction (REC-2006) in hepatoma cell lines having different p53 statuses. Higher radioresistance was observed in the HepG2 (p53(++)) cell line in comparison to the Hep3B (p53(-)) cell line, indicating a plausible role of p53 in radioresistance. REC-2006 exhibited nearly twice the survival in p53-expressing HepG2 cells compared with p53-negative Hep3B cells. REC-2006 treatment alone induced p53 expression as compared with untreated controls. However, REC-2006 reduced p53 expression when treated 2 hours before irradiation as compared with the irradiated HepG2 controls, indicating that REC-2006 modulates the expression of p53 to mitigate its apoptotic effect. Induction of p21 in the REC-2006 + radiation treatment group downregulated the expression of cyclin E and CDK2, leading to a delay in the G1 phase of HepG2 cells, which provided time for DNA repair or related processes. However, no significant difference in CDC2 expression in both cell lines suggested that G2 phase arrest might not be the only responsible factor for REC-2006-mediated radioprotection. Significant induction of PCNA and GADD45 expression in HepG2 cells suggested that REC-2006 increased the percentage survival of HepG2 cells by increasing the span of time as well as efficacy for repair processes. In conclusion, REC-2006 modulated the expression of p53 and thereby promoted cell cycle arrest in the G1 phase, encouraging cell proliferation and DNA repair and thus providing significantly higher protection against acute gamma-radiation in the HepG2 cell line.
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PMID:Podophyllum hexandrum fraction (REC-2006) shows higher radioprotective efficacy in the p53-carrying hepatoma cell line: a role of cell cycle regulatory proteins. 1981 96

Hepatocellular carcinoma (HCC) is the fifth most frequent cause of cancer deaths in males and was the third most frequent cause of cancer deaths in 2007 throughout the world. The incidence rate is 2-3 times higher in developing countries than in developed countries. Animal models have enabled study of the mechanism of HCC and the development of possible strategies for treatment. Diethylnitrosamine (DEN) is a representative chemical carcinogen with the potential to cause tumors in various organs, including the liver, skin, gastrointestinal tract, and respiratory system. Specifically in HCC, DEN is a complete carcinogen. Many lines of evidence have demonstrated a relationship between carcinogenesis and cell cycle regulation. In this study we found that cell cycle regulatory proteins were critically involved in cancer initiation and promotion by DEN. Cyclin D1, cyclin E, cdk4, and p21(CIP1/WAF1) are factors whose expression levels may be useful as criteria for the classification of hepatic disease. In particular, cdk4 had a pivotal role in the transition to the neoplastic stage. In conclusion, we suggest that changes in the level of cdk4 may be useful as a biomarker for detection of HCC.
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PMID:Diethylnitrosamine (DEN) induces irreversible hepatocellular carcinogenesis through overexpression of G1/S-phase regulatory proteins in rat. 1982 96

Scutellaria baicalensis is an anti-inflammatory and antineoplastic Chinese herbal therapy. We have previously shown that S. baicalensis can inhibit hepatocellular carcinoma (HCC) cell growth in vitro. In this study, we sought to determine the effect of S. baicalensis on the cell signaling network using our newly developed Pathway Array technology, which screens cell signaling pathways involved in cell cycle regulation. The HCC cell line (HepG2) was treated with S. baicalensis extract in vitro. The effect on the cell cycle was analyzed by flow cytometry, and the expression of various signaling proteins was assayed with Pathway Array. Our results indicate that S. baicalensis exerts a strong growth inhibition of the HepG2 cells via G(2)/M phase arrest. The Pathway Array analysis of 56 proteins revealed a total of 14 differentially expressed proteins or phosphorylations after treatment. Of these, 9 showed a dose-dependent decrease (p53, ETS1, Cdc25B, p63, EGFR, ERK1/2, XIAP, HIF-2alpha, and Cdc25C) whereas one demonstrated a dose-dependent increase (Cyclin E) after treatment with 200 microg/ml of S. baicalensis. Using computer simulation software, we identified additional hubs in the signaling network activated by S. baicalensis. These results indicate that S. baicalensis exerts a broad effect on cell signaling networks leading to a collective inhibition of cell proliferation.
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PMID:The effect of Scutellaria baicalensis on the signaling network in hepatocellular carcinoma cells. 1983 25

Lysosomal protein transmembrane 4 beta (LAPTM4B) was originally identified as a hepatocellular carcinoma (HCC)-associated gene. This gene and its protein product LAPTM4B-35, are both overexpressed in a variety of human cancers. However, its specific role in cell transformation and malignancy has remained elusive. In the present study we investigated the effects of LAPTM4B-35 overexpression on the malignant phenotypic features in the HLE cell line. Our data show that overexpression of LAPTM4B-35 promotes cell proliferation, exogenous growth-stimulating factor-independent and anchorage-independent growth, and enhances metastatic potential, including promotion of both cell migration and invasion. Study of the underlying mechanisms demonstrated alterations of molecular events involved in these processes, which included upregulation of proliferation-promoting transcription factors such as c-Myc, c-Jun, and c-Fos, and cell cycle-promoting proteins such as cyclin D1 and cyclin E. In addition, mutagenesis study showed that the PPRP motif in the N-terminal region of LAPTM4B-35 plays a critical role in promoting proliferation, migration, and invasion, as well as in the upregulation of the oncoproteins noted above. These data offer insight into the mechanism by which this novel tetratransmembrane protein contributes to the pathogenesis of liver cancer, and suggest that it may be a potential target for cancer therapy.
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PMID:LAPTM4B-35, a novel tetratransmembrane protein and its PPRP motif play critical roles in proliferation and metastatic potential of hepatocellular carcinoma cells. 1984 73

Hepatocellular carcinoma (HCC) results from the cumulative effects of deregulated tumor suppressor genes and oncogenes. The tumor suppressor and oncogenes commonly affected include growth factors, receptors and their downstream signaling pathway components. The overexpression of transforming growth factor alpha (TGF-alpha) and the inhibition of TGF-beta signaling are especially common in human liver cancer. Thus, we assessed whether TGF-alpha overexpression and TGF-beta signaling inactivation cooperate in hepatocarcinogenesis using an in vivo mouse model, MT1/TGFa;AlbCre/Tgfbr2(flx/flx) mice ("TGFa;Tgfbr2(hepko)"), which overexpresses TGF-alpha and lacks a TGF-beta receptor in the liver. TGF-beta signaling inactivation did not alter the frequency or number of cancers in mice with overexpression of TGF-alpha. However, the tumors in the TGFa;Tgfbr2(hepko) mice displayed increased proliferation and increased cdk2, cyclin E and cyclin A expression as well as decreased Cdkn1a/p21 expression compared to normal liver and compared to the cancers arising in the TGF-alpha overexpressing mice with intact TGF-beta receptors. Increased phosphorylated ERK1/2 expression was also present in the tumors from the TGFa;Tgfbr2(hepko) mice and correlated with downregulated Raf kinase inhibitor protein expression, which is a common molecular event in human HCC. Thus, TGF-beta signaling inactivation appears to cooperate with TGF-alpha in vivo to promote the formation of liver cancer that recapitulates molecular features of human HCC.
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PMID:TGF-beta inactivation and TGF-alpha overexpression cooperate in an in vivo mouse model to induce hepatocellular carcinoma that recapitulates molecular features of human liver cancer. 2002 Apr 90


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