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)

We evaluated the effects of two putative non-genotoxic hepatic carcinogens, hexabromocyclododecane (HBCD) and 17-beta oestradiol (E(2)) on global and CpG promoter DNA methylation in both primary human hepatocytes and hepatocellular carcinoma (HepG2) cells. The mRNA gene expression levels of genes involved particularly in cell cycle were also evaluated and potential correlation with DNA methylation status examined. HBCD at 0.03 and 0.3 ng/mL did not produce statistically significant differences in global genomic methylation. However, E(2) (0.1 ng/mL) significantly lowered global DNA methylation levels in HepG2 cells by approximately 65% (P<0.01). In primary hepatocytes, the promoter regions of N-cym and ERalpha were methylated in both control and treated groups, signifying lack of promoter demethylation by both HBCD and E(2). Furthermore, CpG promoter methylation of RB1 was observed in HepG2 cells but this was unaffected by treatments. The remaining genes (p16, C-myc, H-ras, THRalpha, histone H3, TBK1 and TNFRalpha) were unmethylated in their CpG promoter regions in both test systems. Quantitative RT-PCR showed that HBCD at 0.03 ng/mL up-regulated the expression of N-cym whereas E(2) up-regulated the expression of ERalpha and THRalpha genes in primary hepatocytes. In HepG2 cells, the mRNA gene expression levels of p16, RB1 and N-cym were significantly down regulated by HBCD (0.03 ng/mL) and E(2) (0.1 ng/mL) while HBCD at 0.3 ng/mL, significantly down regulated the expression levels of N-cym, ERalpha and ERbeta genes. Thus, while both HBCD and E(2) may alter the expression of certain genes involved in proliferation, the mechanisms appear unrelated to DNA methylation.
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PMID:Changes in gene expression and assessment of DNA methylation in primary human hepatocytes and HepG2 cells exposed to the environmental contaminants-Hexabromocyclododecane and 17-beta oestradiol. 1902 19

Studies on rodents and humans demonstrate an inherited predisposition to hepatocellular carcinoma (HCC). Analysis of the molecular alterations involved in the acquisition of a phenotype resistant or susceptible to hepatocarcinogenesis showed a deregulation of G1 and S phases in HCC of genetically susceptible F344 rats and a G1-S block in lesions of resistant Brown norway (BN) rats. Unrestrained extracellular signal-regulated kinase (ERK) activity linked to proteasomal degradation of dual-specificity phosphatase 1 (DUSP1), a specific ERK inhibitor, by the CKS1-SKP2 ubiquitin ligase complex occurs in more aggressive HCC of F344 rats and humans. This mechanism is less active in HCC of BN rats and human HCC with better prognosis. Upregulation of iNos cross-talk with IKK/NF-kappaB and RAS/ERK pathways occurs in rodent liver lesions at higher levels in the most aggressive models represented by HCC of F344 rats and c-Myc-TGF-alpha transgenic mice. iNOS, IKK/NF-kappaB, and RAS/ERK upregulation is highest in human HCC with a poorer prognosis and positively correlates with tumor proliferation, genomic instability and microvascularization, and negatively with apoptosis. Thus, cell cycle regulation and the activity of signal transduction pathways seem to be modulated by HCC modifier genes, and differences in their efficiency influence the susceptibility to hepatocarcinogenesis and probably the prognosis of human HCC.
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PMID:Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis. 1903 60

Comparative analysis of hepatocellular carcinoma (HCC) in rat strains that are either susceptible or resistant to the induction of HCC has allowed the mapping of genes responsible for inherited predisposition to HCC. These studies show that the activity of several low penetrance genes and a predominant susceptibility gene regulate the development of hepatocarcinogenesis in rodents. These studies shed light on the epidemiology of human HCC. The identified genes regulate resistance to hepatocarcinogenesis by affecting the capacity of the initiated cells to grow autonomously and to progress to HCC. Analysis of the molecular alterations showed highest iNos cross-talk with IKK/NF-kB and RAS/ERK pathways in most aggressive liver lesions represented by HCC in the susceptible F344 rats. Unrestrained extracellular signal-regulated kinase (Erk) activity linked to proteasomal degradation of dual-specificity phosphatase 1 (Dusp1), a specific ERK inhibitor, by the CKS1-SKP2 ubiquitin ligase complex was highest in more aggressive HCC of genetically susceptible rats. Furthermore, deregulation of G1 and S phases of the cell cycle occurs in HCC of susceptible F344 rats, leading to pRb hyperphosphorylation and elevated DNA synthesis, whereas a block to G1-S transition is present in the HCC of resistant BN rats. Importantly, similar alterations in the signaling pathways that regulate cell cycle progression were found in human HCC with poorer prognosis (as defend by patients' survival length), whereas human HCC with better prognosis had molecular characteristics similar to the lesions in the HCC of resistant rat strains. This review discusses the role of molecular alterations involved in the acquisition of resistance or susceptibility to HCC and the importance of genetically susceptible and resistant rat models for the identification of prognostic markers, and chemopreventive or therapeutic targets for the biological network therapy of human disease.
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PMID:Genetic and epigenetic control of molecular alterations in hepatocellular carcinoma. 1942 55

Nuclear factor kappaB (NF-kappaB) is one of the main transcription factors involved in regulating apoptosis, inflammation, chronic liver disease, and cancer progression. The IKK complex mediates NF-kappaB activation and deletion of its regulatory subunit NEMO in hepatocytes (NEMO(Delta hepa)) triggers chronic inflammation and spontaneous hepatocellular carcinoma development. We show that NEMO(Delta hepa) mice were resistant to Fas-mediated apoptosis but hypersensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as the result of a strong up-regulation of its receptor DR5 on hepatocytes. Additionally, natural killer (NK) cells, the main source of TRAIL, were activated in NEMO(Delta hepa) livers. Interestingly, depletion of the NK1.1(+) cells promoted a significant reduction of liver inflammation and an improvement of liver histology in NEMO(Delta hepa) mice. Furthermore, hepatocyte-specific NEMO deletion strongly sensitized the liver to concanavalin A (ConA)-mediated injury. The critical role of the NK cell/TRAIL axis in NEMO(Delta hepa) livers during ConA hepatitis was further confirmed by selective NK cell depletion and adoptive transfer of TRAIL-deficient(-/-) mononuclear cells. Our results uncover an essential mechanism of NEMO-mediated protection of the liver by preventing NK cell tissue damage via TRAIL/DR5 signaling. As this mechanism is important in human liver diseases, NEMO(Delta hepa) mice are an interesting tool to give insight into liver pathophysiology and to develop future therapeutic strategies.
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PMID:Hepatocyte-specific NEMO deletion promotes NK/NKT cell- and TRAIL-dependent liver damage. 1963 61

Multitarget compounds that act on a diverse set of regulatory pathways are emerging as a therapeutic approach for a variety of cancers. Toward a more specified use of this approach, we hypothesize that the desired efficacy can be recreated in terms of a particular combination of relatively more specific (i.e., ostensibly single target) compounds. We test this hypothesis for the geldanamycin analogue 17-Allylamino-17-demethoxygeldanamycin (17AAG) in hepatocellular carcinoma cells, measuring critical phosphorylation levels that indicate the kinase pathway effects correlating with apoptotic responsiveness of the Hep3B cell line in contrast to the apoptotic resistance of the Huh7 cell line. A principal components analysis (PCA) constructed from time course measurements of seven phosphoprotein signaling levels identified modulation of the AKT, IkappaB kinase, and signal transducer and activator of transcription 3 pathways by 17AAG treatment as most important for distinguishing these cell-specific death responses. The analysis correctly suggested from 17AAG-induced effects on these phosphoprotein levels that the FOCUS cell line would show apoptotic responsiveness similarly to Hep3B. The PCA also guided the inhibition of three critical pathways and rendered Huh7 cells responsive to 17AAG. Strikingly, in all three hepatocellular carcinoma lines, the three-inhibitor combination alone exhibited similar or greater efficacy to 17AAG. We conclude that (a) the PCA captures and clusters the multipathway phosphoprotein time courses with respect to their 17AAG-induced apoptotic responsiveness and (b) we can recreate, in a more specified manner, the cellular responses of a prospective multitarget cancer therapeutic.
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PMID:Three-kinase inhibitor combination recreates multipathway effects of a geldanamycin analogue on hepatocellular carcinoma cell death. 1967 54

IKK-NF-kappaB signaling is regarded as an important factor in hepatocarcinogenesis and a potential target for liver cancer therapy. Therefore, in this study, we analyzed the expression of mRNAs encoding components and targets of NF-kappaB signaling including IKKalpha, IKKbeta, RANK, RANKL, OPG, CyclinD3, mammary serine protease inhibitor (Maspin), CyclinD1, c-FLIP, Bcl-xl, Stat3, Cip1 and Cip2 by real-time PCR in 40 patients with liver cancer. After statistical analysis, 7 indices including IKKalpha, IKKbeta, RANK, Maspin, c-FLIP, Cip2 and cyclinD1 were found to show significant differences between tumor tissue and its corresponding adjacent tissue. When IKKalpha and IKKbeta were downregulated in the hepatocellular carcinoma (HCC) cell lines of MHCC-97L and MHCC-97H in vitro, the numbers of BrdU positive cells were decreased in both IKKalpha and IKKbeta knockdown cells. Levels of apoptosis were also investigated in IKKalpha and IKKbeta knockdown cells. The growth of HCC was inhibited in the subcutaneous implantation model, and lung metastatogenesis was also significantly inhibited in the kidney capsule transplantation model. Downregulation of IKKalpha and IKKbeta in HCC cultured in vitro revealed that increased Maspin, OPG and RANKL expression was associated with metastasis of HCC. These findings were associated with downregulation of Bcl-XL and c-FLIP, which may be the reason for increased apoptosis. The therapeutic effect of IKKalpha and IKKbeta downregulation depends on extent of NF-kappaB inhibition and the malignant nature of the HCC. We anticipate that IKK-targeted gene therapy can be used in the treatment of HCC, a cancer that is notoriously resistant to radiation and chemotherapy.
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PMID:High expression levels of IKKalpha and IKKbeta are necessary for the malignant properties of liver cancer. 1972 35

Tumor angiogenesis, induced by tumor-secreted pro-angiogenic factors, is an essential process for cancer development and metastasis. CD146 is identified as an endothelial cell adhesion molecule and implicated in blood vessel formation, however, its exact role in angiogenesis, particularly tumor angiogenesis, and its potential function of mediating downstream signaling are still unclear. In present study, we evidenced that silencing endogenous endothelial CD146 by RNAi significantly impaired hepatocarcinoma cell secretions-promoted tubular morphogenesis and -enhanced motility of endothelial cells. Biochemical studies revealed that CD146 was required for the activation of p38/IKK/NF kappaB signaling cascade and up-regulation of NF kappaB downstream pro-angiogenic genes, notably IL-8, ICAM-1 and MMP9, in response to tumor secretions. Interestingly, specific anti-CD146 mAb AA98, which bound a conformational epitope depending on C452-C499 disulfide bond, could abrogate NF kappaB activation and tumor angiogenesis, whereas another anti-CD146 mAb AA1 recognizing a linear epitope containing aa50-54 did not have such effects. Further structure-function analysis identified that C452-C499 disulfide bond within the fifth extracellular Ig domain was indispensible for CD146-mediated signaling and tube formation. Moreover, dimerization of CD146, which was enhanced by tumor secretions and suppressed by AA98 but not AA1, also relied on C452 and C499. Together, this study for the first time uncovered the pro-angiogenic role of CD146 and also pinpointed the key structural basis responsible for its signaling function and dimerization. These findings also suggested that CD146 might serve as not just a cell adhesion molecule but also a membrane signal receptor in tumor-induced angiogenesis.
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PMID:Endothelial CD146 is required for in vitro tumor-induced angiogenesis: the role of a disulfide bond in signaling and dimerization. 1978 48

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

NF-kappaB is a dimeric transcription factor that has emerged as an important regulator of liver homeostasis and is mechanistically implicated in a variety of liver pathologies including hepatitis, steatosis, fibrosis, and hepatocellular carcinoma. The question remains as to whether NF-kappaB can really be exploited for the development of therapeutics for these pathologies in the diseased human liver. This review casts a critical eye on the experimental evidence gathered to date and in particular questions the rationale for the current focus on components of the upstream IKK complex as therapeutic targets. We make the argument that translation of NF-kappaB biology to new therapies is more likely to emerge from a re-focus of basic research back to the NF-kappaB/Rel subunit functions and the complexities of their post-translational modifications and context-dependent co-regulator interactions.
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PMID:NF-kappaB signalling: embracing complexity to achieve translation. 2002 29

Hepatocellular carcinoma (HCC) is the fifth most frequent human cancer and a fatal disease. Therapies with pharmacological agents do not improve the prognosis of patients with unresectable HCC. This emphasizes the need to identify new targets for early diagnosis, chemoprevention, and treatment of the disease. Available evidence indicates that clinical outcome of HCC could reflect the genetic predisposition to cancer development and progression. Numerous loci controlling HCC progression have been identified in rodents. In this review, we describe results of recent studies on effector mechanisms of susceptibility/resistance genes, responsible for HCC progression, aimed at identifying new putative prognostic markers and therapeutic targets of this tumor. Highest c-myc amplification and overexpression, alterations of iNOS crosstalk with IKK/NF-kB and RAS/ERK signaling, ubiquitination of ERK and cell cycle inhibitors, and deregulation of FOXM1 and cell cycle key genes occur in rapidly progressing dysplastic nodules and HCC, induced in genetic susceptible rat strains, compared to the lesions of resistant rats. Notably, alterations of these mechanisms in human HCC subtypes with poorer or better prognosis, are similar to those present in genetically susceptible and resistant rats, respectively, and function as prognostic markers and therapeutic targets. Attempts to cure advanced HCC by molecular therapy directed against specific targets led to modest survival benefit. Thus, efforts are necessary to identify and test, in pre-clinical and clinical studies, new therapeutic targets for combined molecular treatments of HCC. They may take advantage from the comparative analysis of signal transduction in HCCs differently prone to progress, in rats and humans.
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PMID:Prognostic markers and putative therapeutic targets for hepatocellular carcinoma. 2017 48

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