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)

Metastasis is considered to be the major cause of death in patients with cancers, and hepatocellular carcinoma (HCC) is a highly metastatic cancer. Ganoderma lucidum , a well-known mushroom with various biological effects, is a functional food known to contain lucidenic acid. The objectives of this study were to investigate the anti-invasion effect of a lucidenic acid-rich G. lucidum extract (GLE) on human hepatoma HepG2 cells as well as the antiproliferative and antimetastatic effects of GLE in human hepatoma cells implanted into ICR-nu/nu mice. Phorbol-12-myristate-13-acetate (PMA)-induced invasion and matrix metalloproteinase (MMP)-9 expression levels of HepG2 cells were reduced by GLE treatment in a dose-dependent manner. The inhibitory effects of GLE on MMP-9 expression proceeded by inhibiting the phosphorylation of extracellular signal-regulated kinase (ERK1/2) and protein kinase B in the cytosol as well as reducing activator protein-1 and nuclear factor-kappa B levels in the nucleus of HepG2 cells. In a human tumor xenograft model, a dose-response inhibition was observed in the average size, volume, and weight of tumors upon oral administration of GLE. The number of metastatic tumor-bearing mice, the number of affected organs, and the number of tumor foci as well as the MMP-2 and -9 activities in serum of mice were also significantly suppressed by oral administration of GLE. These results suggest that the lucidenic acid-rich GLE could serve as a chemopreventive agent for the tumorigenesis and metastasis of highly invasive hepatoma cells.
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PMID:Inhibitory effects of ganoderma lucidum on tumorigenesis and metastasis of human hepatoma cells in cells and animal models. 1942 27

Hepatocellular carcinoma (HCC) is a major challenge because of its resistance to conventional cytotoxic chemotherapy and radiotherapy. Multi-targeted therapy might be a new option for HCC treatment. Our previous study showed that N-ras gene was activated in HCC and was inhibited by RNA interference. In the present study, we investigated the alternation of gene expression by microarray in N-Ras-siRNA-treated HepG2 cells. The results revealed that the EREG gene, encoding epiregulin, was dramatically up-regulated in response to silence of N-ras. We speculated that the up-regulation of epiregulin was involved in the compensatory mechanism of N-ras knockdown for cell growth. Therefore, we evaluated whether dual silence of N-ras and epiregulin display a greater suppression of cell growth. The results confirmed that dual knockdown of N-ras and epiregulin synergistically inhibited cell growth. Our results also showed that dual knockdown of N-ras and epiregulin significantly induced cell arrest at G0/G1 phase. Furthermore, Western blot assay showed that dual knockdown of N-ras and epiregulin markedly reduced the phosphorylations of ERK1/2, Akt and Rb, and inhibited the expression of cyclin D1. Our findings imply that multi-targeted silence of oncogenes might be an effective treatment for HCC.
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PMID:Dual knockdown of N-ras and epiregulin synergistically suppressed the growth of human hepatoma cells. 1956 83

The role of T-type Ca2+ channels in hepatocellular carcinoma cell proliferation was investigated in vitro. Eleven hepatocellular carcinoma cell lines and one immortalized liver cell line (LO2) were examined for the status of T-type Ca2+ channels with RT-PCR and voltage-clamp recordings. Except HBxF344, other cell lines tested had one, two or all three of alpha1-subunits (alpha1G, alpha1H and alpha1I) mRNA expression. Obvious T-type current was recorded in SNU449 cells, while others exhibited a minimal or no T-type current. SNU449, PLC/PRF5, Hep3B and LO2 cell lines were subjected to growth assay in the presence of Mibefradil, a T-type Ca2+ channel blocker, only the proliferation of SNU449 cell which had functional T-type Ca2+ channel was reduced by Mibefradil treatment. Furthermore, the persistent increase of phosphorylated ERK1/2 in SNU449 cells was found when treated with Mibefradil. A microarray assay also demonstrated some down-regulated genes were mainly associated with cell cycle and cell proliferation in Mibefradil treated SNU449 cells. In conclusion, this study showed that the functional T-type Ca2+ channels probably participate in modulating the proliferation of some hepatocellular carcinoma cells. The cell proliferation reduction of SNU449 with Mibefradil treatment is possibly associated with the persistent increase of phosphorylated ERK1/2.
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PMID:A role of functional T-type Ca2+ channel in hepatocellular carcinoma cell proliferation. 1978 44

Insulin receptor substrate-4 (IRS-4) transmits signals from the insulin-like growth factor receptor (IGF-IR) and the insulin receptor (IR) to the PI3K/AKT and the ERK1/2 pathways. IRS-4 expression increases dramatically after partial hepatectomy and plays an important role in HepG2 hepatoblastoma cell line proliferation/differentiation. In human hepatocarcinoma, IRS-4 overexpression has been associated with tumor development. Herein, we describe the mechanism whereby IRS-4 depletion induced by RNA interference (siRNA) sensitizes HepG2 cells to treatment with actinomycin D (Act D) and combined treatment with Act D plus tumor necrosis factor-alpha (TNF-alpha). Similar results have been obtained in HuH 7 and Chang cell lines. Act D therapy drove the cells to a mitochondrial-dependent apoptotic program involving cytochrome c release, caspase 3 activation, PARP fragmentation and DNA laddering. TNF-alpha amplifies the effect of Act D on HepG2 cell apoptosis increasing c-jun N-terminal kinase (JNK) activity, IkappaB-alpha proteolysis and glutathione depletion. IRS-4 depleted cells that were treated with Act D showed an increase in cytochrome c release and procaspase 3 and PARP proteolysis with respect to control cells. The mechanism involved in IRS-4 action is independent of Akt, IkappaB kinase and JNK. IRS-4 down regulation, however, decreased gamma-glutamylcysteine synthetase content and cell glutathione level in the presence of Act D plus TNF-alpha. These results suggest that IRS-4 protects HepG2 cells from oxidative stress induced by drug treatment.
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PMID:RNAi-mediated silencing of insulin receptor substrate-4 enhances actinomycin D- and tumor necrosis factor-alpha-induced cell death in hepatocarcinoma cancer cell lines. 1979 87

The mitogen-activated protein kinases MEK/ERK pathway regulates fundamental processes in malignant cells and represents an attractive target in the development of new cancer treatments especially for human hepatocarcinoma highly resistant to chemotherapy. Although gene extinction experiments have suggested distinct roles for these proteins, the MEK/ERK cascade remains widely considered as exhibiting an overlap of functions. To investigate the functionality of each kinase in tumorigenesis, we have generated stably knock-down clones for MEK1/2 and ERK1/2 isoforms in the human hepatocellular carcinoma line HuH7. Our results have shown that RNAi strategy allows a specific disruption of the targeted kinases and argued for the critical function of MEK1 in liver tumor growth. Transient and stable extinction experiments demonstrated that MEK1 isoform acts as a major element in the signal transduction by phosphorylating ERK1 and ERK2 after growth factors stimulation, whereas oncogenic level of ERK1/2 phosphorylation appears to be MEK1 and MEK2 dependent in basal condition. In addition, silencing of MEK1 or ERK2 abolished cell proliferation and DNA replication in vitro as well as tumor growth in vivo after injection in rodent. In contrast, targeting MEK2 or ERK1 had no effect on hepatocarcinoma progression. These results strongly corroborate the relevance of targeting the MEK cascade as attested by pharmacologic drugs and support the potential application of RNAi in future development of more effective cancer therapies. Our study emphasizes the importance of the MEK/ERK pathway in human hepatocarcinoma cell growth and argues for a crucial role of MEK1 and ERK2 in this regulation.
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PMID:RNAi-mediated MEK1 knock-down prevents ERK1/2 activation and abolishes human hepatocarcinoma growth in vitro and in vivo. 1981 36

Scutellaria baicalensis is an anti-inflammatory and antineoplastic Chinese herbal therapy. We have previously shown that S. baicalensis can inhibit hepatocellular carcinoma (HCC) cell growth in vitro. In this study, we sought to determine the effect of S. baicalensis on the cell signaling network using our newly developed Pathway Array technology, which screens cell signaling pathways involved in cell cycle regulation. The HCC cell line (HepG2) was treated with S. baicalensis extract in vitro. The effect on the cell cycle was analyzed by flow cytometry, and the expression of various signaling proteins was assayed with Pathway Array. Our results indicate that S. baicalensis exerts a strong growth inhibition of the HepG2 cells via G(2)/M phase arrest. The Pathway Array analysis of 56 proteins revealed a total of 14 differentially expressed proteins or phosphorylations after treatment. Of these, 9 showed a dose-dependent decrease (p53, ETS1, Cdc25B, p63, EGFR, ERK1/2, XIAP, HIF-2alpha, and Cdc25C) whereas one demonstrated a dose-dependent increase (Cyclin E) after treatment with 200 microg/ml of S. baicalensis. Using computer simulation software, we identified additional hubs in the signaling network activated by S. baicalensis. These results indicate that S. baicalensis exerts a broad effect on cell signaling networks leading to a collective inhibition of cell proliferation.
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PMID:The effect of Scutellaria baicalensis on the signaling network in hepatocellular carcinoma cells. 1983 25

Increasing data indicate that stress hormones and their corresponding receptors play an important role in the carcinogenesis and progression of hepatocellular carcinoma (HCC). However, there is presently no study investigating the influence of stress hormones in correlation with beta2-AR on human HCC cells. We examined the expression of alpha1- and beta-ARs in human HCC cell line HepG2 and MHCC97H cells in comparison with that in human normal hepatic cell line HL-7702 cells (L-02), and the influence of isoproterenol (ISO) on the growth of these HCC cells using blocking agents in correlation with beta2-AR and its downstream signaling pathways. We found that alpha1-AR was down-regulated and beta2-AR was up-regulated in HepG2 and MHCC97H cells. ISO dose-dependently promoted the growth of both HepG2 and MHCC97H cells. ISO-induced growth and survival of HCC cells were effectively attenuated by ICI 118551, U0126 and PD153035, but not by H-89 or LY294002. ISO transiently activated MAPK/ERK1/2 in tumor cells which could be blocked either by ICI 118551 or U0126, but not by H-89, LY294002, or PD153035. These findings indicate that ISO mimicking a mitogen promoted the growth of HepG2 and MHCC97H cells via beta2-AR-mediated activation of both MAPK/ERK1/2 dependent and independent signaling pathways, and ISO activated MAPK/ERK1/2 by an EGFR-independent mechanism.
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PMID:The mitogenic effectors of isoproterenol in human hepatocellular carcinoma cells. 1995 75

Hepatocellular carcinoma (HCC) results from the cumulative effects of deregulated tumor suppressor genes and oncogenes. The tumor suppressor and oncogenes commonly affected include growth factors, receptors and their downstream signaling pathway components. The overexpression of transforming growth factor alpha (TGF-alpha) and the inhibition of TGF-beta signaling are especially common in human liver cancer. Thus, we assessed whether TGF-alpha overexpression and TGF-beta signaling inactivation cooperate in hepatocarcinogenesis using an in vivo mouse model, MT1/TGFa;AlbCre/Tgfbr2(flx/flx) mice ("TGFa;Tgfbr2(hepko)"), which overexpresses TGF-alpha and lacks a TGF-beta receptor in the liver. TGF-beta signaling inactivation did not alter the frequency or number of cancers in mice with overexpression of TGF-alpha. However, the tumors in the TGFa;Tgfbr2(hepko) mice displayed increased proliferation and increased cdk2, cyclin E and cyclin A expression as well as decreased Cdkn1a/p21 expression compared to normal liver and compared to the cancers arising in the TGF-alpha overexpressing mice with intact TGF-beta receptors. Increased phosphorylated ERK1/2 expression was also present in the tumors from the TGFa;Tgfbr2(hepko) mice and correlated with downregulated Raf kinase inhibitor protein expression, which is a common molecular event in human HCC. Thus, TGF-beta signaling inactivation appears to cooperate with TGF-alpha in vivo to promote the formation of liver cancer that recapitulates molecular features of human HCC.
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PMID:TGF-beta inactivation and TGF-alpha overexpression cooperate in an in vivo mouse model to induce hepatocellular carcinoma that recapitulates molecular features of human liver cancer. 2002 Apr 90

Epidermal growth factor (EGF) is a key regulator of cell survival and proliferation involved in the pathogenesis and progression of different types of cancer. The EGF receptor (EGFR) is activated by binding of the specific ligand but also by transactivation triggered by different growth factors including GH. Chronically, elevated GH levels have been associated with the progression of hepatocellular carcinoma. Considering EGF and GH involvement in cell proliferation and their signaling crosstalk, the objective of the present study was to analyze GH modulatory effects on EGF signaling in liver. For this purpose, GH receptor-knockout (GHR-KO) and GH-overexpressing transgenic mice were used. EGFR content was significantly decreased in GHR-KO mice. Consequently, EGF-induced phosphorylation of EGFR, AKT, ERK1/2, STAT3, and STAT5 was significantly decreased in these mice. In contrast, EGFR content as well as its basal tyrosine phosphorylation was increased in transgenic mice overexpressing GH. However, EGF stimulation caused similar levels of EGFR, AKT, and ERK1/2 phosphorylation in normal and transgenic mice, while EGF induction of STAT3 and STAT5 phosphorylation was inhibited in the transgenic mice. Desensitization of the STATs was related to decreased association of these proteins to the EGFR and increased association between STAT5 and the tyrosine phosphatase SH2-containing phosphatase-2. While GHR knockout is associated with diminished expression of the EGFR and a concomitant decrease in EGF signaling, GH overexpression results in EGFR overexpression with different effects depending on the signaling pathway analyzed: AKT and ERK1/2 pathways are induced by EGF, while STAT3 and STAT5 activation is heterologously desensitized.
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PMID:GH modulates hepatic epidermal growth factor signaling in the mouse. 2003 99

Na(+)/H(+) exchanger 1 (NHE1) plays a significant role in tumor metastasis. However, the exact mechanisms by which NHE1 mediates cell invasion and migration, especially in hepatocellular carcinoma (HCC), are not yet known. In the current study, we show for the first time that the inhibition of NHE1 by 5-(N-ethyl-N-isopropyl) amiloride (EIPA) is able to suppress migration and invasion of HepG2 cells under hypoxic conditions. In addition, hypoxia activated ERK1/2, which in turn promoted the production of MMP-2, MMP-9 and VEGF. EIPA's suppressive role was determined to act through down-regulation of MMP-2, MMP-9 and VEGF in an ERK1/2 dependent manner. The data demonstrate that NHE1 plays a role in HCC invasion and that NHE1 may be a potential therapeutic target for HCC treatment.
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PMID:Inhibition of Na(+)/H(+) exchanger 1 by 5-(N-ethyl-N-isopropyl) amiloride reduces hypoxia-induced hepatocellular carcinoma invasion and motility. 2033 84


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