UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The kringle 1 domain of human hepatocyte growth factor (HGFK1) was previously shown to inhibit bovine aortic endothelial cell proliferation, suggesting that it might be an antiangiogenic molecule. Here, we evaluated the in vivo efficacy of a recombinant adenoassociated virus carrying HGFK1 (rAAV-HGFK1) for the treatment of hepatocellular carcinoma (HCC) in a rat orthotopic HCC model and explored its molecular mechanisms in vitro in both endothelial and tumor cells. We first showed that rAAV-HGFK1 treatment significantly prolonged the survival time of rats transplanted with tumor cells. Treatment with rAAV-HGFK1 inhibited tumor growth, decreased tumor microvessel density, and completely prevented intrahepatic, lung, and peritoneal metastasis in this in vivo model. In vitro, rAAV-HGFK1 exhibited both antiangiogenic and antitumor cell effects, inhibiting the proliferation of both murine microvascular endothelial cells (MEC) and tumor cells, and inducing apoptosis and G(0)-G(1) phase arrest in these cells. To our surprise, rAAV-HGFK1 did not act through the hepatocyte growth factor/hepatocyte growth factor receptor pathway. Instead, it worked mainly through epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) signaling, with more minor contributions from vascular endothelial growth factor/vascular endothelial growth factor receptor and beta fibroblast growth factor (bFGF)/beta fibroblast growth factor receptor (bFGFR) signaling. In both MECs and tumor cells, rAAV-HGFK1 acted through two pathways downstream of EGFR, namely inhibition of extracellular signal-regulated kinase activation and stimulation of p38 mitogen-activated protein kinase/c-Jun-NH(2)-kinase activation. These results suggest for the first time that HGFK1 exerts both antiangiogenic and antitumor cell activities mainly through EGF/EGFR signaling, and may thus be considered as a novel therapeutic strategy for the treatment of HCC.
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PMID:The kringle 1 domain of hepatocyte growth factor has antiangiogenic and antitumor cell effects on hepatocellular carcinoma. 1819 34

Hepatocellular carcinoma has been described to exhibit characteristics similar to that of neuroendocrine tumors (NETs). This includes similar anti-neoplastic responses to extracellular signal-regulated kinase (ERK) activation. NET cells and HepG2 cells have both shown growth inhibition with ERK activation. ZM336372, a Raf-1 activating agent, has been shown to cause growth inhibition and suppression of hormone secretion in a neuroendocrine cell line. Here we examine treatment of the HepG2 cell line with ZM336732 to determine if a similar anti-proliferative response will be obtained. HepG2 cells were treated with ZM336372 or solvent (dimethyl sulfoxide). The resulting effect on the proliferation was measured using the 3,4-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Western blot analysis was performed to examine the activation of the Raf-1/mitogen-activated protein kinase kinase/ERK pathway, chromogranin A production, and p21CIP1 level. Growth inhibition was observed with ZM336372 in a dose-dependent fashion. Minimal baseline phosphorylation of ERK 1/2 was observed; however, activation was observed after treatment with ZM336372. Chromogranin A secretion was suppressed due to treatment with ZM336372. A dose-dependent up-regulation of p21CIP1 was observed in response to ZM336372 treatment. ZM336372 causes growth inhibition, suppression of hormone secretion, and up-regulation of cell cycle inhibitors in a human hepatocellular carcinoma cell line, similar to that previously seen in NETs.
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PMID:ZM336372, a Raf-1 activator, causes suppression of proliferation in a human hepatocellular carcinoma cell line. 1829 43

Caffeine has been reported to prevent hepatocarcinogenesis. We investigated the molecular mechanisms by which caffeine inhibits the growth of hepatocellular carcinoma (HCC) cells. We found that caffeine inhibited the proliferation of HCC cells via cell cycle arrest independent of apoptosis. We revealed a novel signalling axis for caffeine involving activation of the mitogen-activated ERK-regulating kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway that resulted in the downstream up-regulation of epidermal growth factor receptor (EGFR), although the MEK/ERK/EGFR signalling pathway was not involved in the growth inhibitory effect of caffeine. Our data reveal that caffeine could be a promising candidate for the treatment of patients with HCC.
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PMID:Caffeine inhibits the proliferation of liver cancer cells and activates the MEK/ERK/EGFR signalling pathway. 1834 49

Hepatocellular carcinoma (HCC) is associated with a poor prognosis due to late diagnoses and a lack of effective treatment options. Epidermal growth factor receptor (EGFR)-targeted therapies have been effective in other cancers. However, erlotinib and cetuximab have shown only modest efficacy in clinical trials of HCC. We examined epithelial-to-mesenchymal transition (EMT) as a determinant of sensitivity of HCC to EGFR inhibitors. A panel of 12 human hepatoma cell lines were classified as epithelial or mesenchymal based on their expression of E-cadherin and vimentin. The resulting classification correlated with a previous microarray analysis of human hepatoma cell lines whereby the mesenchymal cell lines were shown to have increased expression of genes involved in metastasis and invasion. Sensitivity to erlotinib, gefitinib, and cetuximab was assessed and the epithelial cell lines were found to be significantly more susceptible to all three agents. Analysis of the EGFR pathway showed that EMT status was independent of EGFR expression or downstream extracellular signal-regulated kinase activation and only the epithelial cell lines expressed ErbB3. Interestingly, mesenchymal cells resistant to EGFR inhibitors had increased AKT and signal transducer and activator of transcription-3 activation through elevated expression of integrin-linked kinase (ILK). Mesenchymal cell lines were therefore experimentally transformed with kinase-inactive ILK (KI-ILK) with a resulting decrease in ILK activity and activation of AKT. KI-ILK transformants showed increased sensitivity to EGFR inhibitors both in vitro and in an in vivo xenograft model. These data suggest that EMT predicts HCC sensitivity to EGFR-targeted therapies and that ILK is a novel target to overcome HCC resistance to EGFR inhibition.
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PMID:Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells. 1838 47

Glypican-3 (gpc3) is the gene responsible for Simpson-Golabi-Behmel overgrowth syndrome. Previously, we have shown that GPC3 is overexpressed in hepatocellular carcinoma (HCC). In this study, we demonstrated the mechanisms for GPC3-mediated oncogenesis. Firstly, GPC3 overexpression in NIH3T3 cells gave to cancer cell phenotypes including growing in serum-free medium and forming colonies in soft agar, or on the other way, GPC3 knockdown in HuH-7 cells decreased oncogenecity. We further demonstrated that GPC3 bound specifically through its N-terminal proline-rich region to both Insulin-like growth factor (IGF)-II and IGF-1R. GPC3 stimulated the phosphorylation of IGF-1R and the downstream signaling molecule extracellular signal-regulated kinase (ERK) in an IGF-II-dependent way. Also, GPC3 knockdown in HCC cells decreased the phosphorylation of both IGF-1R and ERK. Therefore, GPC3 confers oncogenecity through the interaction between IGF-II and its receptor, and the subsequent activation of the IGF-signaling pathway. This data are novel to the current understanding of the role of GPC3 in HCC and will be important in future developments of cancer therapy.
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PMID:Glypican-3-mediated oncogenesis involves the Insulin-like growth factor-signaling pathway. 1841 66

Heat shock protein 27, one of the low molecular weight stress proteins, is recognized as a molecular chaperone; however, other functions have not yet been well established. Phosphorylated heat shock protein 27 levels inversely correlate with the progression of human hepatocellular carcinoma. This study shows that phosphorylated heat shock protein 27 interferes with cell growth of the hepatocellular carcinoma-derived HuH7 cells in the presence of the proinflammatory cytokine, tumor necrosis factor-alpha, via inhibition of the sustained activation of the extracellular signal-regulated kinase signal pathway. The activities of Raf/extracellular signal-regulated kinase and subsequent activator protein-1 transactivation and the induction levels of cyclin D1 were lower in HuH7 cells transfected with phosphorylated heat shock protein 27 than those with unphosphorylated heat shock protein 27. Moreover, phosphorylated heat shock protein 27 up-regulated the levels of p38 mitogen-activated protein kinase and mitogen-activated protein kinase phosphatase-1, an inhibitory protein of extracellular signal-regulated kinase. These results indicate that phosphorylated heat shock protein 27 might suppress the extracellular signal-regulated kinase activity in the hepatocellular carcinoma cells via two separate pathways in an inflammatory state. The extracellular signal-regulated kinase activity is inversely correlated with phosphorylated heat shock protein 27 at serine 15 and also in human hepatocellular carcinoma tissues in vivo. Because the extracellular signal-regulated kinase signal pathway is a major proliferation signal of hepatocellular carcinoma, activator protein-1 activation is an early event in hepatocarcinogenesis. These findings strongly suggest that the control of the phosphorylated heat shock protein 27 levels could be a new therapeutic strategy especially to counter the recurrence of hepatocellular carcinoma.
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PMID:Phosphorylated heat shock protein 27 represses growth of hepatocellular carcinoma via inhibition of extracellular signal-regulated kinase. 1847 63

Sustained activation of extracellular signal-regulated kinase (ERK) has been detected previously in numerous tumors in the absence of RAS-activating mutations. However, the molecular mechanisms responsible for ERK-unrestrained activity independent of RAS mutations remain unknown. Here, we evaluated the effects of the functional interactions of ERK proteins with dual-specificity phosphatase 1 (DUSP1), a specific inhibitor of ERK, and S-phase kinase-associated protein 2 (SKP2)/CDC28 protein kinase 1b (CKS1) ubiquitin ligase complex in human hepatocellular carcinoma (HCC). Levels of DUSP1, as assessed by real-time reverse transcription-PCR and Western blot analysis, were significantly higher in tumors with better prognosis (as defined by the length of patients' survival) when compared with both normal and nontumorous surrounding livers, whereas DUSP1 protein expression sharply declined in all HCC with poorer prognosis. In the latter HCC subtype, DUSP1 inactivation was due to either ERK/SKP2/CKS1-dependent ubiquitination or promoter hypermethylation associated with loss of heterozygosity at the DUSP1 locus. Noticeably, expression levels of DUSP1 inversely correlated with those of activated ERK, as well as with proliferation index and microvessel density, and directly with apoptosis and survival rate. Subsequent functional studies revealed that DUSP1 reactivation led to suppression of ERK, CKS1, and SKP2 activity, inhibition of proliferation and induction of apoptosis in human hepatoma cell lines. Taken together, the present data indicate that ERK achieves unrestrained activity during HCC progression by triggering ubiquitin-mediated proteolysis of its specific inhibitor DUSP1. Thus, DUSP1 may represent a valuable prognostic marker and ERK, CKS1, or SKP2 potential therapeutic targets for human HCC.
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PMID:Dual-specificity phosphatase 1 ubiquitination in extracellular signal-regulated kinase-mediated control of growth in human hepatocellular carcinoma. 1851 78

A newly synthesized dithiocarbamate derivative, 4-methylpiperazine-1-carbodithioc-acid-3-cyano-3,3-diphenylpropyl ester hydrochloride (TM208), has demonstrated anticancer effects with low toxicity in earlier studies; however, the mechanism has yet to be identified. We explored antitumor effects of TM208 and the possible mechanisms by which it inhibited the growth of human hepatocellular carcinoma cell line QGY-7703 xenograft tumors. Cell proliferation was evaluated with the sulforhodamine B assay in vitro. The results suggested that TM208 had slightly antiproliferative activity on QGY-7703 cells. The antitumor effect of TM208 was assessed in nude mice xenografted with QGY-7703 tumors. We found that TM208 significantly inhibited tumor growth but did not cause loss of body weight or leukocytopenia. Western blotting was used to detect the expression of protein kinase C alpha, mitogen-activated protein kinase signal pathways, and cell cycle-related proteins. The results showed that TM208 decreased the expression of protein kinase C alpha, phospho-extracellular signal-regulated kinase-1/2, phospho-p38, cyclin B1, cell division cycle 2 (cdc2), and phospho-cdc2 (Thr161) and increased the expression of phospho-cdc2 (Tyr15). Taken together, our data show that TM208 has little antiproliferative effect on QGY-7703 cells in vitro, whereas it significantly inhibits the growth of QGY-7703 xenograft tumors with low toxicity in vivo. The inhibition of mitogen-activated protein kinase signal pathways and the regulation of the G2/M phase may be responsible for its antitumor effects.
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PMID:Effect of TM208 on QGY-7703 xenograft tumor growth. 1852 18

Insulin-like growth factor-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of gastrointestinal (GI) cancers. In this study, we sought to evaluate the effect of a new tyrosine kinase inhibitor of IGF-IR, NVP-AEW541, on the signal transduction and the progression of GI carcinomas. We assessed the effect of NVP-AEW541 on signal transduction, proliferation, survival, and migration in four GI cancer cells: colorectal adenocarcinoma HT29, pancreatic adenocarcinoma BxPC3, esophageal squamous cell carcinoma TE1, and hepatoma PLC/PRF/5. The effects of NVP-AEW541 alone and with chemotherapy were studied in vitro and in nude mouse xenografts. We also analyzed the effects of NVP-AEW541 on insulin signals and hybrid receptor formation between IGF-IR and insulin receptor. NVP-AEW541 blocked autophosphorylation of IGF-IR and both Akt and extracellular signal-regulated kinase activation by IGF but not by insulin. NVP-AEW541 suppressed proliferation and tumorigenicity in vitro in a dose-dependent manner in all cell lines. The drug inhibited tumor as a single agent and, when combined with stressors, up-regulated apoptosis in a dose-dependent fashion and inhibited mobility. NVP-AEW541 augmented the effects of chemotherapy on in vitro growth and induction of apoptosis. Moreover, the combination of NVP-AEW541 and chemotherapy was highly effective against tumors in mice. This compound did not influence hybrid receptor formation. Thus, NVP-AEW541 may have significant therapeutic utility in human GI carcinomas both alone and in combination with chemotherapy.
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PMID:Insulin-like growth factor-I receptor blockade by a specific tyrosine kinase inhibitor for human gastrointestinal carcinomas. 1856 19

Since hepatocellular carcinoma (HCC) is a hypervascular cancer, anti-angiogenic therapy is a promising approach to treat HCC. In the present study, we investigated the antiangiogenic and antitumor effects of tum-1, a fragment of tumstatin, gene transduction into HCC in vitro and in vivo. Tum-1 gene was cloned into a pSecTag2B mammalian expression vehicle to construct pSecTag2B-tum-1. pSecTag2B-tum-1 or vehicle were transfected into human HCC cells, PLC/PRF/5 cells stably and Huh-7 cells tran-siently. pSecTag2B-tum-1 transfection slightly repressed the proliferation of both PLC/PRF/5 and Huh-7 cells in vitro. Addition of conditioned media (CM) from tum-1 expressing PLC/PRF/5 cells significantly inhibited the spontaneous and vascular endothelial growth factor (VEGF)-induced proliferation and migration of human umbilical vein endothelial cells (HUVEC) in vitro with diminishing the VEGF-induced phosphorylation of both Akt and extracellular signal-regulated kinase (ERK) that are known to mediate VEGF-induced proliferation and migration of endothelial cells. In in vivo experiments, intratumoral injection of pSecTag2B-tum-1 significantly repressed the growth of pre-established Huh-7 tumors in athymic mouse models accompanying the decreased density of CD34 positive vessels in tumors. In conclusion, our results suggest that antiangiogenic gene therapy using tum-1 gene may be an efficient strategy for the treatment of HCC.
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PMID:Tum-1, a tumstatin fragment, gene delivery into hepatocellular carcinoma suppresses tumor growth through inhibiting angiogenesis. 1857 48

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