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)

Indirubin-3'-monoxime (I3M) is a derivative of indirubin, an active component from a Chinese medicinal recipe with known anti-cancer function. I3M has been well established as a cyclin-dependent kinase (CDK) inhibitor, while the molecular mechanism underlying I3M-induced apoptosis has not been fully elucidated. In this study, we focused on the critical role of the pro-apoptosis Bcl-2 family members in I3M-induced apoptosis. We first observed I3M-induced apoptosis in a time- and dose-dependent manner in three different types of human cancer cells-cervical cancer HeLa, hepatoma HepG2 and colon cancer HCT116. Induction of the caspase cascade for both the extrinsic and intrinsic pathways was demonstrated, including caspase-8, -9 and -3 activation. Initiation of the death receptor pathway started with enhanced surface expression of DR4 and DR5, as well as increased total protein level, which correlated with the up-regulation of p53 and its transcriptional activity. Importantly, we found in HeLa cells that caspase-8 activation resulted in Bid cleavage, followed by Bax conformational change and hence the amplification of the apoptotic signals through the mitochondrial pathway. Consistently, stable knockdown of Bid abrogated I3M-induced Bax conformational change and cell death. Moreover, ectopic expression of a viral caspase inhibitor (CrmA) or Bcl-2 partially protected I3M-induced apoptosis. In conclusion, our results indicate that I3M mainly elicites apoptosis through extrinsic pathway with type II response mediated by the pro-apoptotic Bcl-2 family members (Bid and Bax).
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PMID:Critical role of Bid and Bax in indirubin-3'-monoxime-induced apoptosis in human cancer cells. 1837 73

The effect of cyclin-dependent kinase inhibitors Cip1/Waf1 (p21) on regulatory expression of survivin transcription in human hepatocellular carcinoma cell HepG2 was observed and the related mechanisms explored. Doxorubicin (DOX) was used to treat HepG2. Eukaryotic vector pEGFP-C2-p21 was transfected into HepG2 by lipofectamine and positive clones were screened out by G418. The mRNA expression of p21 and survivin was detected by real-time fluorescent quantitative polymerase chain reaction (RQ-PCR). Flow cytometry was used to examine the cell cycle, and reverse transcription polymerase chain reaction (RT-PCR) was used to measure the levels of E2F-1 and p300. The results showed that: (1) After treatment with DOX, the expression of p21 was increased, whereas that of survivin was reduced during 24 h of treatment; (2) After transfection of pEGFP-C2-p21 into HepG2, p21 level was significantly enhanced to 2100.11-folds or 980.89-folds in comparison to HepG2 or HepG2-C2 group, and survivin level was markedly down-regulated to 0.54% or 0.59% relative to the control groups; (3) Overexpressed p21 resulted in G1/G0 phase arrest (F=31.59, P<0.01), meanwhile E2F-1 mRNA and p300 mRNA were reduced as compared with those of controls (F(E2F-1)=125.28, P<0.05; F(p300)=46.01, P<0.01). It was suggested that p21 could be a potential mediator of survivin suppression at transcription level in HepG2 cell, which might be through the block at G1/G0 phase and down-regulation of transcription factors E2F-1 and p300.
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PMID:Effect of survivin regulation of transcription level by p21waf1 overexpression in HepG2 hepatocellular carcinoma cells. 1856 30

Hepatocellular carcinoma (HCC) frequently includes abnormalities in cell cycle regulators, including up-regulated cyclin-dependent kinase (Cdks) activities due to loss or low expression of Cdk inhibitors. In this study, we show that xylocydine, a cyclin-dependent kinase (Cdk) specific inhibitor, is a good anti-cancer drug candidate for HCC treatment. Xylocydine (50muM) selectively down-regulates the activity of Cdk1 and Cdk2, accompanied by significant cell growth inhibition in HCC cells. Xylocydine also strongly inhibits the activity of Cdk7 and Cdk9, in vitro as well as in cell cultures, that is temporally associated with apoptotic cell death in xylocydine-induced HCC cells. This is associated with inhibition of phosphorylation of RNA polymerase II at serine residues 5 and 2, which are targets of Cdk7 and Cdk9, respectively. The effects on apoptosis are concomitant with changes in the levels of anti-apoptotic proteins, Bcl-2, XIAP, and survivin, which are markedly down-regulated, and pro-apoptotic molecules, p53 and Bax, which are elevated in HCC cells after treatment with xylocydine. The up-regulated level of p53 was associated with increased stability of the protein, as levels of Ser15 and Ser392 phsophorylated p53 are similarly elevated in the inhibitor treated cells. We demonstrated that xylocydine can effectively suppress the growth of HCC xenografts in Balb/C-nude mice by preferentially inducing apoptosis in the xenografts, whereas the drug did not cause any apparent toxic effect on other tissues. Taken together, these data suggest that the novel Cdk inhibitor xylocydine is a good candidate for an anti-cancer drug for HCC therapy.
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PMID:Xylocydine, a novel Cdk inhibitor, is an effective inducer of apoptosis in hepatocellular carcinoma cells in vitro and in vivo. 1961 71

Previously, we demonstrated that magnolol isolated from the bark of Magnolia officinalis has anticancer activity in colon, hepatoma, and leukemia cell lines. In this study, we show that magnolol concentration dependently (0-40 microM) decreased the cell number in a cultured human glioblastoma cancer cell line (U373) and arrested the cells at the G0/G1 phase of the cell cycle. Magnolol treatment decreased the protein levels of cyclins A and D1 and increased p21/Cip1, but not cyclins B and D3, cyclin-dependent kinase (CDK)2, CDK4, CDC25C, Weel, p27/Kip1, and p53. The CDK2-p21/Cip1 complex was increased, and the CDK2 kinase activity was decreased in the magnolol-treated U373. Pretreatment of U373 with p21/Cip1 specific antisense oligodeoxynucleotide prevented the magnolol-induced increase of p21/Cip1 protein levels and the decrease of DNA synthesis. Magnolol at a concentration of 100 microM induced DNA fragmentation in U373. Our findings suggest the potential applications of magnolol in the treatment of human brain cancers.
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PMID:Magnolol inhibits human glioblastoma cell proliferation through upregulation of p21/Cip1. 1964 6

DNA copy number aberrations in human hepatocellular carcinoma (HCC) cell lines were investigated using a high-density oligonucleotide microarray, and a novel amplification at the chromosomal region 7q21 was detected. Molecular definition of the amplicon indicated that PEG10 (paternally expressed gene 10), a paternally expressed imprinted gene, was amplified together with CDK14 (cyclin-dependent kinase 14; previously PFTAIRE protein kinase 1, PFTK1) and CDK6 (cyclin-dependent kinase 6). An increase in PEG10 copy number was detected in 14 of 34 primary HCC tumors (41%). PEG10, but not CDK14 or CDK6, was significantly overexpressed in 30 of 41 tumors (73%) from HCC patients, compared with their nontumorous counterparts. These results suggest that PEG10 is a probable target, acting as a driving force for amplification of the 7q21 region, and may therefore be involved in the development or progression of HCCs.
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PMID:PEG10 is a probable target for the amplification at 7q21 detected in hepatocellular carcinoma. 2036 26

Cyclin D2s (CCND2s) are members of the D-type cyclin family. They interact and construct complexes with cyclin-dependent kinase (CDK)4 or 6. The cyclin D2/CDK4 or CDK6 complexes have key roles in controlling the progression of cell cycle from the Gap 1 (G1) phase to the synthesis (S) phase. Overexpression of cyclin D2 is associated with the development of tumors. In this study, we identified 16 sequence variants of CCND2 polymorphisms through direct DNA sequencing in 24 individuals, and 5 common variants were selected for genotyping in larger-scale subjects (n=1100). Genetic associations of those polymorphisms with hepatitis B virus (HBV) clearance and hepatocellular carcinoma (HCC) outcome among patients with HBV were analyzed. Although no significant association was observed between the polymorphisms and HCC outcome among HBV patients, one common polymorphism in the 5'-untranslated region (that is, rs1049606) and the most common haplotype (CCND-ht1 [T-C-T-A-T]), however, were significantly associated with HBV clearance (odds ratio=0.69, P=0.0002, Pcorr=0.001 and odds ratio=1.37, P=0.0009, Pcorr=0.004, respectively). The minor allele frequency of rs1049606 among the spontaneously recovered (SR) group was significantly higher than that of the chronic carrier (CC) group (frequency=0.403 vs 0.336, P=0.0002). In contrast, the frequency of CCND-ht1 was higher among the CC group than among the SR group (frequency=0.429 vs 0.374, P=0.0009). The information identified in this study might provide valuable insights into generating strategies for control of HBV.
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PMID:CCND2 polymorphisms associated with clearance of HBV infection. 2041 51

The intrinsic oncolytic specificity of vesicular stomatitis virus (VSV) is currently being exploited to develop alternative therapeutic strategies for hepatocellular carcinoma (HCC). Identifying key regulators in diverse transduction pathways that define VSV oncolysis in cancer cells represents a fundamental prerequisite to engineering more effective oncolytic viral vectors and adjusting combination therapies. After having identified defects in the signalling cascade of type I interferon induction, responsible for attenuated antiviral responses in human HCC cell lines, we have now investigated the role of cell proliferation and translation initiation. Cell cycle progression and translation initiation factors eIF4E and eIF2Bepsilon have been recently identified as key regulators of VSV permissiveness in T-lymphocytes and immortalized mouse embryonic fibroblasts, respectively. Here, we show that in HCC, decrease of cell proliferation by cell cycle inhibitors or siRNA-mediated reduction of G(1) cyclin-dependent kinase activities (CDK4) or cyclin D1 protein expression, do not significantly alter viral growth. Additionally, we demonstrate that translation initiation factors eIF4E and eIF2Bepsilon are negligible in sustaining VSV replication in HCC. Taken together, these results indicate that cellular proliferation and the initiation phase of cellular protein synthesis are not essential for successful VSV oncolysis of HCC. Moreover, our observations indicate the importance of cell-type specificity for VSV oncolysis, an important aspect to be considered in virotherapy applications in the future.
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PMID:Cell cycle progression or translation control is not essential for vesicular stomatitis virus oncolysis of hepatocellular carcinoma. 2053 60

Entry into the cell cycle is governed by cyclins, cyclin-dependent kinases (CDKs) and CDK-inhibitors (CDKIs). The p53-regulated inhibitor of CDKs (PIC1) is a universal CDKI whose gene expression is directly induced by the p53 tumor suppressor protein. Reverse transcription and polymerase chain reaction revealed strong PIC1 gene expression in control MRC-5 human embryo lung cells, but relatively weaker bands in A549 lung carcinoma; Hep3B, Mahlavu, PLC/PRF/5 hepatocellular carcinoma; SiHa, CaSki, HeLa cervical carcinoma; T24 bladder carcinoma; MCF7 breast carcinoma; Raji Burkitt lymphoma; HT-1080 fibrosarcoma; and G-401 Wilms' tumor cell lines. These data are consistent with other results obtained by Northern and Western blot and immunoprecipitation techniques, indicating diminished PIC1 expression in cancer cells especially those harboring mutated p53, or human papillomavirus E6 oncoproteins which abrogate p53 activity. PIC1 gene expression was absent in the Molt-4 T-lymphoblastic leukemia cell line with a previously documented alternatively-spliced p53 transcript translating into p53 protein truncated at the carboxyl terminus. It is proposed that this aberrant p53 interferes with the binding of wild-type p53 and other transcription factors to the PIC1 promoter thereby abolishing PIC1 gene expression. This Molt-4 cell line could serve as a useful experimental system for studying the interaction between p53 and other cellular factors with the PIC1 gene. Single-strand conformation polymorphism and direct cycle DNA sequencing analyses demonstrated a PIC1 variant (with an AGC to AGA substitution at codon 31 culminating in a serine to arginine replacement) in Mahlavu, PLC/PRF/5, SiHa, A549 and Raji cell lines. The higher proportion of the PIC1 variant in cancer cell lines (5/13 or 38%) compared with normal individuals (14%), coupled with differences between the predicted secondary structures of the normal and variant PIC1 proteins merit further investigations to elucidate the biological significance of this variant.
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PMID:The gene encoding the p53-regulated inhibitor of cdks (pic1) is not expressed in the molt-4 leukemia-cell line with p53 truncated at the carboxyl-terminus, and harbors a nucleotide substitution at codon-31 in several other cancer cell-lines. 2155 14

Hispolon is an active phenolic compound of Phellinus igniarius , a mushroom that has recently been shown to have antioxidant, anti-inflammatory, and anticancer activities. This study investigated the antiproliferative effect of hispolon on human hepatocellular carcinoma Hep3B cells by using the MTT assay, DNA fragmentation, DAPI (4,6-diamidino-2-phenylindole dihydrochloride) staining, and flow cytometric analyses. Hispolon inhibited cellular growth of Hep3B cells in a time-dependent and dose-dependent manner, through the induction of cell cycle arrest at S phase measured using flow cytometric analysis and apoptotic cell death, as demonstrated by DNA laddering. Hispolon-induced S-phase arrest was associated with a marked decrease in the protein expression of cyclins A and E and cyclin-dependent kinase (CDK) 2, with concomitant induction of p21waf1/Cip1 and p27Kip1. Exposure of Hep3B cells to hispolon resulted in apoptosis as evidenced by caspase activation, PARP cleavage, and DNA fragmentation. Hispolon treatment also activated JNK, p38 MAPK, and ERK expression. Inhibitors of ERK (PB98095), but not those of JNK (SP600125) and p38 MAPK (SB203580), suppressed hispolon-induced S-phase arrest and apoptosis in Hep3B cells. These findings establish a mechanistic link between the MAPK pathway and hispolon-induced cell cycle arrest and apoptosis in Hep3B cells.
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PMID:Hispolon induces apoptosis and cell cycle arrest of human hepatocellular carcinoma Hep3B cells by modulating ERK phosphorylation. 2163 Jun 38

p19INK4D belongs to the family of cyclin-dependent kinase inhibitors (CdkIs) that target the cyclin-dependent kinases and inhibit their catalytic activity. The role of p19INK4D in cell cycle progression in hepatocellular carcinoma (HCC) is poorly characterized. The aim of this study was to examine the expression of p19INK4D in various liver diseases including HCC and to assess its clinical significance in HCC. We examined the expression of p19INK4D by immunohistochemistry in 81 cases of various liver diseases, including 51 HCCs. We analyzed the relationship among p19INK4D expression in HCC in combination with histopathological stage, differentiation, several histopathological factors of possible prognostic value and patient survival. Immunohistochemical analysis revealed the frequent loss of p19INK4D expression consistent with the differentiation of HCC. The loss of p19INK4D expression was shown to be associated with a poor prognosis by analyzing clinicopathological features. In conclusion, we found that loss of p19INK4D protein was frequent in HCC, especially in poorly differentiated HCC, suggesting that p19INK4D may play a role in the differentiation of HCC. Furthermore, expression of p19INK4D may be an effective predictor of clinical behavior in HCC, and therefore, a new prognostic marker for HCC.
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PMID:Frequent loss of p19INK4D expression in hepatocellular carcinoma: relationship to tumor differentiation and patient survival. 2190 Dec 51


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