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)

Transforming growth factor-beta (TGF-beta)-Smad signaling pathway participates in the regulation of a variety of cellular activities. Unlike the high incidences of Smad4 mutation or deletion in pancreatic cancer and gastrointestinal cancers, Smad4 gene is seldom mutated or deleted in hepatocellular carcinoma (HCC). The role of TGF-beta-Smad4 signaling pathway in leading to carcinogenesis of liver cells remains unknown. In this study, we succeeded in silencing Smad4 using lentiviral-mediated Smad4 RNA interference (RNAi). We investigated the role of Smad4 in TGF-beta1-induced cell proliferation and apoptosis of HCC cell line SMMC-7721. We determined cell proliferation, apoptosis, and expression of p21, p16, p53 and caspase 3. Results showed that TGF-beta1 not only had a significant anti-proliferation effect but also induced cellular apoptosis in SMMC-7721 cells. These effects induced by TGF-beta1 were almost completely blocked by the knockdown of Smad4. Western blot analysis revealed that p16 was up-regulated and caspase 3 was activated by silencing of Smad4, and the expression of p21 and wild-type p53 were not affected. These results suggest that TGF-beta1-induced cell growth inhibition by up-regulating p16 expression and cellular apoptosis by activating caspase 3 was Smad4-dependent. Additionally, the knock down of a specific gene using lentiviral-mediated RNAi appears to be a promising tool and strategy for analyzing endogenous gene function.
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PMID:Lentiviral-mediated Smad4 RNAi induced anti-proliferation by p16 up-regulation and apoptosis by caspase 3 down-regulation in hepatoma SMMC-7721 cells. 1894 1

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

Cellular senescence is a process leading to terminal growth arrest with characteristic morphological features. This process is mediated by telomere-dependent, oncogene-induced and ROS-induced pathways, but persistent DNA damage is the most common cause. Senescence arrest is mediated by p16(INK4a)- and p21(Cip1)-dependent pathways both leading to retinoblastoma protein (pRb) activation. p53 plays a relay role between DNA damage sensing and p21(Cip1) activation. pRb arrests the cell cycle by recruiting proliferation genes to facultative heterochromatin for permanent silencing. Replicative senescence that occurs in hepatocytes in culture and in liver cirrhosis is associated with lack of telomerase activity and results in telomere shortening. Hepatocellular carcinoma (HCC) cells display inactivating mutations of p53 and epigenetic silencing of p16(INK4a). Moreover, they re-express telomerase reverse transcriptase required for telomere maintenance. Thus, senescence bypass and cellular immortality is likely to contribute significantly to HCC development. Oncogene-induced senescence in premalignant lesions and reversible immortality of cancer cells including HCC offer new potentials for tumor prevention and treatment.
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PMID:Senescence and immortality in hepatocellular carcinoma. 1907 Apr 23

The Hint1 protein, a member of the histidine triad (HIT) family, is highly conserved in diverse species and ubiquitously expressed in mammalian tissues. Previous studies in mice provided evidence that Hint1 may be haploinsufficient with respect to its function as a tumor suppressor. In the present study, we investigated the aberrant methylation of Hint1 and explored possible relationships between aberrant methylation and clinicopathological features in hepatocellular carcinoma (HCC). Hypermethylation of Hint1 was evaluated by the methylation specific PCR (MSP) method in 40 patients with HCC (tumor and paired adjacent non-tumor tissues) from Taiwan, 22 cases of normal liver tissue (14 from Taiwan and 8 from the US). HINT1 expression in tissues was detected by immunohistochemistry. The frequencies of hypermethylation of Hint1 in tumor, paired adjacent non-tumor and normal liver tissue were 55.0%, 37.5% and 9.1%, respectively. A statistically significant inverse association was found between Hint1 methylation status and expression of the HINT1 protein in tumor tissues (p=0.003). The relationship between Hint1 methylation status and clinical features and other, previously measured biomarkers was also analyzed. p16 hypermethylation was statistically significantly associated with Hint1 methylation status (p=0.035). There were no correlations between Hint1 methylation and hepatitis B (HBV) or hepatitis C (HCV) infection status or aflatoxin B(1) (AFB(1)-) and polycyclic aromatic hydrocarbons (PAHs)-DNA adduct levels. These results suggest that promoter hypermethylation of Hint1 may play a role in hepatocarcinogenesis.
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PMID:Silencing of Hint1, a novel tumor suppressor gene, by promoter hypermethylation in hepatocellular carcinoma. 1908 73

Many tumors are resistant to drug-induced cell-cycle arrest and apoptosis. We have reported that apoptosis can be restored in human multidrug-resistant (MDR) hepatocellular carcinoma cell lines by celecoxib. Here we show that P-glycoprotein (P-gp) mediates cell-cycle arrest and autophagy induced by celecoxib in human MDR overexpressing hepatocellular carcinoma cell line by down-regulation of the HGF/MET autocrine loop and Bcl-2 expression. Exposure of cells to a low concentration of celecoxib down-regulated the expression of mTOR and caused G1 arrest and autophagy, while higher concentration triggered apoptosis. Cell growth inhibition and autophagy were associated with up-regulation of the expression of TGFbeta1, p16(INK4b), p21(Cip1) and p27(Kip1) and down-regulation of cyclin D1, cyclin E, pRb and E2F. The role of P-glycoprotein expression in resistance of MDR cell clone to cell-cycle arrest, autophagy and apoptosis was shown in cells transfected with MDR1 small interfering RNA. These findings demonstrate that the constitutive expression of P-gp is involved in the HGF/MET autocrine loop that leads to increased expression of Bcl-2 and mTor, inhibition of eIF2alpha expression, resistance to autophagy/apoptosis and progression in the cell-cycle. Since mTor inhibitors have been proposed in treatment of "drug resistant" cancer, these data may help explain the reversing effect of mTor inhibitors.
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PMID:Down-regulation of the HGF/MET autocrine loop induced by celecoxib and mediated by P-gp in MDR-positive human hepatocellular carcinoma cell line. 1944 20

Hepatocyte growth factor (HGF) inhibits the proliferation of several tumor cell lines and tumor growth in vivo. We showed previously that HGF induces cell cycle arrest at G1 in a human hepatoma cell line, HepG2, by up-regulating the expression of p16INK4a through strong activation of extracellular signal-regulated kinase (ERK). However, although essential, the activation was not sufficient for the up-regulation of p16. In this study, we examined regulatory mechanisms of p16 expression through a transcription factor, Ets, which has been shown previously to bind to the promoter. The treatment of HepG2 cells with HGF induced ERK-dependent phosphorylation of Ets, which leads to its activation, before the up-regulation of p16, suggesting that another factor suppresses Ets activity. We found that HGF reduces the amount of Id1, which is a dominant-negative inhibitor of Ets, leading to a decrease in Ets associated with Id1. Id1 was down-regulated via transcriptional regulation not via the ubiquitin-proteasome-mediated pathway. Inhibition of the HGF-induced high-intensity ERK activity had a modest effect on the Id1 down-regulation, and inhibition of the phosphatidylinositol 3-kinase pathway had no effect, showing that Id1 is regulated by ERK-dependent and -independent pathways other than the phosphatidylinositol 3-kinase pathway. Exogenously expressed Id1 suppressed the up-regulation of p16 by HGF and the antiproliferative effect of HGF. Knockdown of Id1 significantly enhanced the activity of the p16 promoter coordinately with the activation of ERK. Our results indicated that down-regulation of Id1 plays a key role in the inhibitory effect of HGF on cell proliferation and provides a molecular basis for cancer therapy with HGF.
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PMID:Id1 is down-regulated by hepatocyte growth factor via ERK-dependent and ERK-independent signaling pathways, leading to increased expression of p16INK4a in hepatoma cells. 1956 83

Cellular senescence is an important tumor suppression process under diverse oncogenic conditions, entering a state of irreversible growth arrest to prevent damaged cells from undergoing aberrant proliferation. Developing a means of evading senescence thus seems to be a fundamental task that all cancer cells should solve early on. Here, we show that an oncogenic X protein of hepatitis B virus (HBx) overcomes cellular senescence provoked by a universal premature senescence inducer, H(2)O(2), in human hepatoma cells, as demonstrated by impaired induction of senescence-associated biomarkers, including morphological change, G(1) arrest, and beta-galactosidase activity, in the presence of HBx. HBx induced DNA hypermethylation of p16(INK4a) promoter and subsequently interfered action of transcription factors like Ets1 and Ets2 activated by H(2)O(2) through the p38(MAPK) pathway, resulting in inhibition of its transcription. Down-regulation of p16(INK4a) expression by HBx subsequently led to activation of G(1)-CDKs, phosphorylation of Rb, activation of E2F1, and finally evasion from G(1) arrest induced by H(2)O(2). Levels of another senescence regulator, p21(waf1), however, were not affected by HBx under our senescence-inducing conditions. In addition, the potentials of HBx to inactivate Rb and subsequently inhibit cellular senescence almost completely disappeared when levels of p16(INK4a) were recovered either by exogenous complementation or inhibition of the promoter hypermethylation. To our knowledge, our present study represents the first report that an oncogenic virus evades cellular senescence through epigenetic down-regulation of p16(INK4a) expression.
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PMID:Hepatitis B virus X protein overcomes stress-induced premature senescence by repressing p16(INK4a) expression via DNA methylation. 1965 18

The aim of the present study was to authenticate the involvement of DNA methyltransferases (DNMTs) and methyl-CpG binding domain protein 2 (MBD2) in the process of HBx induced p16(INK4A) promoter hypermethylation in HBV-related hepatocellular carcinoma (HCC) and their corresponding noncancerous liver tissues. Eighty-eight fresh tissue specimens of surgically resected HBV-associated HCC and their corresponding noncancerous liver tissues were studied. The methylation status of the p16(INK4A) promoter was determined by methylation-specific polymerase chain reaction (MSP). Reverse transcription and real-time polymerase chain reaction (RT-PCR) showed the expression of DNMTs, MBD2 and HBx. Western blot and immunohistochemistry were used for the protein analysis of HBx, DNMT1, DNMT3A and P16. Tissue HBV-DNA levels were determined by RT-PCR. HBV genotype was examined by nested PCR and restriction fragment length polymorphism (RFLP). In the corresponding noncancerous liver tissues, higher HBx expression was associated with the hypermethylation of the p16(INK4A) promoter. HBx was positively correlated with the DNMT1 and DNMT3A at both the mRNA and protein level. Furthermore, HBx, DNMT1 and DNMT3A protein expression were negatively correlated with p16 protein expression. In HCC tissues, HBx was positively correlated with DNMT1 and DNMT3A at both mRNA and protein level, but HBx expression did not correlate with hypermethylation of the p16(INK4A) promoter or p16 protein expression. The methylation status of the p16(INK4A) promoter did not correlate with clinicopathological characteristics. DNMT1 and DNMT3A may play important roles in the process of HBx inducing hypermethylation of the p16(INK4A) promoter in the early stages of HBV-associated HCC. HBx-DNMTs-p16(INK4A) promoter hypermethylation may constitute a mechanism for tumorigenesis during HBV-associated hepatocarcinogenesis.
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PMID:Hepatitis B virus X protein induces hypermethylation of p16(INK4A) promoter via DNA methyltransferases in the early stage of HBV-associated hepatocarcinogenesis. 1973 23

There is significant regional variation in the etiologic agents responsible for hepatocellular carcinoma (HCC), which influences the genetic and epigenetic mechanisms of malignant transformation. The aim of the present study was to investigate the prevalence of allelic imbalance (AI) and CpG island methylation in HCCs from Australia and South Africa. Genomic DNA was extracted from malignant and non-malignant liver from 37 Australian and 24 South African HCCs and histologically normal liver from 20 transplant donors. AI was examined at 1p, 4p, 4q, 8p, 9p, 13q, 16q and 17p, using 23 microsatellite markers. Methylation status of p14, p16, p15, RIZ1, E-cadherin and O6-MGMT was examined using methylation specific PCR, while MINTs 1, 2, 12, 25 and 31 were assessed using combined bisulfite restriction analysis. The highest prevalence of AI was observed at 9p (69%) and 17p (52%). AI was significantly higher in South African HCCs (p<0.05). The prevalence of promoter methylation of the six genes was significantly higher in Australian cases in both malignant and non-malignant liver tissue (p<0.05). MINT assays revealed an increasing degree of CpG island methylation in the progression of hepatocarcinogenesis which was significant for MINTs 1, 12 and 31 (p<0.05). MINT methylation was more prominent in Australian HCCs. These data indicate that methylation is an early event preceding malignant transformation. Methylation was more and AI less prevalent in Australian than South African HCCs. These data suggest that there are different mechanisms of malignant transformation in HCCs from Australia and South Africa.
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PMID:Varying etiologies lead to different molecular changes in Australian and South African hepatocellular carcinomas. 1978 62

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the fourth leading cause of cancer mortality globally. HCC incidence has doubled in Egypt in the past 10 years, which could be attributed to the high prevalence of hepatitis C virus (HCV) and hepatitis B virus (HBV), although HBV rates have declined after the introduction of the vaccine in 1992. Aberrant DNA methylation may play an important role in hepatocarcinogenesis. Liver biopsy is the current gold standard for methylation studies; however, imaging techniques often suffice for diagnosis making tissue samples increasingly scarce. The efficacy of conducting DNA methylation studies in molecular epidemiology using plasma DNA is still unclear. We compared tumor methylation profile for the tumor suppressor genes APC, FHIT, p15, p16, and E-cadherin in tumor tissues and plasma to test the concordance between the two types of specimen from the same HCC patients. Twenty-eight HCC patients with matching tissue and plasma DNA were recruited from a case-control study in Gharbiah, Egypt. Concordance between the tissue and plasma was statistically significant in all five genes as follows: APC (23/28, 82.1%, p=0.001), FHIT (24/28, 85.7%, p=.0001), p15 (25/28, 89.2%, p=0.045), p16 (19/28, 67.9%, p=0.037), and E-cadherin (22/28, 78.5%, p=0.0008). The average specificity was 90%, 86%, 96%, 86%, and 100%, respectively. There was no significant association between methylation and hepatitis viral infection for any of the genes tested in this study. Plasma DNA can be reliable for testing methylation profile in liver cancer patients in this population. Future studies on a larger sample size should investigate methylation profile in populations with higher rates of HBV, HCV, and other risk factors.
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PMID:Concordance of DNA methylation pattern in plasma and tumor DNA of Egyptian hepatocellular carcinoma patients. 1981 50

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