Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The investigation of differentially expressed proteins was used together with other techniques to study the inhibitory effects of two different doses of berberine in human liver cancer cell line HepG2. For HepG2 cells treated with 24.0 mg l(-1) of berberine, an increase in the sub G(0) phase that was indicative of cell death was observed in cell cycle analysis with flow cytometry. However, no significant increase in sub G(0) was observed in HepG2 cells treated with 4.0 mg l(-1) of berberine. Using flow cytometric analysis, significant activation of caspase 3 was not observed with HepG2 cells treated with 4.0 and 24.0 mg l(-1) of berberine. In this work, labeling of cells with stable isotope was not used in the proposed method developed. The whole cell lysates from the control and treated cells were digested with trypsin and the peptides were separated by two-dimensional (cation exchange and reversed phase) liquid chromatography and tandem mass spectrometry. Our preliminary data showed that the proposed platform provided a rapid approach to study the molecular mechanism due to the inhibitory effects of different doses of the berberine on HepG2 cell lines. This included a network of proteins involved in mitogen-activated protein kinase (MAPK) phosphorelay systems, metabolism, regulation of cell cycle and DNA damage response. The differentially expressed proteins identified using the current approach were consistent with the data obtained from cell cycle analysis with flow cytometry.
Mol Biosyst 2006 May
PMID:Investigation of differentially expressed proteins due to the inhibitory effects of berberine in human liver cancer cell line HepG2. 1688 Sep 43

Targeted oncolytic viruses and immunostimulatory therapeutics are being developed as novel cancer treatment platforms. These approaches can be combined through the expression of immunostimulatory cytokines from targeted viruses, including adenoviruses and herpesviruses. Although intratumoral injection of such viruses has been associated with tumor growth inhibition, eradication of distant metastases was not reported. The major limitations for this approach to date have been (1) inefficient intravenous virus delivery to tumors and (2) the lack of predictive, immunocompetent preclinical models. To overcome these hurdles, we developed JX-594, a targeted, thymidine kinase(-) vaccinia virus expressing human GM-CSF (hGM-CSF), for intravenous (i.v.) delivery. We evaluated two immunocompetent liver tumor models: a rabbit model with reproducible, time-dependent metastases to the lungs and a carcinogen-induced rat liver cancer model. Intravenous JX-594 was well tolerated and had highly significant efficacy, including complete responses, against intrahepatic primary tumors in both models. In addition, whereas lung metastases developed in all control rabbits, none of the i.v. JX-594-treated rabbits developed detectable metastases. Tumor-specific virus replication and gene expression, systemically detectable levels of hGM-CSF, and tumor-infiltrating CTLs were also demonstrated. JX-594 holds promise as an i.v.-delivered, targeted virotherapeutic. These two tumor models hold promise for the optimization of this approach.
Mol Ther 2006 Sep
PMID:Systemic armed oncolytic and immunologic therapy for cancer with JX-594, a targeted poxvirus expressing GM-CSF. 1684 20

Hepatitis B virus (HBV) is one of the major etiological factors responsible for the development of hepatocellular carcinoma (HCC). We used a transgenic mouse, containing HBV sequences, as a model system to unravel the molecular mechanisms of hepatocarcinogenesis induced by HBV. We chose this animal model because it consistently develops liver cancer after intermediate steps that mimic the natural history of HBV infection in humans. In this study, we focus our attention on the early events leading to liver cancer. We compared the gene expression profile of 3-month-old transgenic mice with that of 3-month-old wild-type (wt) animals. In the transgenic mouse, microarray data analysis showed a total of 45 significantly differentially expressed genes, 25 highly expressed (fold change > or =2; P = 0.0025), and 20 downregulated (fold change < or =0.5; P = 0.0025). These genes belong to several different functional categories such as the regulation of immunological response, transcription, intracellular calcium ion mobilization, regulation of cell cycle and proliferation, NF-kappab signal transduction cascades, and apoptosis. In particular, the upregulation of the antiapoptotic gene NuprI and the downregulation of the proapoptotic gene Bnip3 were found. This observation was supported by an in vitro apoptosis assay that showed downregulation of apoptosis in hepatocytes of HBV transgenic mouse compared with wt mice treated with staurosporine. In conclusion, our experimental approach allowed identification of new genes modulated by HBV and showed that the apoptotic process was deregulated in transgenic mouse hepatocytes. These data shed light on one possible mechanism by which HBV induces hepatocarcinogenesis.
Mol Med
PMID:Gene expression analysis in HBV transgenic mouse liver: a model to study early events related to hepatocarcinogenesis. 1695 57

Hepatocellular carcinoma (HCC) is the leading cause of cancer related deaths in the world, with increasing incidence in many developed countries. Epidemiological data suggest that consumption of soy products may be associated with a decreased risk of cancer. We investigate the effects of genistein on cell proliferation, apoptosis and caspase-3 in DEN induced (200 mg/kg body weight; by single intraperitoneal injection) and Phenobarbital promoted (0.05% through drinking water for 14 successive weeks) cancer-bearing rats. Immunohistochemistry was employed to detect cell proliferating markers proliferating cell nuclear antigen (PCNA), DNA fragmentation was determined by agarose gel electrophoresis and terminal deoxynucleatide transferase dUTP nick labeling (TUNEL) staining and caspase by enzyme-linked immunosorbent assay. We found inhibition of cell proliferation, induction of apoptosis and activation of caspase-3 in genistein treated animals. From these results, we conclude that genistein inhibit cell proliferation, induced apoptosis. This activation of caspsase-3 in genistein treated liver cancer bearing animals correlated well with its apoptosis inducing effect.
Mol Cell Biochem 2007 Mar
PMID:Inhibition of cell proliferation and induction of apoptosis by genistein in experimental hepatocellular carcinoma. 1700 17

Hepatocellular carcinoma (HCC) is a common malignancy in Asia and Africa. We previously reported that overexpression of extracellular signal-regulated kinase (ERK) kinase 1/2 (MEK1/2) and ERK1/2 was detected in HCC, and that their activation was required for liver cancer cell proliferation and survival. In the present study, we determined the efficacy of a specific MEK1/2 inhibitor AZD6244 (ARRAY-142886) in treatment of HCC. Treatment of primary HCC cells with AZD6244 led to growth inhibition, elevation of the cleavage of caspase-3 and caspase-7, and cleaved poly(ADP)ribose polymerase, but inhibition of ERK1/2 and p90RSK phosphorylation. Studying the protein expression profile of seven HCC xenografts revealed that their growth rate was positively correlated with the levels of phosphorylated MEK. AZD6244, when given p.o. to mice bearing these xenografts, resulted in a dose-dependent inhibition of tumor growth. AZD6244-induced growth suppression was associated with inactivation of ERK1/2 and p90RSK, and up-regulation of activated caspase-3 and caspase-7, and cleaved poly(ADP)ribose polymerase. Our data suggest that the MEK-ERK pathway plays an important role in the growth and survival of liver cancer cells and that the HCC xenograft models are excellent tools for screening preclinical drugs. Targeted inhibition of the MEK-ERK pathway with AZD6244 may represent an alternative approach for the treatment of this disease.
Mol Cancer Ther 2007 Jan
PMID:Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma. 1723 74

Previously, we showed that magnolol induces cell-cycle arrest in cultured colon and liver cancer cells through an upregulation of the p21 protein. The aim of this study was to delineate the molecular mechanism underlying this magnolol-induced increase of p21 protein. Thus our RT-PCR analysis demonstrated that the mRNA levels of p21 were increased at 1 h after magnolol treatment and sustained for at least 24 h. The p21 promoter activity was also increased by magnolol treatment. Western blot analysis demonstrated that treatment of COLO-205 cells with magnolol increased the levels of phosphorylation of extracellular signal-regulated kinase (ERK). Pretreatment of the cells with PD98059 abolished the magnolol-induced upregulation of p21 protein, suggesting the involvement of an ERK pathway in the magnolol-induced upregulation of p21 in COLO-205 cells. Ras inhibitor peptide abolished the magnolol-induced increase of phosphorylated ERK protein levels, increase of p21 protein, and decrease of thymidine incorporation. Moreover, treatment of COLO-205 with magnolol increased the phosphorylated Raf-1 protein (the Ras target molecule). Pretreatment of the cells with Raf-1 inhibitor reversed the magnolol-induced decrease in thymidine incorporation. Treatment of the cells with CaM kinase inhibitor, but not protein kinase A (PKA) inhibitor or phosphatidylinosital 3-kinase (PI3K) inhibitor, abolished the magnolol-induced activation of ERK and decrease of thymidine incorporation. Taken together, our results suggest that magnolol activates ERK phosphorylation through a Ras/Raf-1-mediated pathway. Subsequently, p21 expression is increased, and finally thymidine incorporation is decreased.
Mol Carcinog 2007 Apr
PMID:Involvement of Ras/Raf-1/ERK actions in the magnolol-induced upregulation of p21 and cell-cycle arrest in colon cancer cells. 1729 39

Stem cells are characterized by self-renewal and multipotency to produce multiple lineages of progenitor and differentiated cells. PROM1 gene encodes CD133 protein, which is a cell surface marker of hematopoietic stem cells, prostatic epithelial stem cells, pancreatic stem cells, leukemic stem cells, liver cancer stem cells, and colorectal cancer stem cells. Here, comparative integromics analyses on PROM1 orthologs were performed. Human PROM1 RefSeq NM_006017.1 was a truncated transcript, while AK027422.1 was the representative human PROM1 cDNA. Chimpanzee PROM1 gene, consisting of 27 exons, was identified within NW_001234057.1 genome sequence. Chimpanzee 5-transmembrane protein CD133 showed 99.2% and 60.9% total-amino-acid identity with human and mouse CD133 orthologs, respectively. Only 2 of 8 Asn-linked glycosylation sites in primate CD133 orthologs were conserved in rodent CD133 orthologs. Comparative proteomics revealed that CD133 orthologs were relatively divergent between primates and rodents. PROM1 mRNA was expressed in human embryonic stem (ES) cells, trachea, small intestine, NT2 cells, diffuse-type gastric cancer, and colorectal cancer. Human PROM1 mRNA transcribed from exon 1A was the major transcript. Comparative genomics revealed that the region around exon 1A corresponding to 5'-UTR of human PROM1 mRNA was not conserved in mouse and rat. Intron 2 of PROM1 orthologs was relatively well conserved among mammals. Tandem TCF/LEF-binding sites with 7-bp spacing within intron 2 were conserved among human, chimpanzee, mouse, and rat PROM1 orthologs. Together these facts indicate that canonical WNT signaling activation is implicated in CD133 expression in ES cells, adult stem cells, and cancer stem cells.
Int J Mol Med 2007 Jun
PMID:Comparative genomics on PROM1 gene encoding stem cell marker CD133. 1748 31

The role of mast cells in tumor growth is still controversial. In this study we analyzed the effects of both histamine and pre-formed mediators spontaneously released by mast cells on the growth of two human hepatocellular carcinoma cell lines, HA22T/VGH and HuH-6, with different characteristics of differentiation, biological behavior and genetic defects. We showed that total mast cell releasate, exocytosed granules (granule remnants) and histamine reduced cell viability and proliferation in HuH-6 cells. In contrast, in HA22T/VGH cells granule remnants and histamine induced a weak but significant increase in cell growth. We showed that both cell lines expressed histamine receptors H(1) and H(2) and that the selective H(1) antagonist terfenadine reverted the histamine-induced inhibition of HuH-6 cell growth, whereas the selective H(2) antagonist ranitidine inhibited the histamine-induced cell growth of HA22T/VGH cells. We demonstrated that histamine down-regulated the expression of beta-catenin, COX-2 and survivin in HuH-6 cells and that this was associated with caspase-3 activation and PARP cleavage. On the contrary, in HA22T/VGH cells expression of survivin and beta-catenin increased after treatment with granule remnants and histamine. Overall, our results suggest that mediators stored in mast cell granules and histamine may affect the growth of liver cancer cells. However, mast cells and histamine may play different roles depending on the tumor cell features. Finally, these data suggest that histamine and histamine receptor agonists/antagonists might be considered as "new therapeutic" drugs to inhibit liver tumor growth.
Exp Mol Med 2007 Jun 30
PMID:Histamine and spontaneously released mast cell granules affect the cell growth of human hepatocellular carcinoma cells. 1760 79

Hepatocellular carcinoma (HCC), the predominant histological subtype of primary human liver cancer, is one of the most prevalent cancer types worldwide, accounting for an estimated 500,000 deaths annually. The clinical management of HCC is challenging on many counts. HCC is a phenotypically and genetically heterogeneous polyclonal disease and is resistant to most conventional chemotherapy. Early manifestation of HCC is characteristically silent and slow growing with few symptoms, and HCC is therefore often diagnosed at an advanced stage, when potentially curative surgical or local ablative therapy is not feasible. Therefore, clinically validated biomarkers that could confer pathological and functional changes associated with the formation and progression of HCC are urgently needed to provide important molecular basis for the development of novel treatments. Recently, comprehensive molecular gene profiling of primary liver cancer tissues has been employed to identify specific genes that are linked to hepatocarcinogenesis. Current attempts to translate molecular knowledge to design strategies for the experimental gene therapy of HCC are reviewed.
Curr Opin Mol Ther 2007 Aug
PMID:Current approaches in the transcriptional-guided gene therapy of human hepatocellular carcinoma. 1769 50

Liver cancer is one of the most frequent solid cancers that kills more than 650,000 people around the world each year. Though great improvements have been done in last 10 years on the understanding the molecular mechanisms involved in liver oncogenesis, the prognosis of patients affected by liver cancer is still poor for most of them. Even in those where a relatively early diagnosis is done, the course of the disease is often fatal due to the underlying liver cirrhosis. In this review authors report the most recent findings on the pathogenesis of liver cancer and on therapeutic approaches, included those emerging from the most recent literature.
Mol Aspects Med
PMID:Hepatocellular carcinoma: epidemiology and clinical aspects. 1806 Dec 52


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