Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

PTEN gene, a novel tumor suppressor is frequently mutated or deleted in several malignancies including human hepatocellular carcinoma (HCC). We report previously that human hepatitis B virus-X (HBx) protein achieves protection from apoptotic cell death through-PI3K-Akt-Bad signaling that is p53-independent in liver cells (JBC; 276, 16969 (2000)). In this report, we demonstrated the PTEN effect on HBx induced anti-apoptotic signaling in Chang liver cells (CHL). Expression of PTEN in CHL cells downregulate HBx induced PI3K, Akt activities, Akt, Bad phosphorylations, decreased caspase 3 activity and protection from DNA fragmentations. PTEN suppression of CHL cell growth at G1 phase (JBC;278,4057(2003)) in cell cycle analysis, which is overcome by HBx activated Akt/PKB further confirmed that same PI3K/Akt pathway is involved in cell survival and apoptosis by HBx and PTEN. PTEN suppression of HBx-mediated cell survival through PI3K pathway is specific, since PTEN does not suppress the effect of HBx on the protection from Fas-mediated apoptosis. Taken together, these findings demonstrate that PTEN potently modulate HBx-mediated signaling and is a viable target in therapeutic approaches to inhibit the formation of HCC caused by HBV infections.
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PMID:PTEN modulates hepatitis B virus-X protein induced survival signaling in Chang liver cells. 1687 8

Cyclin D1 overexpression is a frequent change in hepatocellular carcinomas (HCCs). Our present study demonstrated that cyclin D1 overexpression with abundant cyclin E, cdk4, cdk2, and p27Kip1 (p27) occurred in neoplastic hepatocytes from the early stage of mouse hepatocarcinogenesis. While cyclin D1 expression was mainly found in the cytoplasm of the tumor cells, it shifted to the nucleus in association with cell proliferation after the animals were subjected to a partial hepatectomy (PH), and then returned once more to the cytoplasm when the cells became quiescent. Inhibition of PI3 kinase (PI3K) by Ly294002 in mouse HCC cells in vitro suppressed the nuclear shift of cyclin D1 as well as cell proliferation, while PI3K activation by PTEN suppression failed to induce nuclear shift of cyclin D1, suggesting that PI3K activation is essential but not sufficient for the cyclin D1 nuclear shift. While MEK-ERK1/2 inhibition by PD98059 and mTOR inhibition by rapamycin affected the cyclin D1 nuclear shift and cell proliferation to a lesser extent, both these inhibitors reduced cyclin D1 levels. Finally, although p27, cdk4 and calmodulin (CaM) were detected in the cyclin D1 immunoprecipitates from both quiescent and proliferating HCC cells, Hsc70 and SSeCKS were detected only in the immunoprecipitate from quiescent cells, and p21Waf1/Cip1 (p21) was detected only in that from proliferating cells, suggesting that the cyclin D1 complex is different in quiescent and proliferating cells. These observations indicate that the nuclear/cytoplasmic localization of cyclin D1 plays an important role in the proliferation/quiescence of neoplastic hepatocytes.
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PMID:Neoplastic hepatocyte growth associated with cyclin D1 redistribution from the cytoplasm to the nucleus in mouse hepatocarcinogenesis. 1701 36

To establish a cell line with a permanent suppression of hLRH-1 in this study, a stable RNAi vector (pSineohLRH-1) targeting hLRH-1 was constructed and introduced into hepatocellular carcinoma cell, BEL-7402. By semiquantitative RT-PCR analysis, the expression of hLRH-1 in BEL-7402 cells carrying pSineohLRH-1 was shown to be significantly suppressed by up to approximately 60%. In addition, microarray analysis was carried out to assess the extent of altered gene expression in BEL-7402 cells with stable knockdown of hLRH-1. Direct comparison of gene-expression profiles of more than 18,000 genes showed that 405 of the expressed genes in hLRH-1-knockdown cells differed dramatically in expression levels from those in controls, which suggested the even extensive biological functions of hLRH-1. Interestingly, among those differentially expressed genes, some are cancer-associated such as Gadd45beta and PTEN, and their expressions were further validated. Although the identification of the exact relationship between these genes and hLRH-1 awaits intensive investigation, the findings of this study provide new insights into the mechanism by which hLRH-1 is involved in tumorigenesis.
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PMID:Microarray analysis of gene-expression profile in hepatocellular carcinoma cell, BEL-7402, with stable suppression of hLRH-1 via a DNA vector-based RNA interference. 1704 88

MAGI-2, a multidomain scaffolding protein, contains nine potential protein-protein interaction modules, including a GuK domain, two WW domains and six PDZ domains. In this study, we examined eight human hepatocarcinoma cell lines (HHCCs) and found that MAGI-2 was expressed only in 7721 cells. After 7721, 7404 and 97H cells were transfected with myc-MAGI-2 plasmid, their migration and proliferation was significantly inhibited, which was associated with downregulation of p-FAK and p-Akt. It is known that p-FAK is a substrate of PTEN and p-Akt can be regulated by PTEN via PIP(3). We demonstrated that PTEN was upregulated after myc-MAGI-2 transfection, which was due to the enhancement of PTEN protein stability rather than mRNA levels. Furthermore, MAGI-2-induced inhibition of cell migration and proliferation was attenuated in 7721 cells with PTEN silence or in PTEN-null cell line U87MG, and PTEN transfection could restore the effect of MAGI-2 in U87MG cells. Finally, the molecular association between PTEN and MAGI-2 was confirmed. Our results suggested that PTEN played a critical role in MAGI-2-induced inhibition of cell migration and proliferation in HHCCs.
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PMID:MAGI-2 Inhibits cell migration and proliferation via PTEN in human hepatocarcinoma cells. 1788 Sep 12

We aimed to evaluate the interaction of two tumor suppressor genes PTEN and p53 and their relationship with cell cycle protein proliferating cell nuclear antigen (PCNA) in hepatocellular carcinoma (HCC). A total of 124 resected HCC paraffin specimens were collected from 1987 to 1999 for immunohistochemistry. Expression of PTEN, p53 and PCNA in HCC were analyzed for clinicopathologic correlation. The study revealed decreased or absent PTEN immunostaining (PTEN down-regulation) in 42.7% and positive p53 (p53+) immunostaining in 41.9% of HCC. There was a positive correlation between PTEN down-regulation and p53 (+) (P=0.001). PTEN down-regulation or p53 (+) correlated with increased HCC dedifferentiation, advanced pathologic stages and high PCNA labeling index (LI) of tumors (P<0.05). Patients with either PTEN down-regulation, p53 (+), or high PCNA LI had shorter survival and higher recurrence rates than patients with intact PTEN expression, p53 (-), or low PCNA LI respectively (P<0.05). By combining the three genes, patients with all PTEN down-regulation (+)/p53 (+)/high PCNA LI had the shortest overall survival (P<0.001) and the highest recurrence rates (P<0.001), followed by patients with two, one and none of three events accordingly. Combination of PTEN/p53/PCNA represented an independent prognostic factor for tumor recurrence and disease-specific survival (P<0.05). In conclusion, the down-regulated PTEN expression and p53 over-expression are involved in the pathogenesis of HCC. They correlate with high PCNA expression, HCC de-differentiation and advanced HCC stages. A combination of the three genes predicts patient outcome more powerfully than any of the individual genes.
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PMID:Down-regulation of tumor suppressor gene PTEN, overexpression of p53, plus high proliferating cell nuclear antigen index predict poor patient outcome of hepatocellular carcinoma after resection. 1798 25

We report here that alpha-lipoic acid (alpha-LA), a naturally-occurring antioxidant, scavenges reactive oxygen species (ROS) followed by an increase in apoptosis of human hepatoma cells. Apoptosis induced by alpha-LA was dependent upon the activation of the caspase cascade and the mitochondrial death pathway. alpha-LA induced increases in caspase-9 and caspase-3 but had no significant effect on caspase-8 activity. Apoptosis induced by alpha-LA was found to be mediated through the tensin homologue deleted on chromosome 10 (PTEN)/Akt pathway. Prior to cell apoptosis, PTEN was activated and its downstream target Akt was inhibited. Our findings indicate that increasing ROS scavenging could be a therapeutic strategy to treat cancer.
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PMID:Alpha-lipoic acid induces apoptosis in hepatoma cells via the PTEN/Akt pathway. 1843 27

Paeonol, a major phenolic component of Moutan Cortex, is known to have antitumor effects through an unknown mechanism. In this study, we tried to elucidate the anticancer effects of paeonol on human hepatocellular carcinoma (HCC) cell lines BEL-7404, SMMC-7721, and MHCC97-H in vitro. Using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, we compared the cytotoxicity of paeonol with the cytotoxicity of 5-fluorouracil (5-FU) in these three HCC cell lines. In addition, we examined the combined effect of paeonol and 5-FU over time, and found that the two compounds inhibited the proliferation of all three human HCC cell lines in a dose-dependent manner. The concentrations that inhibited the proliferation by 50% ranged from 11.39 to 56.23 mg/l for paeonol, and 6.47 to 37.87 mg/l for 5-FU. We determined that exposure to these compounds led to an upregulation of the anti-oncogene PTEN, and the downregulation of the oncogene AKT in the cell lines tested as determined by real-time quantitative reverse transcription-PCR and western blot. In addition, paeonol induced DNA fragmentation in the HCC cell line BEL-7404. These observations suggest that paeonol has the potential to be explored for use as an effective antitumor agent for HCC.
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PMID:Antiproliferative and apoptotic effects of paeonol on human hepatocellular carcinoma cells. 1845 50

PTEN is a critical tumor suppressor gene mutated frequently in various human cancers. Previous studies have showed that PTEN mRNA expression is down-regulated by TGF-beta1 in various cell lines. In present study, we have found that TGF-beta1 down-regulates PTEN mRNA and protein expression in a dose- and time-dependent manner in hepatocarcinoma cell line SMMC-7721. Based on the PTEN promoter dual-luciferase report assay, we have found that PTEN transcription is not affected by TGF-beta1. By using transcriptional inhibitor actinomycin D (Act D), the turnover rate of PTEN transcripts appeared to be accelerated during TGF-beta1 stimulation, which indicated that down-regulation of PTEN by TGF-beta1 was post-transcriptional. What interested us was that transfection of PTEN coding sequence increased TGF-beta1-induced degradation of PTEN mRNA, suggesting that PTEN coding region was account for TGF-beta1-mediated down-regulation of PTEN. In addition, TGF-beta1 down-regulated PTEN expression was blocked by the TbetaIR inhibitor SB431542 and the p38 inhibitor SB203580, suggesting Smad and p38 MAPK signal pathways played crucial roles in PTEN down-regulation via TGF-beta1 stimulation. In this study, we also found TGF-beta1 accelerated down-regulation of PTEN through the ubiquitin-proteasome pathway. Collectively, our data clearly demonstrated that TGF-beta1-mediated down-regulation of PTEN was post-transcriptional and post-translational, depending on its coding sequence, Smad and p38-MAPK signal pathways were involved in this down-regulation.
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PMID:Post-transcriptional and post-translational regulation of PTEN by transforming growth factor-beta1. 1920 63

Here we investigated the in vivo effect of morin (500ppm in diet) in fostering apoptosis in diethylnitrosamine (DEN) (200mg/kg bodyweight) mediated experimental hepatocellular carcinogenesis model. We analyzed the expression of cytosolic protein Akt and their important apoptotic downstream targets like caspase-9, Bcl-2, Bax, GSK-3betain vivo, by immunoblot analysis. In silico docking studies indicated that morin could serve as a better inhibitor than the classical PI3K inhibitor LY294002. The results obtained from in vivo studies confirm this. We also demonstrate here that morin's interaction with a defined set of amino acids of PI3K p110gamma catalytic subunit resulted in the down-regulation of p-Akt(Ser473), p-Akt(Thr308) and total Akt causing the attenuation of its downstream targets in DEN-induced hepatocellular carcinoma. Further, morin caused the up-regulation of tumor suppressor PTEN, an important negative regulator of Akt, thus initiating apoptosis. Supplementation of morin to experimental animals modulated Bcl-2/Bax ratio causing the release of cyt C and up-regulation of caspase-3 and -9. Morin was also found to prevent the Akt-mediated suppression of GSK-3beta possibly causing cell cycle arrest at the G1/S phase. These observations were supported by the DNA fragmentation and transmission electron microscopy results, which showed the occurrence of apoptosis. In conclusion, our findings demonstrate that morin begets apoptosis in DEN-induced hepatocellular carcinoma.
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PMID:Morin fosters apoptosis in experimental hepatocellular carcinogenesis model. 1993 19

Lung and liver cancers are among the most deadly types of cancer. Despite improvements in treatment over the past few decades, patient survival remains poor, underlining the need for development of targeted therapies. MicroRNAs represent a class of small RNAs frequently deregulated in human malignancies. We now report that miR-221&222 are overexpressed in aggressive non-small cell lung cancer and hepatocarcinoma cells, as compared with less invasive and/or normal lung and liver cells. We show that miR-221&222, by targeting PTEN and TIMP3 tumor suppressors, induce TRAIL resistance and enhance cellular migration through the activation of the AKT pathway and metallopeptidases. Finally, we demonstrate that the MET oncogene is involved in miR-221&222 activation through the c-Jun transcription factor.
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PMID:miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. 1996 68


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