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)

In this study, we report that the steroid extract 5alpha, 8alpha-epidioxycholest-6-ene-3beta-ol (MME) from Meretrix meretrix has the ability to inhibit growth of hepatoma cells and to induce G1-phase cell cycle arrest in two human hepatoma cell lines, HepG2 and Hep3B. HepG2 cells were more sensitive than Hep3B to MME. The extract markedly up-regulated the expression of p53 and p21WAF1/CIP1 in HepG2, suggesting that MME-induced G1 phase cell cycle arrest in HepG2 might be p53-dependent. Therefore, the up-regulation of p27KIP1and p16INK4A in both cell lines indicates that a p53-independent pathway might be involved in the mechanism of MME inducing cell cycle arrest. In conclusion, MME induces G1 phase cell cycle arrest via both p53-dependent and p53-independent pathways.
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PMID:Inhibition of cell growth and induction of G1-phase cell cycle arrest in hepatoma cells by steroid extract from Meretrix meretrix. 1645 16

It was previously reported that a methanol extract of Gloiopeltis furcata (MEGF), a kind of edible seaweed, inhibited the growth of several human cancer cell lines. In the present study, the effect of MEGF on the growth of human hepatocarcinoma HepG2 cells and its effect on the cyclooxygenases (COXs) expression were investigated. MEGF markedly reduced the viability of HepG2 cells and induced the G2/M arrest of the cell cycle in a concentration dependent manner. These effects were associated with the down-regulation of cyclin A, up-regulation of cyclin-dependent kinase (Cdk) inhibitor p21 (WAF1/CIP1) and dephosphorylation of Cdc25C. Furthermore, it was found that MEGF decreased the levels of COX-2 mRNA and protein expression without significant changes in the levels of COX-1, which was correlated with a decrease in prostaglandin E(2) (PGE(2)) synthesis. These findings indicate that MEGF may have a possible therapeutic potential in hepatoma cancer patients.
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PMID:Methanol extract of the seaweed Gloiopeltis furcata induces G2/M arrest and inhibits cyclooxygenase-2 activity in human hepatocarcinoma HepG2 cells. 1707 9

The objective of this study was to determine in a rat model of hepatocellular carcinoma (HCC) the effects of the antiangiogenic agent TNP-470 on cell proliferation and effectors of the apoptotic pathway, including p53, p21WAF1/CIP1, cyclin D, and cyclin E. Tumor was induced in male Wistar rats by diethylnitrosamine and promoted by two-thirds hepatectomy plus acetaminofluorene administration. Experiments were carried out at 28 weeks after initiating the treatment. TNP-470 was administered at 30 mg/kg, 3 times per week from 20 to 28 weeks. Serum levels of vascular endothelial growth factor (VEGF) and hepatocyte growth factor beta (HGFbeta) liver expression were increased by hepatocarcinogenesis (+38% and +183%, respectively), and treatment with TNP-470 was able to prevent the increase in these angiogenic factors induced by HCC. HCC coursed with reduced expression of p21WAF1/CIP1 and p53 (-63% and -60%, respectively). Hepatic expression of cyclin D and cyclin E were significantly increased in rats with HCC (+108% and +115%, respectively). In animals with experimental carcinogenesis, a significant increase in the expression of Cdk4 and CdK2 was also observed (+119% and +187%, respectively). These effects were prevented by TNP-470 administration. In conclusion, cell-cycle inhibition by TNP-470 is mediated at least in part by an activation of p21WAF1/CIP1 because of a p53-dependent mechanism, with reduction of the cyclin D-Cdk4 and cyclin E-Cdk 2 expression. These cytostatic effects should be considered when assessing the efficacy of TNP-470 for anti-angiogenic therapy. These findings may prove useful for the development of therapies for the treatment of human HCC.
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PMID:Cell-cycle inhibition by TNP-470 in an in vivo model of hepatocarcinoma is mediated by a p53 and p21WAF1/CIP1 mechanism. 1719 22

Integrins, a class of membrane receptors, are major players in transmitting the mechanical force across the plasma membrane. We previously reported that overexpression of integrin beta1 subunit imposed a growth inhibitory effect on the hepatocellular carcinoma cell line SMMC-7721 through transcriptional activation of p21(WAF1/CIP1) gene. In this study, we further determined the molecular mechanisms underlying p21(WAF1/CIP1) expression induced by integrin beta1 overexpression. We report herein that overexpression of integrin beta1 subunit upregulates p21(WAF1/Cip1) transcription through a p53-independent pathway. The overexpressed integrin beta1 activates the p21(WAF1/Cip1) promoter through the Sp1/Sp3 sites and makes more transcription factor Sp1 recruited to the proximal p21 promoter region. In addition, it makes the acetylation value of histone proteins increased across some parts of the p21(WAF1/Cip1) gene, especially in the promoter region. The transcriptional co-activator p300, which possesses intrinsic histone acetyltransferase, was found to be involved in the integrin beta1-mediated histone acetylation and p21 transcriptional activation. Therefore, these findings presented the mechanisms by which integrin beta1 induced the elevated p21 expression in hepatic cancer cells.
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PMID:Increased expression of integrin beta1 subunit enhances p21WAF1/Cip1 transcription through the Sp1 sites and p300-mediated histone acetylation in human hepatocellular carcinoma cells. 1721 49

The objective of this study was to explore whether a specific inhibitor of PI3K, wortmannin, could potentiate the antitumor effect of radiation in vivo, particularly on radioresistant murine tumors. C3H/HeJ mice bearing syngeneic hepatocarcinoma (HCa-I) were treated with 25 Gy radiation, wortmannin, or both. Wortmannin was administered intraperitoneally (1 mg/kg) once daily for 14 days. Tumor response to treatment was determined by a tumor growth delay assay. Possible mechanisms of action were explored by examining the level of apoptosis and regulating molecules. The expression of regulating molecules was analyzed by Western blot for p53 and p21(WAF1/CIP1), and immunohistochemical staining for p21(WAF1/CIP1), CD31 and VEGF. In the tumor growth delay assay, wortmannin increased the effect of tumor radioresponse with an enhancement factor (EF) of 2.00. The level of apoptosis achieved by the combined treatments was shown to be no more than an additive effect; peak apoptotic index was 11% in radiation alone, 13% in wortmannin alone, and 19% in the combination group. Markedly increased areas of necrosis at 24 h in the combination group were noted. Western blotting showed upregulation of p21(WAF1/CIP1) in the combination treatment group, which correlated with low levels of VEGF. Microvascular density was evidently also reduced, based on low expression of CD31. In murine hepatocarcinoma, the antitumor effect of radiation was potentiated by wortmannin. The mechanism seems to involve not only the increase of induced apoptosis but also enhanced vascular injury. Wortmannin, in combination with radiation therapy, may have potential benefits in cancer treatment.
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PMID:Enhancement of tumor radioresponse by wortmannin in C3H/HeJ hepatocarcinoma. 1743 77

Protein kinase C (PKC) superfamily play key regulatory roles on the development of cancer. However, the exact role of these enzymes in human hepatocellular carcinoma (HCC) has not been well established. Using the RT-PCR and Western blotting to analyze the levels of PKC isoforms mRNA and protein in the five different differentiated hepatoma cell lines, we found that PKC alpha was highly expressed in the poor-differentiated HCC cell lines (SK-Hep-1 and HA22T/VGH) as compared with that in the well-differentiated HCC cell lines (PLC/PRF/5, Hep3B, and HepG2). When treated with PKC alpha antisense oligonucleotides (ODN), both HA22T/VGH and SK-Hep-1 cells lines showed the reduction of PKC alpha expression, as well as a deceleration in the growth rate and in the level of cyclin D1, but the increase in the levels of p53 and p21(WAF1/CIP1). Moreover, the reduction of PKC alpha expression also inhibited the migratory and invasive potential of both HA22T/VGH and SK-Hep-1 cells lines, and revealed a down-regulation of several migration/invasion-related genes (MMP-1, u-PA, u-PAR, and FAK). These phenomenon were also confirmed by DNA-based small interfering RNA (siRNA) PKC alpha and PKC alpha/beta specific inhibitor Go6976. Thus, the results indicated that PKC alpha may be associated with regulation of cell proliferation/migration/invasion in human poorly differentiated HCC cells, suggesting a role for the PKC alpha in the malignant progression of human HCC.
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PMID:Reduction of PKC alpha decreases cell proliferation, migration, and invasion of human malignant hepatocellular carcinoma. 1748 87

Strong activation of the ERK signal is required for hepatocyte growth factor (HGF) to inhibit proliferation of the human hepatocellular carcinoma cell line HepG2. However, it is still to be elucidated whether the activation alone is sufficient to induce the inhibitory effect. In this study, we constructed HepG2 cell clones expressing a high level of epidermal growth factor receptor (EGFR), and examined the effect of the strong activation of ERK on the proliferation of the cell clones. EGF treatment of the cell clones induced strong activation of ERK similar to HGF treatment, but did not inhibit cell proliferation. HGF treatment of the cell clones up-regulated the expression of a Cdk inhibitor p16(INK4a), which has previously been shown to be required to inhibit the proliferation of HepG2 cells, but EGF treatment did not. Furthermore, EGF treatment of the cell clones did not induce the up-regulation of another Cdk inhibitor p21(CIP1), whereas HGF treatment did. Knockdown of p21 by siRNA restored the proliferation of HepG2 cells inhibited by HGF, and restored Cdk2 activity suppressed in HGF-treated HepG2 cells. These results suggest that strong activation of ERK alone is not sufficient, and some other pathway(s), which is activated through the HGF receptor but not through EGFR, is also required to induce the up-regulation of p16 and p21 expression, and also suggest that in addition to the up-regulated expression of p16, that of p21 contributes to the suppression of Cdk2 activity leading to the inhibition of proliferation of HGF-treated HepG2 cells.
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PMID:Up-regulation of p21CIP1 expression mediated by ERK-dependent and -independent pathways contributes to hepatocyte growth factor-induced inhibition of HepG2 hepatoma cell proliferation. 1800 40

We previously reported that HS-1200, a synthetic chenodeoxycholic acid derivative, has apoptosis-inducing activity in various human cancer cells. The present study was undertaken to examine whether HS-1200 had an anticancer effect on HepG2 (wild-type p53) and Hep3B (p53 deleted) human hepatoma cells. Treatment of both cells with HS-1200 resulted in growth inhibition and induction of apoptosis as measured by MTT assay, nuclear staining, DNA fragmentation and flow cytometry analysis. The increase in apoptosis was associated with the alteration in the ratio of Bcl-2/Bax protein expression. In addition, flow cytometry analysis indicated that HS-1200 induced G1 phase arrest in both cells. When analyzing the expression of cell cycle-related proteins, we found that HS-1200 reduced the expression levels of cyclin D1, cyclin A, and Cdk2. HS-1200 treatment also caused an increase in the expression levels of p21 WAF1/CIP1 in HepG2 cells in a p53-dependent manner and in Hep3B cells in a p53-independent manner. Moreover, the expression level of p27 KIP1 was increased in both cell lines. We also observed that HS-1200 decreased the levels of cyclooxygenase (COX)-2 mRNA and protein expression. Furthermore, HS-1200 treatment markedly induced the Egr-1 expression at an early time point, and the increased expression levels of p53, p21 WAF1/CIP1, p27 KIP1, and COX-2 after treatment with HS-1200 were completely inhibited in HepG2 cells and partially inhibited in Hep3B cells by silencing of Egr-1, respectively. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anticancer activity of the synthetic bile acid derivative, HS-1200, through Egr-1 regulation.
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PMID:A chenodeoxycholic derivative, HS-1200, induces apoptosis and cell cycle modulation via Egr-1 gene expression control on human hepatoma cells. 1855 81

The N-alpha-acetyltransferase NatB, composed in Saccharomyces cerevisiae by the Nat3p and Mdm20p subunits, is an important factor for yeast growth and resistance to several stress agents. However, the expression and functional role of the mammalian counterpart has not yet been analysed. Here, we report the identification of Nat3p human homologue (hNAT5/hNAT3) and the characterization of its biological function. We found that hNAT5/hNAT3 silencing in HeLa cells results in inhibition of cell proliferation and increased sensitivity to the pro-apoptotic agent MG132. Moreover, inhibition of hNAT5/hNAT3 expression induces p53 activation and upregulation of the antiproliferative protein p21(WAF1/CIP1). The changes of the cellular transcriptome after hNAT5/hNAT3 knockdown confirmed the involvement of this protein in cell growth and survival processes. Among the genes differentially expressed, we observed upregulation of several p53-dependent antiproliferative and pro-apoptotic genes. In the c-myc transgenic mice, which is a model of inducible hepatocarcinoma, we found that hNAT5/hNAT3 was upregulated when the tumour was induced. In accordance with this observation, we noticed increased hNAT5/hNAT3 protein level in neoplastic versus non-neoplastic tissue in a high proportion of patients with hepatocellular carcinoma. Consequently, our results suggest that hNAT5/hNAT3 is required for cellular proliferation and can be implicated in tumour growth.
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PMID:Implication of human N-alpha-acetyltransferase 5 in cellular proliferation and carcinogenesis. 1879 1

Systemic analysis for chromosomal instability and inactivation of cell cycle checkpoints are scarce during hepatocarcinogenesis. We studied 24 patients with chronic B viral cirrhosis including 30 cirrhotic regenerative nodules, 35 low-grade dysplastic nodules, 15 high-grade dysplastic nodules, 7 dysplastic nodules with hepatocellular carcinoma foci, and 18 hepatocellular carcinomas. Eight normal livers were studied as the control group. Telomere length and micronuclei were detected by Southern blot and Feulgen-fast green dyeing technique, respectively, and p21(WAF1/CIP1) expression was studied by immunohistochemistry. Micronuclei >1 per 3000 hepatocytes were found in 17% of low-grade dysplastic nodules, 87% of high-grade dysplastic nodules, and 100% of high-grade dysplastic nodules with hepatocellular carcinoma foci and hepatocellular carcinomas in contrast to those of all normal livers, and 90% of cirrhosis showed no micronuclei. The micronuclei index showed a gradual increase during hepatocarcinogenesis and there was a significant increase between cirrhosis and low-grade dysplastic nodules, low-grade dysplastic nodules and high-grade dysplastic nodules, and high-grade dysplastic nodules and hepatocellular carcinomas. Telomere length showed a gradual shortening during hepatocarcinogenesis and a significant reduction was found in high-grade dysplastic nodules (P=0.024) and hepatocellular carcinomas (P=0.031) compared with normal and cirrhotic livers. The micronuclei index was correlated with telomere shortening (P=0.016). The p21(WAF1/CIP1) labeling index was significantly higher in cirrhosis than in normal livers (P=0.024) and markedly decreased in low-grade dysplastic nodules, high-grade dysplastic nodules, and hepatocellular carcinomas compared with cirrhosis (P<0.05). The p21(WAF1/CIP1) labeling index was associated with telomere length (P<0.001) but not micronuclei index. This study shows that telomere shortening, chromosomal instability, and inactivation of p21(WAF1/CIP1) checkpoint function occur in low-grade dysplastic nodules as well as in high-grade dysplastic nodules, and their cooperation is considered to be critical for malignant transformation during hepatitis B virus associated-multistep hepatocarcinogenesis.
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PMID:Chromosomal instability, telomere shortening, and inactivation of p21(WAF1/CIP1) in dysplastic nodules of hepatitis B virus-associated multistep hepatocarcinogenesis. 1946 4


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