Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

From Oct. 1982 to Apr. 1985, 82 patients with HCC proven by pathology were treated in our hospital. 43 treated by hepatic arterial perfusion, were randomized into PDD group: PDD 10 mg per day X 10, every 3 weeks; control group: fluorouracil (5-Fu) 250 mg per day X 4, every week and thio-tepa (TSPA) 10 mg, twice a week. The other 39 treated by intravenous chemotherapy, were also randomized into PDD group: PDD 20 mg per day X 5, every 3 weeks; control group: 5-Fu 500 mg and TSPA 10 mg, twice a week. The objective response rates were 31.8% (7/22) in PDD group and 23.8% (5/21) in control group by hepatic arterial perfusion, and 20.0% (4/20) in the former and 0% (0/19) in the latter who were treated intravenously. The median survivals were 8 months for all the patients receiving hepatic arterial perfusion, and 6 and 5 months for the intravenous PDD and its control group, respectively. The side effects and kidney toxicity of PDD were tolerable to the patients. It is observed that PDD is better than 5-Fu and TSPA in the treatment of HCC.
 ...
PMID:[Randomized clinical trial of cis-platinum diamminedichloride (PDD) in the treatment of hepatocellular carcinoma (HCC)]. 303 38

The molecular role of hepatitis C virus (HCV) in liver disease has yet to be clarified. In this study, we analyzed the relationship of HCV replication with mRNA expression of growth factors and mutation of tumor suppressor gene, ie, transforming growth factor-beta 1 (TGF-beta 1), which promotes cirrhotic changes; TGF-alpha, insulin-like growth factor-II (IGF-II), which are both related to hepatocyte transformation; and tumor suppressor gene p53, which is associated with HCC progression. A semiquantitative RNA polymerase chain reaction (RNA-PCR) was used to analyze genetic expression in 31 cirrhotic liver specimens from patients with HCV. In order to detect HCV replication, the minus-strand RNA of HCV, which serves as a template for the synthesis of genomic plus-strand RNA, was examined. The expression of the growth factors was semiquantified by RNA-PCR, and the mutation of p53 was detected using PCR-single-strand conformation polymorphism. According to the semiquantitative analysis, HCV replication was not associated with the expression of TGF-beta 1 but was significantly so with the overexpression of TGF-alpha (r = 0.74) and IGF-II (r = 0.65) in the HCV-positive cirrhotic livers. No mutation of p53 was recognized in any of the samples. Our investigation thus suggested that the replication of HCV might mediate the coexpression of TGF-alpha and IGF-II and act as a possible initiating factor for hepatocarcinogenesis.
 ...
PMID:Hepatitis C virus replication is associated with expression of transforming growth factor-alpha and insulin-like growth factor-II in cirrhotic livers. 856 58

TGF-beta 1 has been implicated in the pathogenesis of liver disease. The high frequency of detection of the hepatitis B virus X (HBx) antigen in liver cells from patients with chronic hepatitis, cirrhosis, and liver cancer suggested that expression of HBx and TGF-beta 1 may be associated. To test this possibility, we examined the expression of TGF-beta 1 in the liver of transgenic mice expressing the HBx gene. We show that the patterns of expression of TGF-beta 1 and Hbx protein are similar in these mice and that HBx activates transcription of the TGF-beta 1 gene in transfected hepatoma cells. The cis-acting element within the TGF-beta 1 gene that is responsive to regulation by Hbx is the binding site for the Egr family of transcription factors. We further show that the Egr-1 protein associates with the HBx protein, allowing HBx to participate in the transcriptional regulation of immediate-early genes. Our results suggest that expression of Hbx might induce expression of TGF-beta 1 in the early stages of infection and raise the possibility that TGF-beta 1 may play a role in hepatitis B virus pathogenesis.
 ...
PMID:Regulation of transforming growth factor-beta 1 expression by the hepatitis B virus (HBV) X transactivator. Role in HBV pathogenesis. 856 59

Previous studies have shown 5- to 10-fold higher rates of apoptosis in prestages of liver cancer (putative preneoplastic cell foci [PPF]) than in unaltered liver; fasting or withdrawal of tumor promoters enhanced apoptosis even further. We studied whether transforming growth factor beta 1 (TGF-beta 1), an inducer of apoptosis in normal liver, might be involved in induction of apoptosis in PPF. PPF were produced in 7-week-old female Sprague-Dawley rats with a single oral dose of the genotoxic carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). At 24 weeks of age, TGF-beta 1 was injected into animals (40 micro g/kg intravenously) either once and they were killed 4 hours later (single-dose experiment) or eight times at 24-hour intervals and they were killed 24 hours after the last administration (multiple-dose experiment). Further subgroups received daily subcutaneous injections of tamoxifen (TAM) (8 mg/kg) for 4 consecutive weeks before TGF-beta 1 treatment. In normal liver, the apoptosis incidence was low in solvent- and TAM-only-treated animals, in the single- as well as the multiple-dose experiment. TGF-beta 1, increased the apoptosis incidence severalfold, and the combined administration of TGF-beta 1 with TAM caused a further strong increase. The already-elevated basal apoptotic incidence in PPF was further increased by TGF-beta 1, and particularly by TGF-beta 1 plus TAM treatments, which resulted in a reduction of foci number and size. In summary, these results show that TGF-beta 1 can induce apoptosis in PPF. This apoptosis-inducing activity is strongly enhanced by the additional treatment with the antiestrogen TAM, which by itself does not have any cell death-inducing effect in the liver or PPF. The elevated apoptotic activity of PPF in response to TGF-beta 1 can lead to a selective reduction of the liver load with preneoplastic cells.
 ...
PMID:Transforming growth factor beta 1-induced cell death in preneoplastic foci of rat liver and sensitization by the antiestrogen tamoxifen. 866 40

In this study, 18 BUF rats with 7316 A liver cancer burden were divided into three groups. Groups A underwent simple laparotomy, group B had 70% hepatectomy, and group C with laparotomy plus TGF-beta . Splenic adhesive cells and serum of postoperative day 5 in both group A and B were added into mixed lymphocellular culture and CCL-64 cell culture, TGF-beta was also added into MLC and 7613 A liver cancer culture. It was found that in group B and C the growth rate of tumor cells was greatly accelerated (P < 0.01); whereas MLC and CCL-64 cell proliferation was inhibited by the serum and splenic adhesive cells from group B (P < 0.05). TGF-beta also significantly inhibited MLC through it had no effect on 7316 A liver cancer cells. The authors came to the conclusion that there was the activity of TGF-beta in the serum of the rats with partial hepatectomy which inhibits the proliferation of host immune cells.
 ...
PMID:[A study of mechanism by which tumor growth was induced by partial hepatectomy]. 959 Jul 61

It has been suggested that genetic changes in cancers are related to genomic instability. To evaluate a possible correlation between growth-regulatory genes and genomic instability in HCC, we investigated microsatellite instability and mutations of TGF-beta type II receptor (TGF-beta RII) and E2F-4 genes in each pair of tumor and surrounding nontumor liver tissues, collected from 19 patients with HCC. By the identification of mutations in six different genetic loci (D1S170, D2S123, D4S395, D13S126, D13S260, and D16S402), one or more alterations in microsatellite markers were identified in 13/19 (68%) hepatocellular carcinoma specimens. When two repeated sequences of TGF-beta RII gene, poly(A)(10) tract in exon 8 and poly(GT)(3) tract in exon 9, were analyzed by polymerase chain reaction-single strand conformational polymorphism, none of the 19 hepatocellular carcinoma specimens showed mutations. When amplicons of poly(AGC)(13) tract of E2F-4 were analyzed by cloning and automated sequencing, 5/19 (36%) hepatocellular carcinomas showed deletion mutation in one or two AGC repeats and such mutations were identified only among cases with microsatellite instability. These results suggest that both microsatellite instability and mutations of E2F-4 occur commonly in hepatocellular carcinoma and play an important role in hepatocarcinogenesis.
 ...
PMID:Microsatellite instability and mutations of E2F-4 in hepatocellular carcinoma from Korea. 1070 4

It is still unclear as to whether the gene expression profile in HCV- or HBV-related HCC exhibits a degree of specificity and whether the development of HCC in a context of cirrhosis influences this gene profile. To address these issues, the expression profiles of 15 cases of HCC were analysed using cDNA macroarray. A global analysis and hierarchical clustering, demonstrated the heterogeneity of HCC patterns, with a majority of down-regulated genes. Statistical analysis clearly showed a distinction between the gene expression profiles of HCV- and HBV-related HCC. HBV-associated HCC exhibited involvement of different cellular pathways, those controlling apoptosis, p53 signalling and G1/S transition. In HCV-related HCC we identified a more heterogenous pattern with an over-expression of the TGF-beta induced gene. In HCC developing on non-cirrhotic tissues, beta-catenin encoding gene and genes implicated in the PKC pathway were specifically up-regulated. In addition, our investigation highlighted a distinct profiles of TGF-beta superfamily encoding genes in well, moderately or poorly differentiated HCC. Overall, our study supports the hypothesis that despite the heterogeneity of the HCC pattern, the large-scale screening of gene expression may provide data significant to our understanding of the mechanism of liver carcinogenesis.
 ...
PMID:Identification, using cDNA macroarray analysis, of distinct gene expression profiles associated with pathological and virological features of hepatocellular carcinoma. 1197 55

Methylation events play a critical role in various cellular processes including regulation of gene transcription and proliferation. Recently, RUNX3 gene, one of TGF-beta-Smads signaling transduction pathway genes, showed strong tumor-suppressor activity by regulation of epithelial proliferation and apoptosis. To elucidate the potential etiological role of the RUNX3 gene in the development of hepatocellular carcinoma (HCC), we have analyzed the methylation status of 5' CpG island of the RUNX3 gene in a series of 73 HCC tissues and 11 liver cell lines. Expectedly, promoter methylation of RUNX3 gene was found in 2 (2.7%) of 73 corresponding normal liver, whereas 30 (41.1%) of 73 HCCs and 4 (40%) of 10 liver cancer cell lines showed hypermethylation of the gene, respectively. There was no significant difference between promoter hypermethylaion and clinicopathologic parameters of primary HCC samples, including histologic grade, microvascular invasion, and clinical stage. Interestingly, demethylating agent 5-aza-2-deoxycytidine induced reactivation and more potent expression of RUNX3 gene in HCC cell lines. Our findings indicate that promoter hypermethylation of RUNX3 gene may occur as an early event in the development of HCC and that methylation may be a major mechanism for inactivation of RUNX3 gene in HCC.
 ...
PMID:Hypermethylation of the RUNX3 gene in hepatocellular carcinoma. 1615 4

Polarized hepatocytes expressing hyperactive Ha-Ras adopt an invasive and metastatic phenotype in cooperation with transforming growth factor (TGF)-beta. This dramatic increase in malignancy is displayed by an epithelial to mesenchymal transition (EMT), which mimics the TGF-beta-mediated progression of human hepatocellular carcinomas. In culture, hepatocellular EMT occurs highly synchronously, facilitating the analysis of molecular events underlying the various stages of this process. Here, we show that in response to TGF-beta, phosphorylated Smads rapidly translocated into the nucleus and activated transcription of target genes such as E-cadherin repressors of the Snail superfamily, causing loss of cell adhesion. Within the TGF-beta superfamily of cytokines, TGF-beta1, -beta2 and -beta3 were specific for the induction of hepatocellular EMT. Expression profiling of EMT kinetics revealed 78 up- and 235 downregulated genes, which preferentially modulate metabolic activities, extracellular matrix composition, transcriptional activities and cell survival. Independent of the genetic background, platelet-derived growth factor (PDGF)-A ligand and both PDGF receptor subunits were highly elevated, together with autocrine secretion of bioactive PDGF. Interference with PDGF signalling by employing hepatocytes expressing the dominant-negative PDGF-alpha receptor revealed decreased TGF-beta-induced migration in vitro and efficient suppression of tumour growth in vivo. In conclusion, these results provide evidence for a crucial role of PDGF in TGF-beta-mediated tumour progression of hepatocytes and suggest PDGF as a target for therapeutic intervention in liver cancer.
 ...
PMID:A crucial function of PDGF in TGF-beta-mediated cancer progression of hepatocytes. 1660 86

Hepatocellular carcinoma (HCC), the major manifestation of primary liver cancer, is one of the most frequent and malignant cancers worldwide, especially in Taiwan. Estrogen receptors (ERs) have been reported to play either a proliferation- or apoptosis-enhancing role in the differentiation of cancers, including HCC. In a previous experiment, we showed that transient overexpressed estrogen receptor-alpha induced early stage HCC cell line Hep 3B cell apoptosis by increasing the hTNF-alpha gene expression in a ligand-independent manner. To further clarify if the apoptotic effect occurs in poorly differentiated HCC cell line, HA22T, and elucidate the roles of ERs and TNF-alpha, DNA fragmentation and caspase activity were measured in late stage HCC cell line, HA22T, by measuring the expression of hER-alpha and hER-beta using a Tetracycline-inducible system (Tet-on). Increased DNA fragmentation and caspase-3 activity were found in hERbeta-overexpressed HA22T cells treated with estrogen (10(-8) M) but not in hERalpha-overexpressed HA22T cells. Using RT-PCR/PCR and western blotting in HA22T cells, overexpressed hER-beta was also found to increase the expression of hTNF-alpha mRNA and induce hTNF-alpha-dependent luciferase activity in a ligand-dependent manner. Additionally, LPS treatment and hER-beta overexpression both enhance caspase-8 activities, whereas neither hER-beta nor E2 treatment affected caspase-9 activities. In addition, the overexpressed hER-beta plus E2 enhanced DNA fragmentation and caspase-8 activities were only partially reduced by anti-hTNF-alpha (0.1 ng/ml), which was possibly due to the involvement of P53 and TGF-beta. Taken together, our data indicates that overexpressed hER-beta but not hER-alpha may induce caspase-8-mediated apoptosis by increasing the hTNF-alpha gene expression in a ligand-dependent manner in poorly differentiated HA22T cells.
 ...
PMID:Opposing action of estrogen receptors alpha and beta on tumor necrosis factor-alpha gene expression and caspase-8-mediated apoptotic effects in HA22T cells. 1663 37


1 2 3 Next >>