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)

The 14-3-3 proteins form a highly conserved family of dimeric proteins that interact with various signal transduction proteins and regulate cell cycle, apoptosis, stress response, and malignant transformation. We previously demonstrated that the beta isoform of 14-3-3 proteins promotes tumorigenicity and angiogenesis of rat hepatoma K2 cells. In this study, to analyze the mechanism of 14-3-3beta-induced malignant transformation, yeast two-hybrid screening was performed, and a novel 14-3-3beta-binding factor, FBI1 (fourteen-three-three beta interactant 1), was identified. In vitro binding and co-immunoprecipitation analyses verified specific interaction of 14-3-3beta with FBI1. The strong expression of FBI1 was observed in several tumor cell lines but not in non-tumor cell lines. Forced expression of antisense FBI1 in K2 cells inhibited anchorage-independent growth but had no significant effect on cell proliferation in monolayer culture. Down-regulation of FBI1 also inhibited tumorigenicity and metastasis accompanying a decrease in MMP-9 (matrix metalloproteinase-9) expression. In addition, the duration of ERK1/2 activation was curtailed in antisense FBI1-expressing K2 cells. A luciferase reporter assay revealed that the FBI1-14-3-3beta complex could act as a transcriptional silencer, and MKP-1 (MAPK phosphatase-1) was one of the target genes of the FBI1-14-3-3beta complex. Moreover, chromatin immunoprecipitation analysis demonstrated that FBI1 and 14-3-3beta were presented on the MKP-1 promoter. These results indicate that FBI1 promotes sustained ERK1/2 activation through repression of MKP-1 transcription, resulting in promotion of tumorigenicity and metastasis.
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PMID:A novel binding factor of 14-3-3beta functions as a transcriptional repressor and promotes anchorage-independent growth, tumorigenicity, and metastasis. 1846 Apr 65

The objective of this study was to identify genes regulated by thyroid hormone (T(3)) and associated with tumor invasion. The gene encoding furin, as previously identified by cDNA microarray, is known to be up-regulated by T(3) treatment, and stimulated furin production occurs in thyroidectomized rats after administration of T(3). Presently, by using serial deletion of the promoter and EMSAs, the T(3) response element on the furin promoter was localized to the -6317/-6302 region. T(3)-mediated furin up-regulation was cooperative with TGF-beta because T(3) induction increased after Smad3/4 addition. Furthermore, the invasiveness of HepG2-thyroid hormone receptor (TR) cells was significantly increased by T(3) treatment, perhaps due to furin processing of matrix metalloproteinase-2 and -9. In addition, furin up-regulation either by stable overexpression or T(3) and/or TGF-beta induction was evident in severe-combined immune-deficient mice inoculated with HepG2-TRalpha1 cells. The HepG2-furin mice displayed a higher metastasis index and tumor size than HepG2-neo mice. Notably, the increased liver and lung tumor number or size in the hyperthyroid severe-combined immune-deficient mice as well as TGF-beta mice was attributed specifically to furin overexpression in the HepG2-TRalpha1 cells. Furthermore, this study demonstrated that furin overexpression in some types of hepatocellular carcinomas is TR dependent and might play a crucial role in the development of hepatocellular carcinoma. Thus, T(3) regulates furin gene expression via a novel mechanism or in cooperation with TGF-beta to enhance tumor metastasis in vitro and in vivo.
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PMID:Thyroid hormone promotes cell invasion through activation of furin expression in human hepatoma cell lines. 1846 49

The process of cell dissemination from the primary tumors to distant sites is the most harmful event during cancer progression, and the leading cause of cancer death. We have previously demonstrated that restoration of DLC1 tumor suppressor gene expression in the DLC1-negative Focus and 7703K human hepatocellular carcinoma (HCC) cell lines induced caspase-3 mediated apoptosis, reduced cell growth in vitro and tumorigenicity in vivo and diminished the ability to migrate through Matrigel, a property suggestive of metastatic potential in vivo. We now show that subcutaneous tumors developing after inoculation of Focus and 7703K cells into nude mice disseminate cells to liver and lung, and this process is markedly suppressed by restoration of DLC1 expression. Inhibition of tumor cell dissemination was associated with lower levels of RhoA activity, an increase in rounded cells and a reduction in actin stress fibers and focal adhesion molecules that are of critical importance in cancer cell invasion and metastasis. In addition, DLC1 down-regulated the expression of osteopontin and matrix metalloproteinase-9, which are highly up-regulated in most primary HCC with associated metastases. These observations implicate the DLC1 gene in suppression of HCC cell dissemination and identify novel cellular and genetic alterations that contribute to prevention of metastasis, a life-threatening event in cancer progression.
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PMID:DLC1 suppresses distant dissemination of human hepatocellular carcinoma cells in nude mice through reduction of RhoA GTPase activity, actin cytoskeletal disruption and down-regulation of genes involved in metastasis. 1849 90

Benzyl isothiocyanate (BITC) is a hydrolysis compound of glucotropaeolin in cruciferous vegetables. Many studies have reported that BITC prevents cancers in laboratory animals and might also be chemoprotective in humans. The purpose of this study was to investigate the effects of BITC on cell proliferation, metastasis, and MAPK pathways of SK-Hep1 human hepatocellular carcinoma cells. BITC suppressed SK-Hep1 cell proliferation in a dose-dependent manner, and exposure to 1 and 5 microM BITC reduced cell proliferation by 25% and 30%, respectively. The expression of matrix metalloproteinase (MMP)-2, MMP-9, and membrane type-1/MMP (MT-1/MMP) is a known risk factor for metastatic disease. Gelatin zymography analysis revealed a significant downregulation of MMP-2/-9 protein expression in SK-Hep1 cells treated with 0.1-5 microM BITC. BITC treatment caused dose-dependent decreases in MMP-2/-9 and MT1-MMP mRNA levels as determined by RT-PCR. BITC also increased the mRNA levels of tissue inhibitors of matrix metalloproteinases-2 (TIMP-2) 1.3- and 1.5-fold after a 24 h exposure to 1 and 5 microM BITC, respectively. Increased TIMP-2 expression is mediated by the downregulation of MMP-2 and MT1-MMP. BITC inhibited the phosphorylation activities of all three major mitogen-activated protein kinases (MAPKs) in a dose-dependent manner. BITC at 5 microM reduced the ERK1/2 phosphorylation activity by 50% and p38 activity by 70%. BITC also reduced the p-JNK1/2 level by 30% and 70% at 1 and 5 microM treatments, respectively. These data may represent anti-metastatic activities of BITC through the suppression of MAPKs in SK-Hep1 cells.
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PMID:Benzyl isothiocyanate inhibits metalloproteinase-2/-9 expression by suppressing the mitogen-activated protein kinase in SK-Hep1 human hepatoma cells. 1850 15

There are two types of radiopharmaceuticals for cancer imaging with PET. The first target is a marker of cancer proliferation, and positron-labeled analogs of glucose, amino acid, and nucleic acid are commonly used for this purpose. 18F-FDG is a typical tracer of this approach. The second target is visualization of cancer-specific biological characters. In Tohoku University, we developed 18F-fluorodeoxygalactose(18F-FDGal), 18F-SAV03M, and 18F-FRP170 as tracers of the second category. 18F-FDGal is metabolized and trapped in the tissue by liver-specific galactose metabolic enzymes. It is used for detecting well-differentiated hepatocellular carcinoma which originated from liver cells and still maintains the enzymes. 18F-SAV03M is a substrate for matrix metalloproteinase-2 and was developed for the visualization of tumor invasiveness. 18F-FRP170 was developed for the visualization of hypoxic cancer cells which cause radiotherapy and chemotherapy resistance. In addition, the uses of labeled antisense oligonucleotide and aptamers were introduced for the visualization of specific mRNA and proteins expression.
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PMID:[Imaging of biological character of cancer using positron emission tomography(PET)]. 1870 38

Various molecular changes characterizing organ-specific carcinogenesis have been identified in human tumors; however, the molecular mechanisms of the genomic changes specific for each cancer are not well defined. A transgenic (Tg) mouse model with constitutive expression of the nucleotide-editing enzyme, activation-induced cytidine deaminase (AID), develops tumors in various organs as a result of the mutagenic activities of AID. This phenotypic character of AID Tg mice allowed us to analyze the organ-specific genetic changes in tumor-related genes commonly triggered by AID-mediated mutagenesis. Among the 80 AID Tg mice analyzed, 11 mice developed hepatocellular carcinomas, and 7 developed lung cancers. In addition, 1 developed the gastric cancer and 3 developed gastric adenomas. Organ-specific preferences for nucleotide changes were observed in some of the tumor-related genes in each epithelial tissue of the AID Tg mice. Of note, the c-myc and K-ras genes were the preferential targets of the mutagenic activity of AID in lung and stomach cancers, respectively, whereas mutations in the p53 and beta-catenin genes were commonly observed in all 3 organs. Quantitative RT-PCR analyses revealed that alpha-fetoprotein, insulin-like growth factor-2 and cyclin D1 genes were specifically upregulated in HCC, whereas upregulation of the matrix metalloproteinase-7 gene was more marked in lung cancer. Our findings suggest that AID, a DNA mutator that plays a critical role linking inflammation to human cancers, might be involved in the generation of organ-specific genetic diversity in oncogenic pathways during cancer development.
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PMID:Organ-specific profiles of genetic changes in cancers caused by activation-induced cytidine deaminase expression. 1878 63

Numerous studies have shown that the levels of matrix metalloproteinase (MMP)-2 and/or MMP-9 are associated with the invasive phenotypes of cancer cells. This study investigated the effects of caffeic acid phenethyl ester (CAPE), a chemopreventive phytochemical derived from honeybee propolis, on the invasive phenotype of SK-Hep1 human hepatocellular carcinoma cells (SK-Hep1 cells). CAPE effectively suppressed SK-Hep1 cell invasion in a dose-dependent manner. The constitutive expression of MMP-2 and MMP-9 in SK-Hep1 cells was almost completely abolished by treatment with 12.5 muM CAPE. CAPE also significantly inhibited nuclear factor kappa B (NF-kappaB) DNA-binding activity in SK-Hep1 cells. These results taken together suggest that CAPE exerts antimetastatic potential through inhibition of MMP-2 and MMP-9 expression, possibly by targeting NF-kappaB in hepatocellular carcinoma.
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PMID:Caffeic acid phenethyl ester inhibits invasion and expression of matrix metalloproteinase in SK-Hep1 human hepatocellular carcinoma cells by targeting nuclear factor kappa B. 1885 Feb 24

Previous studies have revealed that acetaldehyde-induced cell invasion and matrix metalloproteinase-9 (MMP-9) activation and are directly involved in hepatic tumorigenesis and metastasis. Acetaldehyde is an important substance for tumor regression. We designed this study to aid in the development of powerful anti-cancer drugs with specific tumor regression and anti-metastatic potentials. Optimal drugs should possess both specific MMP-9 enzyme and gene transcriptional activities at the molecular level. Hesperidin, a flavonoid present in fruits and vegetables, possess anti-inflammatory and chemopreventive activities. Hesperidin suppressed acetaldehyde-induced cell invasion and inhibited the secreted and cytosolic MMP-9 forms in HepG2 cells with acetaldehyde. Hesperidin suppressed acetaldehyde-induced MMP-9 expression through the inhibition of nuclear factor-kappaB (NF-kappaB) and AP-1, and suppressed acetaldehyde-stimulated NF-kappaB translocation into the nucleus through IkappaB inhibitory signaling pathways. Hesperidin also inhibited acetaldehyde-induced AP-1 activity by the inhibitory phosphorylation of p38 kinase and c-Jun N-terminal kinase (JNK) signaling pathways. Results from our study revealed that hesperidin suppressed both acetaldehyde-activated NF-kappaB and activator protein 1 (AP-1) activity by IkappaB, JNK, and p38 signaling pathways. This resulted in the reduction of MMP-9 expression, secretion, and hepatocarcinoma cellular invasion. Our result confirmed the therapeutic potential of hesperidin an anti-metastatic and its involvement in the acetaldehyde-induced cell invasiveness of hepatocellular carcinoma in alcoholic patients.
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PMID:Hesperidin inhibited acetaldehyde-induced matrix metalloproteinase-9 gene expression in human hepatocellular carcinoma cells. 1911 45

A majority of patients with HCC present with advanced disease and are not candidates for liver transplantation, surgical resection, or regional therapy. Systemic cytotoxic chemotherapy agents are minimally effective, can have significant toxicity, and have not been shown to improve patient survival. Hepatocellular carcinomas are inherently chemotherapy-resistant tumors and are known to overexpress the multidrug resistance genes. Hepatocellular carcinoma is a very heterogeneous disease in terms of its etiology, molecular carcinogenic mechanisms, and biological behavior, which complicate our ability to identify rational molecular therapeutic "targets." Nearly every pathway involved in carcinogenesis is altered to some degree in HCC. Changes in hepatocyte growth factor expression, intracellular signaling, protease and matrix metalloproteinase expression, and oncogene expression are seen in HCC. The recent demonstration, in randomized clinical trials, of survival benefit for HCC patients treated with the oral agent sorafenib is encouraging progress in the development of molecularly targeted anticancer agents in HCC.
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PMID:Molecular targeted therapy for hepatocellular carcinoma. 1914 8

Des-gamma-carboxy prothrombin (DCP) is an aberrant prothrombin produced by hepatocellular carcinoma (HCC) cells. Serum and tissue DCP expressions are thought to reflect the biological malignant potential of HCC. However, the role of DCP in the development of angiogenesis is not well understood. Herein, we report the effects of DCP on growth and migration of human vascular endothelial cells. DCP significantly stimulated the proliferation of HUVEC (ECV304) cells in a dose and time dependent manner, as measured by the MTT assay. A continuous rapid migration of ECV304 cells was observed in the presence of DCP measured by the scratch wound assay. The continuous rapid invasive activity, measured by transwell chamber assay also showed that DCP increased endothelial cells migration through the reconstituted extracellular matrix (Matrigel). Further, the tube formation of vascular endothelial cells on 3-D Matrigel showed an increased number of branch points of ECV304 cells induced by DCP in a dose dependent manner. The levels of vascular endothelial cell growth-related angiogenic factors and matrix metalloproteinase were also examined. DCP significantly stimulated the expression levels of epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and matrix metalloproteinase (MMP)-2 (latent and active). Together, these data suggest that DCP is a novel type of vascular endothelial growth factor that possesses potent mitogenic and migrative activities in angiogenesis of HCC.
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PMID:Des-gamma-carboxy prothrombin stimulates human vascular endothelial cell growth and migration. 1926 29


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